CB1 receptor blockade reduces the anxiogenic-like response and ameliorates the neurochemical imbalances associated with alcohol withdrawal in rats.
There is strong evidence that blocking CB1 receptors may reduce alcohol intake in alcohol-dependent individuals. However, there is still limited evidence that CB1 receptor antagonists may also be beneficial in the attenuation of alcohol withdrawal syndrome, even though alcohol withdrawal appears to be milder in CB1 receptor knockout mice. Here we have examined whether the CB1 receptor antagonist rimonabant (SR141716) can alleviate the behavioral symptoms and revert the neurochemical imbalance elicited by a 3-h interruption of chronic alcohol exposure (7.2% in the drinking water for 10 days) in male Wistar rats. Administration of rimonabant attenuated the strong anxiogenic traits of the animals that developed when regular alcohol intake was interrupted. This may reflect the correction of the GABA/glutamate imbalances developed by the animals that received rimonabant in various brain regions involved in emotional (e.g. prefrontal cortex) and motor (e.g. caudate-putamen and globus pallidus) responses. In addition, rimonabant also affected the dopamine deficits generated by alcohol abstinence in the amygdala and ventral-tegmental area, albeit to a lesser extent. However, this antagonist was unable to correct the impairment caused by alcohol abstinence in serotonin and neuropeptide Y. The endocannabinoid activity in the brain of alcohol-abstinent rats indicated that the behavioral and neurochemical improvements caused by rimonabant were not related to the attenuation of a possible increase in this activity generated by alcohol withdrawal. Conversely, the density of CB1 receptors was reduced in alcohol-abstinent animals (e.g. globus pallidus, substantia nigra), as were the levels of endocannabinoids and related N-acylethanolamines (e.g. amygdala, caudate-putamen). Thus, rimonabant possibly enhances an endogenous response generated by interrupting the regular use of alcohol. In summary, rimonabant might attenuate withdrawal symptoms associated with alcohol abstinence, an effect that was presumably due to the normalization of GABA and glutamate, and to a lesser extent, dopamine transmission in emotion- and motor-related areas.
Rubio
Marina
M
Departamento de Bioquímica y Biología Molecular and Centro de Investigación biomédica en Red sobre Enfermedades Neurodegenerativas, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Fernández-Ruiz
Javier
J
de Miguel
Rosario
R
Maestro
Begoña
B
Michael Walker
J
J
Ramos
José A
JA
D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000517:prevention & control* / Q000523:psychology*; D001066:Appetite / Q000187:drug effects; D001095:Arachidonic Acids / Q000494:pharmacology; D001345:Autoradiography; D048588:Benzoxazines / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D002851:Chromatography, High Pressure Liquid; D004644:Emotions / Q000502:physiology; D063388:Endocannabinoids; D004745:Enkephalins / Q000096:biosynthesis; D000431:Ethanol / Q000009:adverse effects*; D004983:Ethanolamines / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D009478:Neuropeptide Y / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011498:Protein Precursors / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013315:Stress, Psychological / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology*
D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D002492:Central Nervous System Depressants; D063388:Endocannabinoids; D004745:Enkephalins; D004983:Ethanolamines; D005989:Glycerides; D009025:Morpholines; D009281:Naphthalenes; D009478:Neuropeptide Y; D018377:Neurotransmitter Agents; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011498:Protein Precursors; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; C029992:proenkephalin; D000431:Ethanol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide