Memantine and Caffeinewww.mindandmuscle.net/forum/
[cannot locate the source of the statement at the moment: found it through a google search and am not a member of the mindandmuscle forums]
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I'm on Namenda right now, and it doesn't seem to be as effective for caffeine. Probably because caffeine doesn't play by the same rules as amphetamine..."
Dopaminergic agonists administered into the nucleus accumbens: Effects on extracellular glutamate and on locomotor activity http://www.mindandmu...showtopic=35395graatch (September 10, 2008):
Sorry, no direct studies exist. It is completely theoretical territory.
However, for our theoretical model in this use (that glutamate hyperexcitation in the nucleus accumbens core occurs secondary to amphetamine use, and that this glutamate hyperexcitation is responsible for downregulating nucleus accumbens core dopamine sensitivity, which is the additional mechanism responsible for the faster tolerance to mood/motivational effects from amphetamine than to concentrative effects, which are mostly mediated prefrontally, where there is both desensitization occurring for instance at tyrosine hydroxylase and the dopamine receptor end, and sensitization probably via neuroplastic mechanisms), there is a wide, complex, shadowy body of work to point to.
Here lesions produces by ibotenic acid (an NMDA agonist used to provoke glutamate neurotoxicity) blunt dopamine response:
http://www.jneurosci...stract/16/2/714Here chronic high cortisol (whose damaging effects seem to be largely mediated by glutamate excess) desensitizes dopamine function:
http://content.karge...roduktNr=223855With memantine (and other NMDA antagonists) decreasing the development of tolerance to opioids, the evidence is fairly extensive, you can look that up yourself. Contrary to what some may expect, opioids also seem to provoke glutamate efflux, especially chronically, and NMDA efflux is implicated in the development of nociception and tolerance to the rewarding effects of morphine.
With Boris Tabakoff's work in alcoholism, he suggests that with alcohol, too, it is glutamate-related excitotoxicity during ethanol withdrawal that desensitizes dopaminergic function in the nucleus accumbens: [url="http://www.scienceblog.com/community/older.../199900066.html...""]http://www.scienceblog.com/community/older...6.html..."[/url]
Asad Dalia1, Norman J. Uretsky and Lane J. Wallace<A href="
http://www.sciencedi...b88c4dc#cor*">*Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
Accepted 9 December 1997. Available online 28 April 1998.
AbstractThe hypothesis to be tested was that increased dopaminergic transmission induced by amphetamine in the nucleus accumbens results in increased glutamatergic neurotransmission in this brain area and that the increase in level of this neurotransmitter contributes to behavioral effects of psychostimulant drugs. Amphetamine (1 mg/kg, i.p.) increased the amount of extracellular glutamate in the accumbens, as measured by in vivo dialysis, and stimulated locomotor activity. Amphetamine (10 mM) infused into the accumbens by reverse dialysis through the probe produced a similar stimulation of locomotor activity as systemic amphetamine but a greater increase in extracellular glutamate levels. Both of these responses to amphetamine were attenuated by either the selective D1 antagonist SCH23390 or the selective D2 antagonist eticlopride. The combination of a D1 and D2 agonist, SKF38393 (20 mM) and quinpirole (50 mM), administered into the accumbens by reverse dialysis also increased extracellular glutamate and stimulated locomotor activity. Administration of a glutamate uptake inhibitor, threo-β-hydroxy-aspartate (50 mM), increased extracellular glutamate but did not stimulate locomotor activity.
Systemic administration of caffeine (15 mg/kg, i.p.) increased locomotor activity but did not increase extracellular levels of glutamate. These data suggest that activation of dopaminergic receptors in the nucleus accumbens results in stimulation of locomotor activity and in activation of glutamatergic transmission in this brain region. However, an increase in glutamate levels in the nucleus accumbens is neither sufficient nor necessary to produce a stimulation of locomotor activity.
http://www.mindandmu...showtopic=35395graatch (September 11, 2008):
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Interestingly the study [above] also found no effect of caffeine on extracellular glutamate at 15 mg/kg i.p. but this study [below] (full text) shows an effect on glutamate release in NaC at 10mg/kg i.p. : http://www.jneurosci...full/22/15/6321 . The lower dose than 10 that was tested was 3mg/kg, which showed no significant effect. The 10mg/kg dose is like ~650 mg of caffeine in humans, except before the rat conversion rate which are supposed to make it equivalent to a considerably lower dose."
http://www.jneurosci...full/22/15/6321Caffeine Induces Dopamine and Glutamate Release in the Shell of the Nucleus AccumbensMarcello Solinas, Sergi Ferré, Zhi-Bing You, Marzena Karcz-Kubicha, Patrizia Popoli, and Steven R. Goldberg
Sections of 1 Preclinical Pharmacology and 2 Behavioral Neuroscience, Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health Intramural Research Program, Baltimore, Maryland 21224, and 3 Department of Pharmacology, Istituto Superiore di Sanita, 00161 Rome, Italy
Abstract
An increase in the extracellular concentration of dopamine in the nucleus accumbens (NAc) is believed to be one of the main mechanisms involved in the rewarding and motor-activating properties of psychostimulants such as amphetamines and cocaine. Using in vivo microdialysis in freely moving rats, we demonstrate that systemic administration of behaviorally relevant doses of caffeine can preferentially increase extracellular levels of dopamine and glutamate in the shell of the NAc. These effects could be reproduced by the administration of a selective adenosine A1 receptor antagonist but not by a selective adenosine A2A receptor antagonist.
This suggests that caffeine, because of its ability to block adenosine A1 receptors, shares neurochemical properties with other psychostimulants, which could contribute to the widespread consumption of caffeine-containing beverages.Discussion
Dopamine release in either the core or the shell of the NAc has been suggested to be causally related to the locomotor stimulant effects of psychostimulants such as amphetamine (Parkinson et al., 1999; Boye et al., 2001), whereas preferential release of dopamine in the shell of the accumbens has been suggested to be causally related to the rewarding effects of psychostimulants (Di Chiara and Imperato, 1988). The close correlations between the motor-activating effects and the previously described discriminative-stimulus effects of caffeine (Mumford and Holtzman, 1991) and the present microdialysis data are consistent with the possibility that the preferential release of dopamine and glutamate in the shell of the NAc may also be involved in the psychostimulant effects of caffeine. Our hypothesis might seem to be in conflict with the studies by Joyce and Koob (1981), who found that 6-hydroxydopamine lesions in the region of the NAc of rats blocked the locomotor activation induced by amphetamines but failed to block the locomotor activation induced by caffeine. Based on these results, the authors suggested that caffeine induces locomotor activity by acting independently of presynaptic terminals in the mesolimbic dopaminergic system (Joyce and Koob, 1981; Swerdlow et al., 1986). However, in view of the demonstrated resistance to 6-hydroxydopamine-induced dopamine denervation in the shell versus the core of the NAc (Meredith et al., 1995; Boye et al., 2001), those studies cannot rule out a preferential role of dopamine release in the shell of the NAc on the motor effects induced by caffeine. Nevertheless, it must be pointed out that other striatal regions can also be involved, because a significant although less pronounced effect of caffeine on dopamine release was also observed in the core of the NAc (see the introductory remarks; Morgan and Vestal, 1989). Surprisingly, the highest dose of caffeine (100 mg/kg) did not produce any effect on extracellular dopamine or glutamate levels in the shell of the NAc. Additional studies are needed to clarify the mechanisms involved in this lack of effect. However, high doses of caffeine are known to exert effects through mechanisms other than adenosine receptor antagonism (e.g., phosphodiesterase inhibition and release of intracellular calcium) (Daly and Fredholm, 1998).
The results obtained with the selective adenosine A1 and A2A receptor antagonists indicate that the effects of the lower 10 and 30 mg/kg doses of caffeine on dopamine and glutamate release are related to adenosine A1 receptor antagonism. Thus, although blockade of adenosine A2A receptors is currently believed to be the main mechanism responsible for the behavioral-activating (psychostimulant) effects of caffeine (Daly and Fredholm, 1998), as suggested previously (Snyder et al., 1981; Nikodijevic et al., 1991; Kaplan et al., 1992; Popoli et al., 1998), blockade of adenosine A1 receptors also may play a relevant role. At the dose used in the present study, the A2A receptor antagonist had been shown previously to induce pronounced motor activation (Popoli et al., 1998). This rules out the possibility that the motor response is responsible for the dopamine release in the NAc induced by caffeine or the A1 receptor antagonist. The most probable localization of the adenosine A1 receptors that modulate caffeine-induced elevations in extracellular dopamine and glutamate levels is in the terminals of dopaminergic and glutamatergic afferents to the NAc. In fact, there is morphological and functional evidence for this presynaptic localization of adenosine A1 receptors (Wood et al., 1989; Okada et al., 1996; Flagmeyer et al., 1997; Golembiowska and Zylewska, 1997). Also, microdialysis studies have shown previously that the striatal perfusion of A1 receptor agonists and antagonists significantly modifies (decreases and increases, respectively) the striatal extracellular concentrations of dopamine and glutamate (Okada et al., 1996; Golembiowska and Zylewska, 1997). Finally, the increase in the extracellular levels of dopamine induced by caffeine and the A1 receptor antagonist could be related to their effects on extracellular glutamate, in view of the evidence for a facilitatory role of glutamate on striatal dopamine release (Morari et al., 1998).
The region-dependent effects of caffeine in the NAc are similar to those produced by other psychostimulants and addictive drugs, such as amphetamine, cocaine, morphine, heroin, nicotine or 9-tetrahydrocannabinol (9-THC), all of which preferentially increase extracellular levels of dopamine in the shell of the NAc (Pontieri et al., 1995). Although the degree of increase in extracellular dopamine levels induced by caffeine is lower than that induced by amphetamine and cocaine, it is in the same range as increases induced by the systemic administration of nicotine (Di Chiara and Imperato, 1988), 9-THC (Chen et al., 1991), morphine (Di Chiara and Imperato, 1988; Pontieri et al., 1995), or ethanol (Di Chiara and Imperato, 1988). Because these neurochemical changes are often considered central to the development of drug dependence, they could contribute to the widespread consumption of caffeine-containing beverages.
