33 replies to this topic

[dilenja]

Case for Memantine

• Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. The D4 receptor is also implicated in a number of studies as an underlying cause of I-ADD. Researchers report elevated resting glutamate in the striatum and prefrontal cortex of D4 Receptor knockout mice. Decreased D4 receptor expression increases extracellular glutamate and alters its regulation in the striatum.
• The D4 receptor is indicated as being involved in modulation of Glutamate neurotransmission, primarily in the striatum. D4 receptors are noted as being most abundant within the prefrontal cortex. The prefrontal cortex has shown increased functional activity of AMPA subtype of glutamate receptors. There is evidence that enhanced AMPA receptor function increases NMDA receptor activity.
• In the hippocampal CA1 region, activation of D4 receptors can selectively decrease NMDA receptor function via activation of platelet derived growth factor. Since the regional distribution of NMDA receptors and D4 receptors in the limbic and cortical brain regions are similar, reseachers have speculated that NMDA receptor antagonism is likely to lead to an increase in dopamine D4 receptor-mediated signalling.
• "Memantine (Namenda) is a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist believed to work by blocking prolonged low-level activation of the NMDA receptor and resultant neuronal damage caused by abnormal glutamatergic activity, yet also allowing normal physiological activity of the NMDA channel." Memantine has also been shown to upregulate protein expression for BDNF through a mechanism believed to be remote from NMDA antagonism.

It would seem to follow from this that that memantine would have the potential to upregulate D4 receptor activity in the prefrontal cortex, which would imply it could be a viable alternative in treating primarily inattentive ADD.


Case for Guanfacine

• "Wang et al suggest that cAMP (cyclic AMP) has powerful influences on Hyperpolarisation Activated Cyclic Nucleotide-gated (HCN) channels that pass on h current when opened. They are localised on distal pyramidal dendrites and according to the authors, are co-expressed with the alpha-2A adrenoreceptor, thus providing a potent substratum for functional integration in the primate PFC. In electrophysiological studies with alpha-2A adrenoreceptor stimulation or cAMP inhibition, HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. "
• Amy Arnsten asserts that uncontrollable stress "via excessive catecholamine release, high levels of D1 receptor stimulation, and activating cAMP have been shown to impair working memory" She goes on to say that under these conditions the PFC is functionally 'disconnected' (and that this may be exacerbated in patients with aberrant genes that regulate cAMP ie. COMT.)
• Additional research suggests that some of the benefiticial effects of norepinephrine are due to binding to the HCN channel to signal prefrontal cortex to stop manufacturing cAMP, which shuts down the prefrontal cortex. This binding is thought to occur on the Alpha-2A receptor site, of which Guanfacine is the most selective Alpha-2A agonist available.
• The mechanism of Guanfacine's ability to strengthen prefrontal cortical congitive function is now known to be at the level of the ion channel. Alpha-2A receptors are colocalized with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels on prefrontal cortical dendritic spines, the sites where prefrontal cortical networks make synapses and interconnect. HCN channels are opened by cyclic adenosine monophosphate (cAMP), and when opened can allow passage of both Na⁺ and K⁺ ions. Thus, opening these channels is akin to punching a hole in the cell's membrane: the membrane resistance is diminished and voltage shifts from synaptic inputs are unable to pass through the spine and into the cell. Thus, high levels of cAMP essentially disconnect network connections.
• Guanfacine reverses this process by inhibiting the production of cAMP, closing the HCN channels, and functionally reconnecting the network, which increases delay-related firing and strengthens cognitive control of behavior.
• Additionally, Guanfacine has been shown to dose-dependantly prevent deficits of spatial working memory, suggesting a role in cognitive deficits associated with NMDA hypofunction. Application of D1 agonist SKF81297 has been shown to cause a prominant increase of steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons, and up-regulation of NMDA receptor activity by dopamine D1 receptors suggests reciprocal interactions between D1 and NMDA receptors

From the above information, the mechanisms by which each of these substances would theoretically address symptoms of executive dysfunction seem to be largely unrelated. The one possible exception I can observe would seem to be that of Guanfacine which may or may not have an influence on NMDA receptors.

My question is this:

Is there any reason why the two of these should not be taken together? I would like to open the floor to the community, to punch holes in the argument that the two of these substances could be used together to ameliorate symptoms of I-ADD caused by executive dysfunction in working memory.

Cheers

Edited by dilenja, 26 May 2010 - 01:19 AM.

[medievil]

Very interesting stuff dilenja!

Here are a few studies regarding NMDA antagonists and D2 if your interested:

...

Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat

G Micheletti, B Lannes, C Haby, E Borrelli, E Kempf, JM Warter, J Zwiller

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Dopamine D2 receptor gene expression was examined in rat striatum after chronic treatment with N-methyl-D-aspartate (NMDA) receptor antagonists (ketamine at 15 mg/kg/day or MK-801 at 0.1, 0.2 and 0.4 mg/kg/day per os, for 50 days). The long-isoform mRNA, as well as the total D2 mRNA expression were induced. No change was noticed in striatal dopamine release or turnover. D2 binding studies carried out in MK-801 chronically treated (0.3 mg/kg/day per os, for 50 days) and control rats revealed an increased receptor density in treated animals without a significant change in receptor affinity. These results suggest that the synthesis of both striatal D2 receptor isoforms is postsynaptically regulated at the transcriptional level, by events triggered by glutamate through the NMDA-type receptor.

Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.
Author: Mele, A : Cabib, S : Oliverio, A
Citation: Psychopharmacology-(Berl). 1995 Feb; 117(3): 313-7
Abstract: The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day x 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.

Summary. Behavioral changes have previously been reported following administrations of uncompetitive NMDA receptor antagonists memantine, amantadine and MK-801 for 14 days, at the doses that produce plasma levels comparable to those seen in patients (20, 100 and 0.31 mg/kg/day respectively). Using the same doses, the effect on receptor binding (autoradiography) was studied in rats. [3H]MK-801 binding was increased in the dentate gyrus and CA3 region of the hippocampus (35.2 and 24.3% respectively) following 3 days S.C. infusion of memantine by ALZET minipumps. One daily injection of memantine for 14 days, increased [3H]MK-801 binding in the frontal cortex by 40.3%. The same treatment with amantadine did increase [3H]raclopride binding to dopamine D2 receptors by 13.5%. None of these treatments changed the expression of muscarinic receptors. It is concluded that subchronic blockade of the NMDA receptor by uncompetitive antagonists at moderate (therapeutically-relevant) doses induced only minor changes in NMDA and dopamine D2 receptor expression.

Decreased striatal dopamine-receptor binding in sporadic ALS: Glutamate hyperactivity?

O. J. M. Vogels, MD, PhD, W. J. G. Oyen, MD, PhD, B. G. M. van Engelen, MD, PhD, G. W. A. M. Padberg, MD, PhD and M. W. I. M. Horstink, MD, PhD
From the Departments of Neurology (Drs. Vogels, van Engelen, Padberg, and Horstink) and Nuclear Medicine (Dr. Oyen), University Hospital Nijmegen, the Netherlands.

Address correspondence and reprint requests to Dr. O.J.M. Vogels, Department of Neurology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.

The pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. The striatum receives massive glutamatergic input. Animal studies suggest that glutamate decreases striatal D2-receptor synthesis. In drug-naïve, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole. Our findings support the glutamatergic excitotoxicity hypothesis in sporadic ALS.

Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.
Rogóz Z, Dlaboga D, Dziedzicka-Wasylewska M.

Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. rogoz@if-pan.krakow.pl
In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptors, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either drug alone given. Since it has been suggested that dopamine receptors, among others, may play a role in anti-immobility effect of IMI, in the present study we examined the effect of AMA (10 mg/kg) and IMI (5 and 10 mg/kg) given separately or jointly, as a single dose or repeatedly (twice daily for 14 days) on the dopamine D2 and D3 receptors in the rat brain, using receptor autoradiography. Following repeated administration of AMA alone or given in combination with IMI (5 mg/kg), the binding of [3H]quinpirole (dopamine D2/D3 receptors agonist) was increased, and similar changes were observed at the level of mRNA encoding dopamine D2 receptors. We used [3H]7-OH-DPAT to selectively label the dopamine D3 receptors. This experiment has shown that AMA given repeatedly did not induce statistically significant changes in the D3 receptor binding, while IMI at both used doses, increased the [3H]7-OH-DPAT binding, and this effect was still observed after repeated joint administration of AMA with both doses of IMI. However, using both radioligands, we did not observe any synergistic or even additive effects in the binding studies after joint administration of AMA and IMI. Nevertheless, we can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain, and this effect may explain their synergistic action observed in the behavioral studies involving dopaminergic transmission.

Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
Nair VD, Savelli JE, Mishra RK.

Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
The expression of dopamine D2 receptor mRNA was studied in rat brain following micro-injection of a competitive N-methyl D-aspartate (NMDA) receptor antagonist at the prefrontal cortex. Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with a competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). The levels of mRNA for NMDA-R1 and dopamine D2 receptors were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and D2 receptor density was quantified by [3H]spiperone binding in the cortex and striatum of these animals. In the prefrontal cortex, the levels of NMDA-R1 receptor mRNA showed significant decrease in CPP-treated animals compared to control animals. However, NMDA-R1 mRNA levels in striatum remained unchanged in any of the experimental groups. The D2 receptor mRNA levels and [3H]spiroperidol binding in prefrontal cortical membranes showed no significant difference between the CPP-treated and control groups of animals. In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP. The increase in D2 mRNA level was correlated with an increase in the D2 receptor binding sites in the striatal membranes. These results suggest a possible interaction between prefrontal cortical NMDA receptors and striatal dopamine receptors.

J Mol Neurosci. 1998 Oct;11(2):121-6.
Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
Nair VD, Savelli JE, Mishra RK.

Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada.
The expression of dopamine D2 receptor mRNA was studied in rat brain following micro-injection of a competitive N-methyl D-aspartate (NMDA) receptor antagonist at the prefrontal cortex. Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with a competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). The levels of mRNA for NMDA-R1 and dopamine D2 receptors were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and D2 receptor density was quantified by [3H]spiperone binding in the cortex and striatum of these animals. In the prefrontal cortex, the levels of NMDA-R1 receptor mRNA showed significant decrease in CPP-treated animals compared to control animals. However, NMDA-R1 mRNA levels in striatum remained unchanged in any of the experimental groups. The D2 receptor mRNA levels and [3H]spiroperidol binding in prefrontal cortical membranes showed no significant difference between the CPP-treated and control groups of animals. In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP. The increase in D2 mRNA level was correlated with an increase in the D2 receptor binding sites in the striatal membranes. These results suggest a possible interaction between prefrontal cortical NMDA receptors and striatal dopamine receptors.

On the other hand:

Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation
Lena Scott*,†, Maria Sol Kruse*,†, Hans Forssberg*, Hjalmar Brismar*, Paul Greengard‡, and Anita Aperia*,§
+ Author Affiliations

*Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children's Hospital Q2:09, S-171 76 Stockholm, Sweden; and ‡Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021-6399
Contributed by Paul Greengard

Abstract

Glutamate, by activating N-methyl-D-aspartate (NMDA) receptors, alters the balance between dopamine D1 and D2 receptor signaling, but the mechanism responsible for this effect has not been known. We report here, using immunocytochemistry of primary cultures of rat neostriatal neurons, that activation of NMDA receptors recruits D1 receptors from the interior of the cell to the plasma membrane while having no effect on the distribution of D2 receptors. The D1 receptors were concentrated in spines as shown by colocalization with phalloidin-labeled actin filaments. The effect of NMDA on D1 receptors was abolished by incubation of cells in calcium-free medium and was mimicked by the calcium ionophore ionomycin. Recruitment of D1 receptors from the interior of the cell to the membrane was confirmed by subcellular fractionation. The recruited D1 receptors were functional as demonstrated by an increase in dopamine-sensitive adenylyl cyclase activity in membranes derived from cells that had been pretreated with NMDA. These results provide evidence for regulated recruitment of a G protein-coupled receptor in neurons, provide a cell biological basis for the effect of NMDA on dopamine signaling, and reconcile the conflicting hyperdopaminergic and hypoglutamatergic hypotheses of schizophrenia.

About your question, i dont think there's a problem combining the 2.

Edited by medievil, 26 May 2010 - 01:31 AM.

[dilenja]

Thanks Medievil. With respect to the last study you posted, that seems to further lend validity to the observation that NMDA and D1 receptors up-regulate and perhaps even downregulate together.

As a certain % of individuals have reported that they do seem to eventually suffer lapses in working memory after prolonged periods of taking Memantine, I wonder if this could be from an interaction of Memantine via NMDA modulation affecting D1?

Vijayraghavan et al. showed that dopamine D₁ receptor stimulation in PFC produced an 'inverted-U' dose-response, whereby either too little or too much D₁ receptor stimulation impaired spatial working memory (http://www.behaviora.../content/4/1/12). If NMDA modulation results in D1 regulating to a level outside of this range, perhaps then it could be via this mechanism that some individuals report lapses in working memory? If so, the question would then be whether or not the change in D1 would be transient or permanent

Edited by dilenja, 26 May 2010 - 01:54 AM.

[dilenja]

Where Do You Think You Are Going? The NMDA-D1 Receptor Trap
Carlos Cepeda and Michael S. Levine^*

Mental Retardation Research Center, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA.

Summary: The number and outcomes of reciprocal interactions between dopamine (DA) D1 receptors and N-methyl-D-aspartate (NMDA)–type glutamate receptors continue to increase. Recent studies have demonstrated close physical interactions in which activation of one receptor affects the function of the other. In one physical interaction, the activation of NMDA receptors alters the topography and movement of D1 receptors by trapping them in dendritic spines and thus altering their distribution. In a second physical interaction, D1 and subunits of NMDA receptors form heterodimers, which are translocated from the cell interior to the surface. Finally, a third physical interaction posits that the C terminus of D1 receptors makes contact with subunits of the NMDA receptor. These physical interactions can attenuate or potentiate receptor function. In contrast, the more traditional interactions mediated by second messengers generally cause NMDA receptor function to be potentiated through the activation of D1 receptors and the cAMP–PKA–DARPP-32 [adenosine 3',5'-monophosphate (cAMP)–protein kinase A–cAMP-regulated phosphoprotein of 32 kD] or PKC (protein kinase C) cascades. Together, these mechanisms provide a basis for understanding the increasing complexity of D1-NMDA receptor interactions and their importance in physiological and pathological processes.

[dilenja]

An interesting paper linking D1, NMDA, and cAMP.

The Dopamine One NMDA interaction also affects D1 receptor functions (http://www.biochemso...032/0321032.pdf)

"In addition to the Dopamine One/NMDA receptor complex having effects on NMDA receptor functions, we have also demonstrated that there are functional effects on D1 receptormediated signalling events. In COS-7 cells co-expressing D1 and NMDA receptors, pretreatment with NMDA increased D1 receptor-mediated cAMP accumulation by approx. 45%. Experiments with the D5 receptor did not exhibit similar effects. This effect was not only D1-receptor-specific, but it could also be blocked with the D1 antagonist SCH23390 and the NMDA receptor antagonists AP-5 and MK-801. Furthermore, similar to the effects on excitotoxicity, the increase in cAMP accumulation is dependent on the D1-t2–NR1-1a interaction mediated by the CT of both proteins. Given that receptor trafficking is a mechanism to modulate receptor function, we employed both immunocytochemistry and cell-based colorimetric assays to determine if there is a change in D1 receptor localization after NMDA receptor activation. Interestingly, we were able to show that after NMDA treatment there appears to be a mobilization of D1 receptors to the cell surface, which could account for the increase in D1 receptor-mediated cAMP accumulation."

Especially, given that:

Amy Arnsten asserts that uncontrollable stress "via excessive catecholamine release, high levels of D1 receptor stimulation, and activating cAMP have been shown to impair working memory" She goes on to say that under these conditions the PFC is functionally 'disconnected'

Edited by dilenja, 26 May 2010 - 02:39 AM.

[medievil]

Thanks Medievil. With respect to the last study you posted, that seems to further lend validity to the observation that NMDA and D1 receptors up-regulate and perhaps even downregulate together.

As a certain % of individuals have reported that they do seem to eventually suffer lapses in working memory after prolonged periods of taking Memantine, I wonder if this could be from an interaction of Memantine via NMDA modulation affecting D1?

Vijayraghavan et al. showed that dopamine D₁ receptor stimulation in PFC produced an 'inverted-U' dose-response, whereby either too little or too much D₁ receptor stimulation impaired spatial working memory (http://www.behaviora.../content/4/1/12). If NMDA modulation results in D1 regulating to a level outside of this range, perhaps then it could be via this mechanism that some individuals report lapses in working memory? If so, the question would then be whether or not the change in D1 would be transient or permanent

I think that NMDA antagonism itself can be the cause of cognitive impairment in some individuals and not excessive D1 downregulation, but that could also play a role.

Interesting studies.

[dilenja]

Another study, again linking NDMA antagonism with ADD. This one suggests that Atomoxetine (Strattera), a drug which is approved for and demonstrates predominant efficiecy treating I-ADD, blocks NMDA induced membrane currents.

Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations.

PMID: 20423340
Status: In-Process

BACKGROUND AND PURPOSE: There is increasing evidence that not only the monoaminergic but also the glutamatergic system is involved in the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Hyperactivity of glutamate metabolism might be causally related to a hypoactive state in the dopaminergic system. Atomoxetine, a selective noradrenaline reuptake inhibitor, is the first non-stimulant approved for the treatment of this disorder. Here we have evaluated the effects of atomoxetine on glutamate receptors in vitro. EXPERIMENTAL APPROACH: The whole-cell configuration of the patch-clamp technique was used to analyse the effect of atomoxetine on N-methyl-d-aspartate (NMDA) receptors in cultured rodent cortical and hippocampal neurons as well as on NMDA receptors heterologously expressed in human TsA cells. KEY RESULTS: Atomoxetine blocked NMDA-induced membrane currents. Half-maximal inhibition emerged at about 3 microM which is in the range of clinically relevant concentrations found in plasma of patients treated with this drug. The inhibition was voltage-dependent, indicating an open-channel blocking mechanism. Furthermore, the inhibitory potency of atomoxetine did not vary when measured on NMDA receptors from different brain regions or with different subunit compositions. CONCLUSIONS AND IMPLICATIONS: The effective NMDA receptor antagonism by atomoxetine at low micromolar concentrations may be relevant to its clinical effects in the treatment of ADHD. Our data provide further evidence that altered glutamatergic transmission might play a role in ADHD pathophysiology.

[rvdvaart]

Which dopamine receptors do drugs like Adderall and Ritalin act on?

[penisbreath]

i believe certain studies comparing the efficacy of guanfacine to stimulants suggested that it may not be as effective for the motivational difficulties posed by iADD. i'm guessing the same problem would apply to memantine.

[Rational Madman]

Case for Memantine

• Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. The D4 receptor is also implicated in a number of studies as an underlying cause of I-ADD. Researchers report elevated resting glutamate in the striatum and prefrontal cortex of D4 Receptor knockout mice. Decreased D4 receptor expression increases extracellular glutamate and alters its regulation in the striatum.
• The D4 receptor is indicated as being involved in modulation of Glutamate neurotransmission, primarily in the striatum. D4 receptors are noted as being most abundant within the prefrontal cortex. The prefrontal cortex has shown increased functional activity of AMPA subtype of glutamate receptors. There is evidence that enhanced AMPA receptor function increases NMDA receptor activity.
• In the hippocampal CA1 region, activation of D4 receptors can selectively decrease NMDA receptor function via activation of platelet derived growth factor. Since the regional distribution of NMDA receptors and D4 receptors in the limbic and cortical brain regions are similar, reseachers have speculated that NMDA receptor antagonism is likely to lead to an increase in dopamine D4 receptor-mediated signalling.
• "Memantine (Namenda) is a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist believed to work by blocking prolonged low-level activation of the NMDA receptor and resultant neuronal damage caused by abnormal glutamatergic activity, yet also allowing normal physiological activity of the NMDA channel." Memantine has also been shown to upregulate protein expression for BDNF through a mechanism believed to be remote from NMDA antagonism.

It would seem to follow from this that that memantine would have the potential to upregulate D4 receptor activity in the prefrontal cortex, which would imply it could be a viable alternative in treating primarily inattentive ADD.


Case for Guanfacine

• "Wang et al suggest that cAMP (cyclic AMP) has powerful influences on Hyperpolarisation Activated Cyclic Nucleotide-gated (HCN) channels that pass on h current when opened. They are localised on distal pyramidal dendrites and according to the authors, are co-expressed with the alpha-2A adrenoreceptor, thus providing a potent substratum for functional integration in the primate PFC. In electrophysiological studies with alpha-2A adrenoreceptor stimulation or cAMP inhibition, HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. "
• Amy Arnsten asserts that uncontrollable stress "via excessive catecholamine release, high levels of D1 receptor stimulation, and activating cAMP have been shown to impair working memory" She goes on to say that under these conditions the PFC is functionally 'disconnected' (and that this may be exacerbated in patients with aberrant genes that regulate cAMP ie. COMT.)
• Additional research suggests that some of the benefiticial effects of norepinephrine are due to binding to the HCN channel to signal prefrontal cortex to stop manufacturing cAMP, which shuts down the prefrontal cortex. This binding is thought to occur on the Alpha-2A receptor site, of which Guanfacine is the most selective Alpha-2A agonist available.
• The mechanism of Guanfacine's ability to strengthen prefrontal cortical congitive function is now known to be at the level of the ion channel. Alpha-2A receptors are colocalized with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels on prefrontal cortical dendritic spines, the sites where prefrontal cortical networks make synapses and interconnect. HCN channels are opened by cyclic adenosine monophosphate (cAMP), and when opened can allow passage of both Na⁺ and K⁺ ions. Thus, opening these channels is akin to punching a hole in the cell's membrane: the membrane resistance is diminished and voltage shifts from synaptic inputs are unable to pass through the spine and into the cell. Thus, high levels of cAMP essentially disconnect network connections.
• Guanfacine reverses this process by inhibiting the production of cAMP, closing the HCN channels, and functionally reconnecting the network, which increases delay-related firing and strengthens cognitive control of behavior.
• Additionally, Guanfacine has been shown to dose-dependantly prevent deficits of spatial working memory, suggesting a role in cognitive deficits associated with NMDA hypofunction. Application of D1 agonist SKF81297 has been shown to cause a prominant increase of steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons, and up-regulation of NMDA receptor activity by dopamine D1 receptors suggests reciprocal interactions between D1 and NMDA receptors

From the above information, the mechanisms by which each of these substances would theoretically address symptoms of executive dysfunction seem to be largely unrelated. The one possible exception I can observe would seem to be that of Guanfacine which may or may not have an influence on NMDA receptors.

My question is this:

Is there any reason why the two of these should not be taken together? I would like to open the floor to the community, to punch holes in the argument that the two of these substances could be used together to ameliorate symptoms of I-ADD caused by executive dysfunction in working memory.

Cheers

Although Memantine may have tremendous potetntial for a number of off-label uses, I have some concerns with its antagonistic affinity for NMDA receptors and nicotinic receptors---components of its mechanism that may make it contraindicated for number of disorders with a marked reduction in nicotinic receptor expression, or depending on the region, differing expression of NMDA and AMPA receptors. For disorders with pathological neurodegeneration, its neuroprotective properties through gluatamate attenuation is highly desirable, but for the drug to yield clinicially significant results in this regard, it must be administered at doses exceeding 20 mg. Unfortunately, once this dose is reached, there is some evidence that it begins to have a statistically signifiant impact on learning for non-demented individuals---e.g. MS patients for one. In my experience, there was certainly the case, which in spite of its modulatory effects on my mood, and its putative neuroprotective effects, I decided to discontinue use. In consideration of these effects----which become progressively less subtle---I wouldn't use the drug for the treatment of amphetamine tolerance either.

Guanfacine is certainly an interesting drug, and although considerably less studied than other treatment options for ADHD, I find its recorded neurocognitive effects to be quite impressive. However, through its agonistic relationship with alpha-2 receptors, it has the unfortunate effect of reducing blood pressure---and thus inducing fatigue in a significant number of non-hypertensive patients. Due to this effect---which greatly reduces its tolerability---it is not an ideal drug for most patients.

So, what are the best treatment options? I've had considerable success with combining aniracetam, centrophenoxine, adrafinil, nicotine, green tea extract, Vyvanse, and very low doses of Strattera, Luvox, and hydrocortisone. In addition, other supplements that I'm using may be having yet to be determined effects beyond the theoretical and empiracal rationales for their selection. In any case, I imagine this cocktail would be overkill for most patients---and I'm almost certain to make adjustments in the future---but I've found this combination to be quite effective against amotivational symptoms that crippled me in spite of my academic success. For a time, I was also on a very low dose of amisulpride, but I've become increasingly dubious about its long term efficacy---escpecially through its significant effect on prolactin synthesis.

[medievil]

Piracetam added to memantine may be a good option to counteract the cognitive problems in higher doses as they dont appear to counteract eachother. I think that piracetam only upregulates NMDA in certain area's related to cognition.
Personally i didnt notice any cognitive trouble from memantine after the adaptation period at 20mg a day. It actually helped to make me think more clearly.

Memantine, at 20mg a day, has been found effective for ADHD.

1: J Child Adolesc Psychopharmacol. 2007 Feb;17(1):19-33. Links
A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type.Findling RL, McNamara NK, Stansbrey RJ, Maxhimer R, Periclou A, Mann A, Graham SM.
Department of Psychiatry, Case Western Reserve University and Division of Child & Adolescent Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio 44106-5080, USA. Robert.Findling@uhhs.com

BACKGROUND: Disturbances in N-methyl-D-aspartate (NMDA) receptor activity may play a role in attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: This study is a preliminary evaluation of the safety, pharmacokinetics, and effectiveness of the NMDA receptor antagonist memantine in pediatric ADHD. METHODS: An open-label, dose-finding, 8-week, trial in outpatients 6-12 years old with ADHD combined type. Memantine oral solution (2 mg/mL) was titrated to 10 mg/day (n = 8) or 20 mg/day (n = 8). Safety data and blood samples for pharmacokinetic analyses were collected. The ADHD Rating Scale-IV (ADHD-IV) and Clinical Global Impression of Severity (CGI-S) scale measured the effectiveness of memantine. RESULTS: There were no discontinuations due to adverse events (AEs), serious AEs, deaths, or suicides. Most AEs were mild and occurred during the first week of treatment. The 20 mg/day memantine dose was associated with a higher rate of completion and larger mean improvement on the ADHD-IV and CGI-S than 10 mg/day memantine. Pharmacokinetic analyses suggest response to memantine may be dose-dependent beyond an initial threshold concentration. CONCLUSIONS: This pilot study suggests that a memantine dose of 20 mg/day may be a safe and possibly effective treatment for pediatric ADHD. Further investigations of memantine in ADHD appear to be warranted.

PMID: 17343551 [PubMed - indexed for MEDLINE]

I do agree with Rol82 regarding Guanfacine. Personally i beleive that to fully counteract ADHD without stimulants you would need a D1 or D4 agonist, there are 2 options for that.
1. Rotigotine, unfortionally pretty expensive, but it appears to be both a potent D1 and D4 agonist.

• D1 receptor (Ki = 83 nM)
  
• D2 receptor (Ki = 13.5 nM)
• D3 receptor (Ki = 0.71 nM)
• D4.2 receptor (Ki = 3.9 nM)
• D4.4 receptor (Ki = 15 nM)
• D4.7 receptor (Ki = 5.9 nM)
• D5 receptor (Ki = 5.4 nM)
• α1A-adrenergic receptor (Ki = 176 nM)
• α1B-adrenergic receptor (Ki = 273 nM)
• α2A-adrenergic receptor (Ki = 338 nM)
  
• α2B-adrenergic receptor (Ki = 27 nM)
• α2C-adrenergic receptor (Ki = 135 nM)
  
• 5-HT1A receptor (Ki = 30 nM)
• 5-HT7 receptor (Ki = 86 nM)
• H1 receptor (Ki = 330 nM)

2. Lisuride wich is a potent D4 agonist next to its other actions.


Regarding amisulpiride, it also worked good for my motivation, but indeed its prolactin increase can be an issue, i wonder how good a low dose of another dopamine agonist would work against this, without counteracting the benefits. A friend of me had succes with sulpiride and pramipexole, but he takes a big prami dose for social anxiety.

[FunkOdyssey]

Regarding amisulpiride, it also worked good for my motivation, but indeed its prolactin increase can be an issue, i wonder how good a low dose of another dopamine agonist would work against this, without counteracting the benefits. A friend of me had succes with sulpiride and pramipexole, but he takes a big prami dose for social anxiety.

Maybe amisulpride + 0.125mg or 0.25mg cabergoline twice weekly... whatever minimal dose it takes to keep prolactin in the normal range. Cabergoline is alot cleaner and more easily tolerated for this purpose than pramipexole. Would this negate amisulpride's positive effects though?

Edited by FunkOdyssey, 27 May 2010 - 06:54 PM.

[medievil]

Regarding amisulpiride, it also worked good for my motivation, but indeed its prolactin increase can be an issue, i wonder how good a low dose of another dopamine agonist would work against this, without counteracting the benefits. A friend of me had succes with sulpiride and pramipexole, but he takes a big prami dose for social anxiety.

Maybe amisulpride + 0.125mg or 0.25mg cabergoline twice weekly... whatever minimal dose it takes to keep prolactin in the normal range. Cabergoline is alot cleaner and more easily tolerated for this purpose than pramipexole. Would this negate amisulpride's positive effects though?

No idea wheter thats enough for prolacting reduction but i know from my friend that daily dosing of prami does not interrupt the beneficial effects of amisulpiride.

[FunkOdyssey]

Now we need someone to test it. Any volunteers?

[Rational Madman]

Piracetam added to memantine may be a good option to counteract the cognitive problems in higher doses as they dont appear to counteract eachother. I think that piracetam only upregulates NMDA in certain area's related to cognition.
Personally i didnt notice any cognitive trouble from memantine after the adaptation period at 20mg a day. It actually helped to make me think more clearly.

Memantine, at 20mg a day, has been found effective for ADHD.

1: J Child Adolesc Psychopharmacol. 2007 Feb;17(1):19-33. Links
A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type.Findling RL, McNamara NK, Stansbrey RJ, Maxhimer R, Periclou A, Mann A, Graham SM.
Department of Psychiatry, Case Western Reserve University and Division of Child & Adolescent Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio 44106-5080, USA. Robert.Findling@uhhs.com

BACKGROUND: Disturbances in N-methyl-D-aspartate (NMDA) receptor activity may play a role in attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: This study is a preliminary evaluation of the safety, pharmacokinetics, and effectiveness of the NMDA receptor antagonist memantine in pediatric ADHD. METHODS: An open-label, dose-finding, 8-week, trial in outpatients 6-12 years old with ADHD combined type. Memantine oral solution (2 mg/mL) was titrated to 10 mg/day (n = 8) or 20 mg/day (n = 8). Safety data and blood samples for pharmacokinetic analyses were collected. The ADHD Rating Scale-IV (ADHD-IV) and Clinical Global Impression of Severity (CGI-S) scale measured the effectiveness of memantine. RESULTS: There were no discontinuations due to adverse events (AEs), serious AEs, deaths, or suicides. Most AEs were mild and occurred during the first week of treatment. The 20 mg/day memantine dose was associated with a higher rate of completion and larger mean improvement on the ADHD-IV and CGI-S than 10 mg/day memantine. Pharmacokinetic analyses suggest response to memantine may be dose-dependent beyond an initial threshold concentration. CONCLUSIONS: This pilot study suggests that a memantine dose of 20 mg/day may be a safe and possibly effective treatment for pediatric ADHD. Further investigations of memantine in ADHD appear to be warranted.

PMID: 17343551 [PubMed - indexed for MEDLINE]

I do agree with Rol82 regarding Guanfacine. Personally i beleive that to fully counteract ADHD without stimulants you would need a D1 or D4 agonist, there are 2 options for that.
1. Rotigotine, unfortionally pretty expensive, but it appears to be both a potent D1 and D4 agonist.

• D1 receptor (Ki = 83 nM)
  
• D2 receptor (Ki = 13.5 nM)
• D3 receptor (Ki = 0.71 nM)
• D4.2 receptor (Ki = 3.9 nM)
• D4.4 receptor (Ki = 15 nM)
• D4.7 receptor (Ki = 5.9 nM)
• D5 receptor (Ki = 5.4 nM)
• α1A-adrenergic receptor (Ki = 176 nM)
• α1B-adrenergic receptor (Ki = 273 nM)
• α2A-adrenergic receptor (Ki = 338 nM)
  
• α2B-adrenergic receptor (Ki = 27 nM)
• α2C-adrenergic receptor (Ki = 135 nM)
  
• 5-HT1A receptor (Ki = 30 nM)
• 5-HT7 receptor (Ki = 86 nM)
• H1 receptor (Ki = 330 nM)

2. Lisuride wich is a potent D4 agonist next to its other actions.


Regarding amisulpiride, it also worked good for my motivation, but indeed its prolactin increase can be an issue, i wonder how good a low dose of another dopamine agonist would work against this, without counteracting the benefits. A friend of me had succes with sulpiride and pramipexole, but he takes a big prami dose for social anxiety.

As far as I know, both of these drugs have not been studied for their use in ADHD, and because of their undesired effects on impulsivity---may not be feasible as long term options. Besides, there are significant problems with the transdermal delivery mechanism of rotigotine, and availability problems---half life---for Lisuride. So, in the absence of evidence, and due to the aforementioned problems, I wouldn't consider either to be palatable options. If I was inclined to be experimental, I would try either ondansetron or tolcapone.

[medievil]

Lisuride wont cause any gambling as this is caused by reward blunting (wich only happends with D3 selective dopamine agonists). A time released preparation can be made the fix the short half life. While lisuride isnt investigated for ADD it does have alot of potential by being a strong D4 agonist, and imminst is a forum where ppl are open to new things, so id say its worth a try .

Edited by medievil, 30 May 2010 - 10:00 AM.

[dilenja]

i believe certain studies comparing the efficacy of guanfacine to stimulants suggested that it may not be as effective for the motivational difficulties posed by iADD. i'm guessing the same problem would apply to memantine.

This may perhaps be true, however an interesting aspect of Memantine is its influence on BDNF which I think would likely exert a beneficial affect on Motivation. I would hope as well that increased ability and confidence would lead to higher intrinsically-generated motivation, as this is more sustainable over the longer term than anything acquired exogenously.

ScienceDaily (May 29, 2009) - "...Chronic drug users, as noted by previous research, can experience an increase of a naturally-occurring protein called BDNF (brain-derived neurotrophic factor) in the brain's reward circuitry, a region scientists call the ventral tegmental area. In this study, the researchers took the drugs out of the equation and directly infused extra BDNF onto this part of the brain in rats. The Toronto team noted that a single injection of BDNF made rats behave as though they were dependent on opiates (which they had never received). Though rats instinctively prefer certain smells, lighting and texture, these rats left their comfort zone in search of a fix..."

Although Memantine may have tremendous potetntial for a number of off-label uses, I have some concerns with its antagonistic affinity for NMDA receptors and nicotinic receptors---components of its mechanism that may make it contraindicated for number of disorders with a marked reduction in nicotinic receptor expression, or depending on the region, differing expression of NMDA and AMPA receptors. For disorders with pathological neurodegeneration, its neuroprotective properties through gluatamate attenuation is highly desirable, but for the drug to yield clinicially significant results in this regard, it must be administered at doses exceeding 20 mg. Unfortunately, once this dose is reached, there is some evidence that it begins to have a statistically signifiant impact on learning for non-demented individuals---e.g. MS patients for one. In my experience, there was certainly the case, which in spite of its modulatory effects on my mood, and its putative neuroprotective effects, I decided to discontinue use. In consideration of these effects----which become progressively less subtle---I wouldn't use the drug for the treatment of amphetamine tolerance either.

I whole-heartedly agree with you and the Nicotinic Alpha-7 Antagonism is one aspect of Memantine that I (with my very limited technical understanding) am deeply concerned with and am attempting to learn more about. Nicotinic Alpha-7 Agonists are currently being researched for purported nootropic effects and yet Memantine is found to do exactly the opposite. I too wonder if this could underlie ancedotal accounts of memory impairment...

Guanfacine is certainly an interesting drug, and although considerably less studied than other treatment options for ADHD, I find its recorded neurocognitive effects to be quite impressive. However, through its agonistic relationship with alpha-2 receptors, it has the unfortunate effect of reducing blood pressure---and thus inducing fatigue in a significant number of non-hypertensive patients. Due to this effect---which greatly reduces its tolerability---it is not an ideal drug for most patients.

Alas, I am unable to try Guanfacine as it is presently unavailable in Canada (So says my PDoc). Results look incredibly encouraging and I would really, really like to try this drug. My blood pressure runs on the high side of normal so I think perhaps this would be ok for me. I am incredibly impressed with what I've read about Intuniv, and this Gentleman too (http://www.corepsychblog.com/) has not been able to say enough good things about it.

So, what are the best treatment options? I've had considerable success with combining aniracetam, centrophenoxine, adrafinil, nicotine, green tea extract, Vyvanse, and very low doses of Strattera, Luvox, and hydrocortisone. In addition, other supplements that I'm using may be having yet to be determined effects beyond the theoretical and empiracal rationales for their selection. In any case, I imagine this cocktail would be overkill for most patients---and I'm almost certain to make adjustments in the future---but I've found this combination to be quite effective against amotivational symptoms that crippled me in spite of my academic success. For a time, I was also on a very low dose of amisulpride, but I've become increasingly dubious about its long term efficacy---escpecially through its significant effect on prolactin synthesis.

Rol82, thank you I very much appreciate the insight you've so kindly shared. I am presently on Day7 of a new prescription for Straterra, at 30mg per day and understand it takes a month or so to begin working properly. Until then I'll try to continue maintaining objectivity (albeit begrudgingly, hehe), as I feel under the circumstances it is likely the best alternative available to me which my PDoc is also amenable to. I was instructed to take 40mg daily for the first week and to then titrate up to 60mg. 40mg was a bit intense so I decided to split the 60mg capsules in half to be taken over two days. I'd rather it not work for the right reasons than as a result of simply being scared off by increasing the dose too quickly. So far (on 30mg), so good.

Piracetam added to memantine may be a good option to counteract the cognitive problems in higher doses as they dont appear to counteract eachother. I think that piracetam only upregulates NMDA in certain area's related to cognition.
Personally i didnt notice any cognitive trouble from memantine after the adaptation period at 20mg a day. It actually helped to make me think more clearly.

Thanks again Medievil, I plan to look into NMDA mechanisms of Racetam's more closely in the near future to determine more about their MOA and possible applications for ADD. I'll be sure to update with anything Im able to find.

Rotagotine looks interesting due to its D4 agonism, and I wasn't aware there were so many different subtypes of D4. I wonder about the D1 agonism however, as a research paper I read alleged that 'excessive D1 agonism cannot fundementally disconnect the prefrontal cortex'. I feel this may have something to do with the D1, NMDA and cAMP relationships I outlined above. D1 is definately beneficial, however as the researchers described it, there seems to be a therapeutic window for its activity following a U-type curve. It is something I would have to learn more about prior to feeling comfortable with considering it as a potential alternative.

Edited by dilenja, 03 June 2010 - 09:48 PM.

[medievil]

While memantine is a alpha7 antagonist this shouldnt be a big issue as those receptors tend to upregulate rapidly, alpha7 is also required for amphetamine to function properly, and indeed the first few days memantine actually inhibits amphetamine before it potentiates it.

[Rational Madman]

Lisuride wont cause any gambling as this is caused by reward blunting (wich only happends with D3 selective dopamine agonists). A time released preparation can be made the fix the short half life. While lisuride isnt investigated for ADD it does have alot of potential by being a strong D4 agonist, and imminst is a forum where ppl are open to new things, so id say its worth a try .

Well, there's no reason to believe that you'd be placing yourself in peril by using Lisuride or Rotigotine, so go ahead and experiment---I eagerly await to hear about the results. My words of caution were intended more by the desire to prevent the desperate from becoming filled with potentially false hope---especially since the theoretical efficacy of either agent has yet to be substantiated by controlled studies.

Edited by Rol82, 04 June 2010 - 02:17 AM.

[John Barleycorn]

At the risk of stating the obvious, a certain amount of glutamate antagonism can be achieved with GABA agonism. So maybe we could use a case for something like gabapentin? It has to be taken at night because of its sleep-inducing effects at recommended dosages, but maybe that's not such a bad thing. From my limited experience, it can result in a refreshed, mood elevation the next day without memory deficits, although I should point out that benzos in reasonable quantities don't impact my memory either. So maybe this is a way of avoiding some of the (initial?) problems of memantine. How long this persists after chronic administration I don't know. There is also the practical issue of having to taper off it.

[medievil]

Yes Rol82, your correct about that.

Ive recently found out that ropinirole is also a full D4 agonist, its widely available and dirt cheap so i'm gonna start playing with this one pretty soon!
For more info regarding it, see this thread i made on mind and muscle:
http://www.mindandmu...showtopic=42256

[penisbreath]

This may perhaps be true, however an interesting aspect of Memantine is its influence on BDNF which I think would likely exert a beneficial affect on Motivation. I would hope as well that increased ability and confidence would lead to higher intrinsically-generated motivation, as this is more sustainable over the longer term than anything acquired exogenously.

yeah, i think that in my case enhancing my capabilities should increase my motivation. i experience a tremendous amount of cognitive difficulty as a result of my depression; during my initial trial with memantine, these symptoms were pretty much relieved completely over the course of a week or two, but higher doses (20mg) caused me to backslide into a weird, depressed state, scaring me off the drug. unfortunately, nothing better has come along in the interim, so i'm thinking of cautiously revisiting it at lower doses.

[chrono]

If I was inclined to be experimental, I would try either ondansetron or tolcapone.

Would you mind explaining what your thinking is regarding the possible applicability of these two substances to ADD? I looked at the mechanisms briefly, but nothing aligned with my spotty understanding of how other systems might impact attention or motivation.

Also, it seems tolcapone is pretty hepatoxic. Would entacapone serve the same function in this model?

[Rational Madman]

If I was inclined to be experimental, I would try either ondansetron or tolcapone.

Would you mind explaining what your thinking is regarding the possible applicability of these two substances to ADD? I looked at the mechanisms briefly, but nothing aligned with my spotty understanding of how other systems might impact attention or motivation.

Also, it seems tolcapone is pretty hepatoxic. Would entacapone serve the same function in this model?

Due to lack of evidence, neither agent would be indicated for the treatment of ADHD, since the disorder is not causatively linked to the enzyme COMT, or 5ht3 receptor expression---which is a receptor that ondansetron has a strong affinity. However, by limiting the enzymatic breakdown catechloamines via COMT inhibition, tolcapone may improve prefrontal efficiency in subsets with a decreased efficiency in this region. But, in nearly all subjects, improve executive functioning, information processing, and attention. Through 5-ht3 antagonism, ondansetron should improve visuo-spatial memory. However, these effects remain investigational, and since I'm not a desperate individual, not worth testing on myself. Oh, and although there are hepatotoxicity problems associated with tolcapaone, this should be less of a problem with entacapone. Anyway, both drugs have some demonstrated efficacy in the treatment of disorders with a characteristic reduction in the frontal cortical volume of catechloamines---which includes disorders across the spectrum. Because of the potential for cognitive enhancement in normal subjects, though, both drugs have attracted my interest.

Edited by Rol82, 10 June 2010 - 08:52 AM.

[dilenja]

While memantine is a alpha7 antagonist this shouldnt be a big issue as those receptors tend to upregulate rapidly, alpha7 is also required for amphetamine to function properly, and indeed the first few days memantine actually inhibits amphetamine before it potentiates it.

This is really interesting stuff Medievil. Are there any studies to support this?

Due to lack of evidence, neither agent would be indicated for the treatment of ADHD, since the disorder is not causatively linked to the enzyme COMT, or 5ht3 receptor expression---which is a receptor that ondansetron has a strong affinity. However, by limiting the enzymatic breakdown catechloamines via COMT inhibition, tolcapone may improve prefrontal efficiency in subsets with a decreased efficiency in this region. But, in nearly all subjects, improve executive functioning, information processing, and attention. Through 5-ht3 antagonism, ondansetron should improve visuo-spatial memory. However, these effects remain investigational, and since I'm not a desperate individual, not worth testing on myself. Oh, and although there are hepatotoxicity problems associated with tolcapaone, this should be less of a problem with entacapone. Anyway, both drugs have some demonstrated efficacy in the treatment of disorders with a characteristic reduction in the frontal cortical volume of catechloamines---which includes disorders across the spectrum. Because of the potential for cognitive enhancement in normal subjects, though, both drugs have attracted my interest.

I also haven't seen a definitive link yet between COMT and ADD, but with COMT being associated with so many disorders it's not to say it that it someday won't be. In individuals who have the higher turnover Val-polymorphism of COMT I, Tolcapone/Entacapone could especially be of strong interest. I think a 23andme.com test would provide a definitive result for this polymorphism

If I was inclined to be experimental, I would try either ondansetron or tolcapone.

Would you mind explaining what your thinking is regarding the possible applicability of these two substances to ADD? I looked at the mechanisms briefly, but nothing aligned with my spotty understanding of how other systems might impact attention or motivation.

Also, it seems tolcapone is pretty hepatoxic. Would entacapone serve the same function in this model?

Due to lack of evidence, neither agent would be indicated for the treatment of ADHD, since the disorder is not causatively linked to the enzyme COMT, or 5ht3 receptor expression---which is a receptor that ondansetron has a strong affinity. However, by limiting the enzymatic breakdown catechloamines via COMT inhibition, tolcapone may improve prefrontal efficiency in subsets with a decreased efficiency in this region. But, in nearly all subjects, improve executive functioning, information processing, and attention. Through 5-ht3 antagonism, ondansetron should improve visuo-spatial memory. However, these effects remain investigational, and since I'm not a desperate individual, not worth testing on myself. Oh, and although there are hepatotoxicity problems associated with tolcapaone, this should be less of a problem with entacapone. Anyway, both drugs have some demonstrated efficacy in the treatment of disorders with a characteristic reduction in the frontal cortical volume of catechloamines---which includes disorders across the spectrum. Because of the potential for cognitive enhancement in normal subjects, though, both drugs have attracted my interest.

[dilenja]

I found an interesting hypothesis the other day on Memantine taken with adjunctive Galantamine. The research suggests that while Memantine indiscriminately acts as a partial-antagonist at extrasnyaptic and synaptic NMDA receptors, that Galantamine acts as a preferential NMDA agonist at synaptic receptors. The extrasynaptic NMDA receptors are the ones most commonly associated with excito-toxicity, so I take this to mean that Galantamine could theoretically contribute to restoring a more normal functionality to 'synaptic' NMDA receptors while leaving Memantine to suppress the more excito-toxic 'extra-synaptic' receptors.

Memantine is an Alpha-7 antagonist and Galantamine is an allosteric Alpha-7 modulator. And although there are no indications of how the various mechanisms affecting Nicotinic Alpha-7 receptors would interact with one another, I would posit that since Galantamine's actions on synaptic NMDA receptors is facilitated through Nicotinic Receptors (and since the glutaminergic affects are shown to be synergistic in the below studies), that the individual effects on Nicotinic receptors from the two compounds should retain some independance from one another (given that Galantamine's actions on NMDA are proposed to be an nAChR mediated response). I'm uncertain however (despite this) as to the degree that Memantine's Nicotinic Alpha-7 antagonism would continue to detrimentally affect cognition.. (?)

Nevertheless, the implications may be of interest given some of the feedback received here and in other threads with respect to Memantine.


http://www.ncbi.nlm....pubmed/17011596

Several drugs are in clinical use for symptomatic treatment of Alzheimer's disease patients. Since Alzheimer's disease is known to be associated with down-regulation of the cholinergic and N-methyl-D-aspartate (NMDA) systems, most of these drugs inhibit acetylcholinesterase, potentiate the activity of nicotinic acetylcholine receptors (nAChRs), or modulate NMDA receptors. Galantamine is an anticholinesterase and allosterically potentiates the activity of the nicotinic receptors. We have recently found that galantamine potentiates the activity of NMDA receptors as well. Memantine is unique in that it inhibits the NMDA receptors. We have developed a hypothesis that combining galantamine and memantine will be more effective for improving the patient's conditions than monotherapy with either drug. Patch clamp and intracellular Ca(2+) imaging experiments using rat cortical and hippocampal neurons clearly provided the in vitro bases for our hypothesis. Memantine blocked the extrasynaptic NMDA receptor 100 times more potently than the synaptic NMDA receptor at negative membrane potentials and the block of both types of NMDA receptors was attenuated with depolarization. However, galantamine potentiation of the NMDA receptors was not voltage dependent. Thus, co-application of memantine with galantamine prevented the galantamine potentiation and the activation of extrasynaptic NMDA receptors, but membrane depolarization revealed the galantamine potentiation. Therefore, cell death is expected to be prevented by memantine near the resting potential while the NMDA-mediated synaptic transmission, which is down-regulated in the patients, is maintained and potentiated by galantamine. These results provide in vitro bases for the beneficial actions of galantamine and memantine combinations.


http://www.life-enha...ate.asp?id=1732

…conclude that the effects of both agents, working together, should have net positive effects on both the cholinergic and glutamatergic systems in the brains of Alzheimer's patients.¹ This conclusion is not just theoretical but is supported by evidence obtained from preclinical studies (laboratory and animal) on the mechanisms of action of the two agents.²

Computer simulations of the biochemical interactions between galantamine and memantine in the human body predict that combination therapy with these two agents may enhance the neural signal-to-noise ratio even more than memantine does by itself. This should improve the patients' cognitive function, or at least retard its decay.


http://www.ncbi.nlm.nih.gov/pubmed/16809810

The search for effective treatments of Alzheimer's disease (AD) is one of the major challenges facing modern medicine. Acetylcholinesterase (AChE) inhibitors (AChEIs) are effective for the treatment of mild to moderate AD, and memantine, an N-methyl-D-aspartate (NMDA) inhibitor, has been approved for moderate to severe AD. Galantamine is of particular interest because it has a dual mechanism of action: it is postulated to be both an AChEI and an allosteric modulator of nicotinic receptors. Modulation of NMDA and nicotinic receptors by memantine and galantamine may provide an optimal combination therapy for AD. The cholinergic and glutamatergic neurotransmitter systems, which share a close functional relationship, may play a role in the pathogenesis of AD. Close examination of the pharmacology of the 2 compounds suggests that galantamine can augment memantine's glutamatergic noise suppression while simultaneously enhancing the physiologic glutamatergic signal. The link between these systems suggests that AD therapies, which capitalize on this relationship, may be more effective in improving cognition than approaches focusing on a single system.

I'll also point out the following potentially conflicting abstract as well, which states contradictory information about the combination and the efficacy of Memantine in a model of Ischemia in gerbils. I would have expected Memantine to shine here as Ischemia supposedly leads to excitotoxicity - So I'm not certain why Memantine wouldn't have worked?


http://www.ionchanne...p?pmid=19103181

Galantamine is an acetylcholinesterase inhibitor and memantine is a non competitive antagonist of NMDA receptors that are being used to treat Alzheimer's disease (AD) patients. The fact that drugs with different mechanisms of action are available to treat AD introduces the prospect of prescribing drug combinations to amplify drug efficacy. This study was planed to evaluate the potential neuroprotective effects of galantamine combined with memantine in a transient global cerebral ischemia model in gerbils. Animal groups included in the study were: sham, ischemia, and ischemia plus galantamine (1 mg/kg and 10 mg/kg), memantine (10 mg/kg and 20 mg/kg), 1 mg/kg galantamine plus 10 mg/kg memantine, and 10 mg/kg galantamine plus 10 mg/kg memantine, respectively. Surviving pyramidal neurons in the CA1 subfield of the hippocampus, TUNEL, caspase-3 and SOD-2 immunohistochemistries, and the object placement test were evaluated 72 h after reperfusion. Memantine did not exert a clear neuroprotective effect, nor did it prevent spatial memory loss. In a previous study using the same experimental model, galantamine was neuroprotective and improved spatial memory. In this study, the association of 10 mg/kg memantine with 10 mg/kg galantamine increased the number of living pyramidal neurons, reduced TUNEL, active caspase-3 and SOD-2 immunoreactivity, and preserved spatial memory after ischemia-reperfusion injury; however, the effects of the combination were not statistically different from those observed in animals treated with galantamine alone. We believe these results are of interest from a clinical point of view because the association of both drugs is being used in clinical practice and in clinical trials to treat Alzheimer's disease and vascular dementia.

Edited by dilenja, 13 June 2010 - 02:13 PM.

[dilenja]

Some more information about Galantamine. Excerpts taken from http://www.nature.co...l/1301087a.html:

Clinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (AChE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01–1.0 mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant AchE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0 mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine's effect was also prevented by the [/size]7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-D-aspartate antagonist CGP39551 (2.5 mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.

At low doses, it binds allosterically to nicotinic acetylcholine receptors (nAChRs) and potentiates their function, and at high doses it acts as a weak AChE inhibitor (Schrattenholz et al, 1996; Maelicke et al, 2000).

Among the cognitive deficits reliably observed in schizophrenic patients are impairments in working memory, that is, an impaired ability to retain and manipulate information over a short period of time. Working memory is largely executed in various regions of the prefrontal cortex and depends on an accurate level of dopamine D1 receptor stimulation (Arnsten et al, 1994). A recent PET study in schizophrenic patients reported increased dopamine D1 receptor availability in the prefrontal cortex (Abi-Dargham et al, 2002). Furthermore, a negative correlation between the D1 receptor availability and performance on a task requiring working memory was observed. Based on these findings it was suggested that dopamine D1 receptors are upregulated to compensate for decreased release of dopamine. Thus, a dopamine-dependent working memory deficit in schizophrenia is not likely due to a dopamine deficiency at the receptor level, but rather to upstream mechanisms that control the release or degradation of dopamine (Egan et al, 2001).

Recently, galantamine was shown to increase nerve terminal release of dopamine in vitro (Zhang et al, 2004), but because of the in vitro preparation used any action of galantamine within the dopaminergic cell body region could not be detected. However, earlier data from our laboratory has shown that nicotine activates dopamine cell firing rate as well as burst firing (Grenhoff et al, 1986) and that nAChRs in the ventral tegmental area (VTA) are critically involved in nicotine's stimulatory effect on terminal dopamine release (Nisell et al, 1994; Schilström et al, 1998b). Specifically, burst firing induced by nicotine is in all probability due to presynaptic enhancement of afferent glutamate release. Nicotine has been shown to activate presynaptic 7-subunit containing nAChRs in the VTA and enhance glutamate release that leads to stimulation of N-methyl-D-aspartate (NMDA) receptors on dopamine cells (Schilström et al, 1998a, 1998b, 2000; Mansvelder and McGehee, 2000; Schilström et al, 2003). Moreover, heteromeric 2-containing nAChRs on dopamine cell bodies and -amino-byturic acid (GABA)-ergic interneurons also influence the activity of dopaminergic neurons (Calabresi et al, 1989; Picciotto et al, 1998; Mansvelder et al, 2002; Schilström et al, 2003). These studies indirectly suggest additional mechanisms by which galantamine can improve negative and cognitive symptoms in schizophrenia. Thus, through its action as an allosteric modulator of nAChRs, galantamine may, accordingly, facilitate dopamine release by increasing dopaminergic firing through potentiation of nAChR function in the VTA. Therefore, using in vivo single unit recordings, we investigated the effect of galantamine on dopamine cell firing. Galantamine's effect was analyzed pharmacologically using the subtype nonselective nAChR antagonist mecamylamine, the mAChR antagonist scopolamine, the selective AChE inhibitor donepezil as well as the 7-selective nAChR antagonist methyllycaconitine (MLA), and the NMDA receptor antagonist CGP39551. Moreover, using in vivo microdialysis, the effect of galantamine on dopamine output in the prefrontal cortex was examined.

The present data suggest that the mechanism by which galantamine increases dopamine cell firing may be allosteric potentiation of nAChRs. Galantamine was most effective at activating dopaminergic cells at 0.1 mg/kg s.c. Therefore, our pharmacological characterization of galantamine's effect was performed using this dose.

Galantamine's effect on prefrontal dopamine efflux was significant at 0.1 mg/kg but not 1.0 mg/kg, an observation that parallels our electrophysiological data showing that 0.1 mg/kg of galantamine increased both firing rate and burst firing of dopaminergic neurons. Thus, it appears that galantamine enhances dopaminergic activity most effectively at a dose that results only in minor AChE inhibition (Geerts et al, 2005), and the effect may therefore rather be due to allosteric potentiation of nAChRs.

Galantamine Increases Extracellular Levels of Dopamine in the Prefrontal Cortex. Analysis of treatment effects (one-way ANOVA followed by Newman–Keuls multiple comparison test) revealed that 0.1 mg/kg, but not 1.0 mg/kg or saline, increased the mean dopamine output significantly (p<0.05, Figure 5b).

Our pharmacological analysis strongly suggests that galantamine activates dopamine cell firing through allosteric potentiation of nAChRs. This conclusion is based on the observations herein that the effect of galantamine is not dose dependent, that it is antagonized by the nAChR antagonists mecamylamine, but not the mAChR antagonist scopolamine, and that it is not mimicked by the selective AChE inhibitor donepezil. Our results also propose that the effect of galantamine involves an 7 nAChR-mediated presynaptic facilitation of glutamate release that activates NMDA receptors, since it was prevented by the 7 nAChR antagonist MLA and the NMDA receptor antagonist CGP39551. In addition, the finding that the effect of galantamine is reversible suggests that, even if 7 nAChRs and NMDA receptors are involved, galantamine does not induce plasticity the way nicotine does (Mansvelder and McGehee, 2000).

Galantamine was particularly effective at increasing burst firing of dopaminergic cells. It is not known exactly how burst firing may be specifically related to cognitive functions in the prefrontal cortex but since phencyclidine (PCP), a drug that induces a schizophrenia-like syndrome including negative, positive, and cognitive symptoms (Javitt and Zukin, 1991), blocks burst firing of dopaminergic neurons (Svensson, 2000), burst firing is likely to play a critical role. Burst firing is unique in the sense that it results in larger amounts of dopamine release and it induces gene expression in postsynaptic neurons in a dopamine D1 receptor-dependent manner (Gonon and Buda, 1985; Chergui et al, 1996). Burst firing induced by nicotine, which can also enhance cognition (Levin and Simon, 1998), is largely dependent on activation of 7 nAChRs (Schilström et al, 2003), suggesting that galantamine may preferentially modulate 7 nAChRs.

Galantamine is known to bind to the -subunit of nAChRs (Schrattenholz et al, 1996) and, obviously, there are more binding sites for galantamine on the homopentameric 7 nAChRs (Couturier et al, 1990) than on the heteropentameric nAChRs which contain only two or three -subunits (Anand et al, 1991; Cooper et al, 1991). This notion is supported by the observation that in HEK-293 cells galantamine appeared to potentiate 7 nAChR-mediated currents to a greater extent than 4 2 nAChR-mediated currents (Maelicke et al, 2001). Thus, galantamine may not only possess the ability to selectively enhance endogenous acetylcholine transmission occurring at nAChRs but may also provide a preference for 7 nAChRs. Importantly, clinical and preclinical data indicate that 7 nAChRs are implicated in the pathophysiology of schizophrenia and that [size="2"]7 agonists may provide a novel treatment alternative (Martin et al, 2004).

Edited by dilenja, 13 June 2010 - 02:34 PM.

[John Barleycorn]

I'm uncertain however (despite this) as to the degree that Memantine's Nicotinic Alpha-7 antagonism would continue to detrimentally affect cognition.. (?)

There are a couple of other aspects that haven't received enough attention either IMHO:

1. Memantine's dissociative effects. These are supposed to be minor, but they were enough to stop me after 2-3 days of 5mg. It's not clear that these effects adjust themselves away. DXM violently disagrees with me as well at even the lowest dosages, but up till now I have always attributed that to my lack of CYP2D6 metabolism.

2. Memantine's stimulation. Upon reconnecting at about hour 5, there's the clenched jaw to deal with, without too much in the way of a compensating mood boost.

3. Individual differences in nAch circuitry. Nicotine has never done anything at all for me, whether smoked or eaten, and I don't seem to be too bothered by the effect of antagonists either. Apart from these receptors reregulating rapidly, another consideration is that memantine's affinity isn't particularly high in the first place.

[Getting High On Life]

Bump, Considering this.

Also straterra is supposed to decrease global glutamine and increase frontal lobe NE (DP also? not sure).

Where would piracetam play into all of this? would it be bad for the chatterbrained ADD I that has too much glutamate?

[Rational Madman]

Bump, Considering this.

Also straterra is supposed to decrease global glutamine and increase frontal lobe NE (DP also? not sure).

Where would piracetam play into all of this? would it be bad for the chatterbrained ADD I that has too much glutamate?

ha

Actually, atomoxetine has a greater effect on dopamine in the prefrontal cortex----a mechanism which I presume you're referring to---increasing it 4-fold.