title: Dopaminergic augmentation of delta-9-tetrahydrocannabinol (THC) discrimination: possible involvement of D(2)-induced formation of anandamide.
abstract: BACKGROUND
  Although delta-9-tetreahydrocannabinol (THC)-induced elevations in accumbal dopamine levels are believed to play an important role in the abuse-related effects of cannabis, little direct evidence has been provided that the dopaminergic system is involved in the psychotropic effects of THC.
  
  
  OBJECTIVE
  The objective of this study is to investigate whether drugs activating or blocking the dopaminergic system modulate the discriminative effects of THC.
  
  
  RESULTS
  In rats that had learned to discriminate 3 mg/kg of THC from vehicle injections, the indirect dopaminergic agonists cocaine and amphetamine, the D(1)-receptor agonist SKF-38393, and the D(2)-receptor agonists quinpirole and apomorphine did not produce significant THC-like discriminative effects. However, both cocaine and amphetamine and D(2)-, but not the D(1)-, receptor agonists, augmented THC discrimination. Neither the D(1)-receptor antagonist SCH-23390 nor the D(2)-receptor antagonist raclopride reduced the discriminative effects of THC, even at doses that significantly depressed baseline operant responding. However, the D(2)-, but not the D(1)-, antagonist counteracted the augmentation of THC's discriminative effects produced by cocaine and amphetamine. We hypothesized that release of anandamide by activation of D(2) receptors was responsible for the observed augmentation of THC discrimination. This hypothesis was supported by two findings. First, the cannabinoid CB(1)-receptor antagonist rimonabant blocked quinpirole-induced augmentation of THC discrimination. Second, inhibition of anandamide degradation by blockade of fatty acid amide hydrolase augmented the THC-like effects of quinpirole.
  
  
  CONCLUSIONS
  Dopamine does not play a major role in THC discrimination. However, activation of the dopaminergic system positively modulates the discriminative effects of THC, possibly through D(2)-induced elevations in brain levels of anandamide.
authors.affiliation: Laboratoire de Biologie et Physiologie Cellulaires, CNRS-6187, University of Poitiers, 40 Avenue du Recteur Pineau, 86022, Poitiers, France. marcello.solinas@univ-poitiers.fr
authors.forename: Marcello
authors.initials: M
authors.lastname: Solinas
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Wertheim
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D004298:Dopamine; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D013759:Dronabinol; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D011619:Psychotropic Drugs; D043884:Receptor, Cannabinoid, CB1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide