title: CB1 receptor knockout mice are hyporesponsive to the behavior-stimulating actions of d-amphetamine: role of mGlu5 receptors.
abstract: Blockade of the cannabinoid CB1 receptors (CB1R) has been shown to reduce psychostimulant-induced hyperactivity, an effect that we sought to further characterize here. The CB1R antagonist SR141716A dose-dependently decreased d-amphetamine-induced hyperactivity.Also, d-amphetamine-induced hyperlocomotion was reduced in CB1R knockout (KO) mice. However, CB1R KO and wild-type mice showed a similar d-amphetamine-induced increase in nucleus accumbens DA release. Hence, we investigated whether CB1R antagonism/invalidation reduces d-amphetamine-induced hyperlocomotion through a mechanism involving changes in glutamatergic neurotransmission. Blockade of metabotropic-glutamate-receptors-5 (mGluR5)with MPEP, but not blockade of N-methyl-D-aspartate-receptors (NMDA) with MK-801,restored to a great extent the blunted d-amphetamine-induced hyperlocomotion seen after CB1R antagonism/invalidation. Thus, hyporesponsiveness to the psychostimulant effects of d-amphetamine as a result of CB1R antagonism/invalidation is not due to an ensuing decrease in d-amphetamine-induced DA release in the nucleus accumbens, but rather due to a hyperglutamatergic state and facilitation of glutamatergic neurotransmission at the mGlu5, but not NMDA, receptors.
authors.affiliation: Eli Lilly & Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN 46285-0510, USA. eleni.tzavara@snv.jussieu.fr
authors.forename: Eleni T
authors.initials: ET
authors.lastname: Tzavara
authors.forename: Aldemar
authors.initials: A
authors.lastname: Degroot
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wade
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Davis
authors.forename: George G
authors.initials: GG
authors.lastname: Nomikos
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000172:deficiency*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant
chemical_list: D018765:Dopamine Uptake Inhibitors; C578936:Grm5 protein, mouse; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016291:Dizocilpine Maleate; C121465:6-methyl-2-(phenylethynyl)pyridine; D000661:Amphetamine; D000077285:Rimonabant; D004298:Dopamine