Nicotinic alpha 7 receptors as a new target for treatment of cannabis abuse.
Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric alpha7 nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective alpha7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-alpha7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, (1) antagonized the discriminative effects of delta-9-tetrahydrocannabinol (THC), the main active ingredient in cannabis, (2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone, mesylate salt], and (3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of alpha7 nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to alpha7 nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans.
Solinas
Marcello
M
Institut de Biologie et Physiologie Cellulaires, Centre National de la Recherche Scientifique-6187, University of Poitiers, 86022 Poitiers, France.
Scherma
Maria
M
Fattore
Liana
L
Stroik
Jessica
J
Wertheim
Carrie
C
Tanda
Gianluigi
G
Fratta
Walter
W
Goldberg
Steven R
SR
D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D008297:Male; D002189:Marijuana Abuse / Q000188:drug therapy* / Q000503:physiopathology; D009025:Morpholines / Q000008:administration & dosage; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000008:administration & dosage; D018733:Nicotinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism* / Q000502:physiology; D012646:Self Administration; D064569:alpha7 Nicotinic Acetylcholine Receptor
D048588:Benzoxazines; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D009025:Morpholines; D009281:Naphthalenes; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone