Glutamate is believed to play an integral role in the behavioral effects of cocaine related to its abuse. Most previous research has focused on the contribution of ionotropic glutamate receptor (iGluR) mechanisms, but growing evidence suggests that metabotropic glutamate receptors (mGluRs) may play an unexpectedly important role. Recent studies from our laboratory and others have shown that pharmacological blockade or genetic deletion of the mGluR subtype 5 (mGluR5) can attenuate key behavioral effects of cocaine in mice and monkeys. Our proposed research will build on initial findings in squirrel monkeys with three specific aims.
Specific Aim 1 will use IV drug discrimination techniques to investigate the impact of mGluR5 antagonists and related drugs on the discriminative stimulus effects of cocaine. The contribution of dopamine (DA) and iGluR mechanisms in mGluR5 modulation of the discriminative stimulus effects of cocaine will be evaluated in drug interaction studies with direct and indirect DA agonists and NMDA and AMPA/kainate receptor antagonists.
Specific Aim 2 will investigate the effects of mGluR5 antagonists and related drugs on IV self-administration of cocaine under a second-order schedule of reinforcement. Parallel studies using a comparable schedule of food delivery will assess the selectivity with which drugs modulate the reinforcing effects of cocaine without producing a generalized suppression of operant behavior. Observational studies will monitor potential side effects of drugs that selectively attenuate cocaine self-administration.
Specific Aim 3 will use a reinstatement model of cocaine relapse to investigate the effects of mGluR5 antagonists and related drugs on cocaine-seeking behavior that has been extinguished and subsequently restored by cocaine priming and a cocaine-paired stimulus. The results will provide a needed empirical framework for evaluating mGluR5 and related glutamate receptor mechanisms in relevant nonhuman primate models of cocaine abuse and relapse. They should also provide new insights regarding mGluR5 as a potential target for the pharmacological management of cocaine addiction. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017700-04
Application #
7253300
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Thomas, David A
Project Start
2004-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$360,546
Indirect Cost
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Achat-Mendes, Cindy; Platt, Donna M; Spealman, Roger D (2012) Antagonism of metabotropic glutamate 1 receptors attenuates behavioral effects of cocaine and methamphetamine in squirrel monkeys. J Pharmacol Exp Ther 343:214-24
Xu, Tai-Xiang; Sotnikova, Tatyana D; Liang, Chengyu et al. (2009) Hyperdopaminergic tone erodes prefrontal long-term potential via a D2 receptor-operated protein phosphatase gate. J Neurosci 29:14086-99
Achat-Mendes, Cindy; Platt, Donna M; Newman, Amy H et al. (2009) The dopamine D3 receptor partial agonist CJB 090 inhibits the discriminative stimulus but not the reinforcing or priming effects of cocaine in squirrel monkeys. Psychopharmacology (Berl) 206:73-84
Platt, Donna M; Rowlett, James K; Spealman, Roger D (2008) Attenuation of cocaine self-administration in squirrel monkeys following repeated administration of the mGluR5 antagonist MPEP: comparison with dizocilpine. Psychopharmacology (Berl) 200:167-76
Yao, Wei-Dong; Spealman, Roger D; Zhang, Jingping (2008) Dopaminergic signaling in dendritic spines. Biochem Pharmacol 75:2055-69
Haney, Margaret; Spealman, Roger (2008) Controversies in translational research: drug self-administration. Psychopharmacology (Berl) 199:403-19
Valdez, Glenn R; Platt, Donna M; Rowlett, James K et al. (2007) Kappa agonist-induced reinstatement of cocaine seeking in squirrel monkeys: a role for opioid and stress-related mechanisms. J Pharmacol Exp Ther 323:525-33
Adewale, A S; Platt, D M; Spealman, R D (2006) Pharmacological stimulation of group ii metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Ther 318:922-31
Rowlett, James K (2005) Getting back to basics: commentary on McSweeney, Murphy, and Kowal (2005). Exp Clin Psychopharmacol 13:187-9; discussion 194-9
Lee, Buyean; Platt, Donna M; Rowlett, James K et al. (2005) Attenuation of behavioral effects of cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine. J Pharmacol Exp Ther 312:1232-40