title: Acute and chronic administration of clorazepate modifies the cell surface regulation of mu opioid receptors induced by buprenorphine in specific regions of the rat brain.
abstract: The aim of the present study was to investigate the acute and chronic effects of clorazepate (CRZ) alone or in combination with buprenorphine (BPN) on binding of the selective mu opiate tritiated ligand [3H]-DAMGO in the rat brain. Using 0.1 to 5 nM [3H]-DAMGO concentrations and a beta-imager, Bmax (maximal receptor density) and K(D) (the dissociation constant) were directly determined at different regions of interest (ROI) in the brains of rats treated with BPN and/or CRZ administered either once or over 21 consecutive days. Differences in Bmax and K(D) were related to both treatment and location. Acute BPN induced a down-regulation (62% mean decrease in Bmax observed on the whole brain) of mu opiate receptors. CRZ induced a mean 39% decrease in Bmax associated with substantially decreased affinity, particularly after acute administration (136% mean K(D) increase). Addition of CRZ to BPN [mean Bmax decreases of 34% (acute) and 29% (chronic)] induced significantly less down-regulation than did BPN alone, while altering affinity. These changes were maximal in the amygdaloid nucleus. Significant and persistent decreases in Bmax and affinity were also detected in the hippocampus, hypothalamus and thalamus. In the thalamus, an opposite regulation of Bmax was observed that was maximal with the combination. As the regions where changes were greatest have been specifically implicated in memory and socio-emotional functions and/or vegetative and endocrine adaptations, there is reason to suspect that the addition of CRZ to BPN may have clinical consequences. On the one hand, it may have some impact on drug abuse and misuse behaviors towards treatments including heroin substitute and BZD, and on the other, amplify the BPN effect-particularly hedonic or toxic-mainly after sporadic BPN-BZD abuses. These pharmacodynamic findings may explain, at least in part, the well-established preference of patients for the BPN-benzodiazepine combination and the toxicity with which it is associated.
authors: Pharmacology Department, University Hospital Centre, Caen, France. debruyne-d@chu-caen.fr
authors: Danièle
authors: D
authors: Debruyne
authors: Thomas
authors: T
authors: Quentin
authors: Géraldine
authors: G
authors: Poisnel
authors: Véronique
authors: V
authors: Lelong-Boulouard
authors: Louisa
authors: L
authors: Barré
authors: Antoine
authors: A
authors: Coquerel
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D002047:Buprenorphine / Q000494:pharmacology*; D003009:Clorazepate Dipotassium / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000493:pharmacokinetics; D018757:GABA Modulators / Q000008:administration & dosage*; D008297:Male; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D018757:GABA Modulators; D009294:Narcotics; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D002047:Buprenorphine; D003009:Clorazepate Dipotassium