Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane.
The effects of chronic ethanol (EtOH) consumption on the central nervous system may be related in part to its action on biological membranes by altering various receptor functions. In the current study, we examined the effects of chronic EtOH (4 day inhalation) on cannabinoid receptors (CB1) labeled with [3H]CP55,940 in synaptic plasma membranes (SPM) isolated from mouse brain. Our results indicate the presence of a high level of CB1 receptors in controls (Bmax=12.0+/-0.3 pmol mg-1 protein) which decreased significantly (-58%) in SPM from mouse brain chronically exposed to EtOH. This effect occurs without any changes in the receptor affinity (Kd=2. 3+/-0.3 nM for control and 2.9+/-0.3 nM for EtOH group, P>0.05). Dissociation kinetic results showed a dissociation rate constant (K-1) of 0.09+/-0.01 min-1 for control and this dissociation rate constant decreased significantly in the chronic EtOH treated mice brain (0.05+/-0.01 min-1, P<0.05). The competition studies with anandamide resulted in a substantial decrease in [3H]CP55,940 binding in both the control and EtOH group, with a decrease (P<0.05) in the Ki values in the SPM of chronic EtOH exposed mice. Hill transformation analysis showed an nH close to one in control (0. 92+/-0.01). This did not change significantly after chronic EtOH (0. 95+/-0.01) administration, which indicates the existence of a single class of receptor for [3H]CP55,940 binding in SPM from control and EtOH treated mice. The observed down-regulation of CB1 receptors by chronic EtOH may indicate the involvement of cannabinoid receptors in EtOH tolerance and dependence.
Basavarajappa
B S
BS
Division of Analytical Psychopharmacology, New York State Psychiatric Institute, New York, NY 10032, USA.
Cooper
T B
TB
Hungund
B L
BL
D000280:Administration, Inhalation; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D002186:Cannabinoids; D003511:Cyclohexanols / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction; D013570:Synaptic Membranes / Q000187:drug effects*
D002186:Cannabinoids; D003511:Cyclohexanols; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000431:Ethanol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol