19 replies to this topic

[thedevinroy]

Does anyone know about dopamine agonists' effect on ADHD? It would seem that a D4 dopaminergic agonist would correct signalling in the pre-frontal cortex by lowering cAMP and regulating glutamate receptors. The D4 receptor and the DAT have been the focus for ADHD genetic variations (http://www.ncbi.nlm....pubmed/21207241) and sometimes the MAO genes.

Most D4 agonists are research chemicals at the moment. There was one I found that was a patch for Parkinson's, available in Europe, and previously in the USA. I guess the US Govt. said that they didn't want people to have to refrigerate the patches or something... anyhow, the patches have to be reformulated. That was back in 2008. Whatever.

Check out This Study on Rotigotine:

Rotigotine (Neupro) is a non-ergoline dopamine agonist developed for the once daily treatment of Parkinson's disease (PD) using a transdermal delivery system (patch) which provides patients with the drug continuously over 24 h. To fully understand the pharmacological actions of rotigotine, the present study determined its extendedreceptor profile. In standard binding assays, rotigotine demonstrated the highest affinity for dopamine receptors, particularly the dopamine D3 receptor (Ki=0.71 nM) with its affinities to other dopamine receptors being (Ki in nM): D4.2 (3.9), D4.7 (5.9), D5 (5.4), D2 (13.5), D4.4 (15), and D1 (83). Significant affinities were also demonstrated at alpha-adrenergic (alpha2B, Ki=27 nM) and serotonin receptors (5-HT1A Ki=30 nM). In newly developed reporter-gene assays for determination of functional activity, rotigotine behaved as a full agonist at dopamine receptors (rank order: D3>D2L>D1=D5>D4.4) with potencies 2,600 and 53 times higher than dopamine at dopamine D3 and D2L receptors, respectively. At alpha-adrenergic sites, rotigotine acted as an antagonist on alpha2B receptors. At serotonergic sites, rotigotine had a weak but significant agonistic activity at 5-HT1A receptors and a minor or nonexistent activity at other serotonin receptors. Thus, in respect to PD, rotigotine can be characterized as a specificdopamine receptor agonist with a preference for the D3 receptor over D2 and D1 receptors. In addition, it exhibits interaction with D4 and D5 receptors, the role of which in relation to PD is not clear yet. Among non-dopaminergic sites, rotigotine shows relevant affinity to only 5-HT1A and alpha2B receptors. Further studies are necessary to investigate the contribution of the different receptor subtypes to the efficacy of rotigotine in Parkinson's disease and possible other indications such as restless legs syndrome.

Some people think that direct agonism could lead to tolerance, but I am not educated enough on the topic to really say.

Would there be any potential problems associated with direct D4 agonism in treating ADHD?

What about counteracting poor concentration from forskolin use or caffeine tolerance?

[Delta Gamma]

Some people think that direct agonism could lead to tolerance, but I am not educated enough on the topic to really say.

Would there be any potential problems associated with direct D4 agonism in treating ADHD?

What about counteracting poor concentration from forskolin use or caffeine tolerance?

They'll work for ADHD but have been known to cause nightmareish withdrawals, (seaech DAWS on mind and muscle to see what I mean). As far as tolerance goes looking at PD studies they do seem to build a complete tolerance over a period of months to years depending on the dose/frequency, but as far as in healthy individuals I haven't heard anything either way.
And, despite what everyone says caffeine at massive doses in some individuals can cause impaired cognitive function in some individuals. I really don't want to have to bust out 3 different text books to source this argument, but suffice to say 3 weeks caffeine or PDE inhibitor free should help those symptoms lessen.

I really wouldn't touch this stuff unless you do have Parkinson's if I were you.

[thedevinroy]

Some people think that direct agonism could lead to tolerance, but I am not educated enough on the topic to really say.

Would there be any potential problems associated with direct D4 agonism in treating ADHD?

What about counteracting poor concentration from forskolin use or caffeine tolerance?

They'll work for ADHD but have been known to cause nightmareish withdrawals, (seaech DAWS on mind and muscle to see what I mean). As far as tolerance goes looking at PD studies they do seem to build a complete tolerance over a period of months to years depending on the dose/frequency, but as far as in healthy individuals I haven't heard anything either way.
And, despite what everyone says caffeine at massive doses in some individuals can cause impaired cognitive function in some individuals. I really don't want to have to bust out 3 different text books to source this argument, but suffice to say 3 weeks caffeine or PDE inhibitor free should help those symptoms lessen.

I really wouldn't touch this stuff unless you do have Parkinson's if I were you.

Thanks for the input! Withdrawals and tolerance issues are certainly not nootropic. Good to know.

Caffeine and forskolin increase cAMP levels which cause the frontal lobes to have difficulty. The D4 dopaminergic receptor returns cAMP levels to normal in the pre-frontal cortex so that concentrating is easier. That's why I mentioned them. You mentioned PDE inhibitors, which depending on the type, can increase cAMP in the pre-frontal cortex. I believe PDE5 is strictly cGMP and not cAMP, but that's usually just used for treating ED.

[Delta Gamma]

Thanks for the input! Withdrawals and tolerance issues are certainly not nootropic. Good to know.

Caffeine and forskolin increase cAMP levels which cause the frontal lobes to have difficulty. The D4 dopaminergic receptor returns cAMP levels to normal in the pre-frontal cortex so that concentrating is easier. That's why I mentioned them. You mentioned PDE inhibitors, which depending on the type, can increase cAMP in the pre-frontal cortex. I believe PDE5 is strictly cGMP and not cAMP, but that's usually just used for treating ED.

Caffeine and its primary metabolites are all unselective PDE inhibitors at high doses, not to mention possibly toxic to beta cells in your pancreas. Personally I wouldn't go above 2 cups of coffee a day to avoid this, but that's just me.

Its not as simple as increasing/decreasing cAMP will significantly change concentration, its more of a what/when/where/ and how much kind of issue.

[Delta Gamma]

double post

Edited by Delta Gamma, 06 August 2011 - 07:35 PM.

[medievil]

Its indicated under the nhs for RLS, ill try to get it as its both a D1 and D4 agonist wich activate the PFC, ill need to combine it with amisulpiride to block autoreceptor agonism and nausia, the roti will also keep prolactin normal.

[medievil]

So i couldnt get rotigotine wich is a shame as it lacks D1 agonism but got my hands on Ropinorole.

Buccastem was a total fail for the nausia and sedation, affinity's didnt overpower ropi so the above couldnt be tested, even with dex sedated me too much and had bad nausia, not waiting true the adaptation either.

Ill try to get another D2/D3 agonist, ami would be ideal.

[medievil]

I started with the starting dose TID D4 has no autoreceptors so may see benefits soon, my stims block the sedation at this dose and i avoid nausia too. Lets see what shifting balance to D4 does for me.

I started with the starting dose TID D4 has no autoreceptors so may see benefits soon, my stims block the sedation at this dose and i avoid nausia too. Lets see what shifting balance to D4 does for me.

[medievil]

"Ropinirole acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D2. It is weakly active at the 5-HT2, and α2 receptors and is said to have virtually no affinity for the 5-HT1, benzodiazepine, GABA, muscarinic, α1, and β-adrenoreceptors.[7]
"

I notice mild psychedelic effects so double checked for 5HT2A affinity, interesting stuff i bet it would be extremely good for antipacetory anhedonia also because of the da effects.

[medievil]

With ginger i could take 1mg this evening without nausia, still had some sedation not too bad as i combined it with amp tough.

[medievil]

Looks like i could tolerate the parkinson dose allready, just too sedating atm and prob lowering of da and ne to see much benefits.

"Usual Adult Dose for Parkinson's Disease

Immediate-release tablets:
Initial:
0.25 mg orally three times daily

Dosage may be titrated upwards with weekly increments to achieve maximum therapeutic effect:

Week 1, give 0.25 mg orally three times daily, not to exceed a daily dose of 0.75 mg
Week 2, give 0.5 mg orally three times daily, not to exceed a daily dose of 1.5 mg
Week 3, give 0.75 mg orally three times daily, not to exceed a daily dose of 2.25 mg
Week 4, give 1 mg orally three times daily, not to exceed a daily dose of 3 mg
Week 5 or greater, see section below: dose adjustments"

[medievil]

Im back on my desoxy mdpv combo wich are extremely dopaminergic, ill experiment with ropi added with extreme caution, altough in low doses its studied as a antipsychotic (prami atleast).

I know from those stims i benefit alot from da agonism, ap's turn me shizophrenic with stims, altough they can cause psychosis benzo's completely prevents this so im curious with extra da agonism will do.

After a couple weeks without stims i should see some good benefits in theory.

Edited by medievil, 11 May 2013 - 04:50 PM.

[medievil]

Mov Disord. 2012 Sep 1;27(10):1327-8. doi: 10.1002/mds.25134. Epub 2012 Aug 17.
Spontaneous unwelcome orgasms due to pramipexole and ropinirole.
Kaut O, Asmus F, Paus S.
PMID: 22903628 [PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances
LinkOut - more resources

Better prepare myself with extra new boxers.

[medievil]

Int J Neurosci. 2012 Jan;122(1):22-5. doi: 10.3109/00207454.2011.617016. Epub 2011 Sep 29.
Outcomes from switching from rotigotine patch to alternate therapies in Parkinson's disease.

Chitnis S, Jaffery M, Dewey RB.

Source

Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, Texas, USA. shilpa.chitnis@utsouthwestern.edu

Abstract


BACKGROUND:

When rotigotine patch was withdrawn from the US market, we prospectively gathered data on efficacy, side effects, and daytime sedation on patients while taking rotigotine and following the switch to alternate therapies.
METHODS:

Patients rated the efficacy of rotigotine on a scale of 0-5 (ineffective to extremely effective) and completed the Epworth Sleepiness Scale. At a follow-up visit a mean of 3 months later, patients rated their change in efficacy and side effects on a scale of -3 to +3 (much worse to much better) and again completed the Epworth Sleepiness Scale.
RESULTS:

Thirty-three patients were switched to a single alternate treatment. On rotigotine, the average efficacy score was 3.5, and after switching, the average change in efficacy was -0.67 (worsening). Average change scores for efficacy and adverse effects were 0.25 and 0.38 for levodopa, -0.88 and -0.25 for ropinirole IR, -1.2 and -0.83 for ropinirole XL, -0.80 and 1.0 for pramipexole, and -1.0 and 0.50 for rasagiline, respectively. Average change in Epworth score on each alternate agent was -3.9, -2.3, 1.3, 3.0, and 1.
CONCLUSION:

Rotigotine was an effective treatment with all groups deteriorating after switch except for the levodopa group. Fifty-eight percent of patients preferred rotigotine versus 36% preferring the alternate treatment.

Shame i didnt get that one.

[medievil]

1mg ropi down the hatch, will see what happeneds.

[medievil]

Bit of nausia, took more ginger stims seem inhibited a bit, no extra benefits atm but thats expected as TH expression, DA and ne will be lowered alot especially reducing D1 agonism as roti doesnt take that over for a part.

Will redose stims.

[medievil]

J Pharmacol Exp Ther. 2013 Feb;344(2):501-10. doi: 10.1124/jpet.112.198895. Epub 2012 Nov 29.
In vivo occupancy of dopamine D3 receptors by antagonists produces neurochemical and behavioral effects of potential relevance to attention-deficit-hyperactivity disorder.

Barth V, Need AB, Tzavara ET, Giros B, Overshiner C, Gleason SD, Wade M, Johansson AM, Perry K, Nomikos GG, Witkin JM.

Source

Psychiatric Drug Discovery, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0501, USA.

Abstract

Dopamine D(3) receptors have eluded definitive linkage to neurologic and psychiatric disorders since their cloning over 20 years ago. We report a new method that does not employ a radiolabel for simultaneously defining in vivo receptor occupancy of D(3) and D(2) receptors in rat brain after systemic dosing using the tracer epidepride (N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-5-iodo-2,3-dimethoxybenzamide). Decreases in epidepride binding in lobule 9 of cerebellum (rich in D(3) receptors) were compared with nonspecific binding in the lateral cerebellum. The in vivo occupancy of the dopamine D(3) receptors was dose dependently increased by SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide) and U99194 (2,3-dihydro-5,6-dimethoxy- N,N-dipropyl-1H-inden-2-amine). Both antagonists increased extracellular levels of acetylcholine (ACh) in the medial prefrontal cortex of rats and modified brain-tissue levels of ACh and choline. Consistent with these findings, the D(3) receptor antagonists enhanced the acquisition of learning of rats either alone or in the presence of the norepinephrine uptake blocker reboxetine as with the attention-deficit-hyperactivity disorder (ADHD) drug methylphenidate. Like reboxetine, the D(3) receptor antagonists also prevented deficits induced by scopolamine in object recognition memory of rats. Mice in which the dopamine transporter (DAT) has been deleted exhibit hyperactivity that is normalized by compounds that are effective in the treatment of ADHD. Both D(3) receptor antagonists decreased the hyperactivity of DAT(-/-) mice without affecting the activity of wild type controls. The present findings indicate that dopamine D(3) receptor antagonists engender cognition-enhancing and hyperactivity-dampening effects. Thus, D(3) receptor blockade could be considered as a novel treatment approach for cognitive deficits and hyperactivity syndromes, including those observed in ADHD.

CNS Neurol Disord Drug Targets. 2008 Nov;7(5):410-21.
Selective antagonism at dopamine D3 receptors as a target for drug addiction pharmacotherapy: a review of preclinical evidence.

Heidbreder C.

Source

Altria Group, Inc., Centre for Research & Technology, 601 East Jackson Street, Richmond, VA 23261, USA. Christian.Heidbreder@altria.com

Abstract

The focal distribution of the dopamine (DA) D(3) receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will review the most recent lines of research in support of the use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D(3) receptor in the rodent and human brain; (2) changes in expression of the DA D(3) receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D(3) receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D(2)/D(3) receptor antagonists or partial D(3) receptor agonists. Growing evidence suggests that selective DA D(3) receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D(3) receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.

Drug Discov Today. 2005 Jul 1;10(13):917-25.
Dopamine D3 receptor antagonists as therapeutic agents.

Joyce JN, Millan MJ.

Source

T.H. Christopher Center for Parkinson's Disease, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, 85351, USA. Jeff.Joyce@sunhealth.org

Abstract

The behavioral and pathophysiological role of the dopamine D(3) receptor, which was deduced from anatomical, lesion and drug treatment studies in the ten years following cloning of the receptor, indicated that its functions differed from those of the D(2) receptor. There is increasingly strong evidence that D(3) receptor antagonists will be effective antipsychotic agents. In this regard, an amelioration of the negative and cognitive symptoms of schizophrenia holds the most promise for D(3) receptor antagonists, a concept currently under clinical evaluation. In addition, D(3) receptors could be involved in behavioral sensitization and the potential application of D(3) receptor antagonists in the treatment of drug abuse is undergoing intensive experimental investigation.

[medievil]

Amisulpiride added would block D3, D2 too tough.


Roti occupying the receptors it acts on makes the da release go to D1.

I beleive i need d3 blockade tough for true ADHD relief.

As an aside it blocked the rewarding stim effects for a big deal.

[NeuroNootropic]

Any updates, medievil? Benefits, side effects? Motivation, focus, energy, libido, appetite, etc?

[Mind_Paralysis]

Yeah, I'm ressurrecting this thread, because it would definitely be cool to hear what Medievil's results from trying various Dopamine-agonists was.

It should be noted tho', that while reading this, I was quite puzzled why he was focusing so much on these NON-D4 agonists? Surely he knew there was growing evidence as early as 2009 that the DRD4 Vntr7 -polymorphism is the prime candidate when it comes to potential errors with cognition and attention?

Hence... why anyone who knows this, would try D1, D2, D3, D5 agonist, INSTEAD of the D4-selective ones, is quite puzzling to me.

 

Why'd you do it, Medievil? Surely you know that the D4-receptor is the safest one to start experimenting with too, yeah? It's highly resistant towards down AND upregulation - the other ones are not.