In Vitro electrophysiology of dorsal raphe serotonergic neurons in subchronic cocaine-treated rats: Development of tolerance to acute cocaine administration.
An in vitro, extracellular slice preparation was used to examine the effects of subchronic cocaine administration on serotonergic cell firing in the dorsal raphe. Male Sprague-Dawley rats were administered cocaine (30 mg/kg, ip) for 7 days prior to experimentation. Following a 24-h washout period, rats were decapitated and dorsal raphe nucleus slices (400 mum) obtained. Slices were superfused with ACSF containing 1 AM phenylephrine and 1 muM 5-hydroxytryptamine (5-HT). Acute cocaine application was found to inhibit basal firing rates in both saline- and cocaine-pretreated rats. In addition, an apparent tolerance to acute cocaine application was found in animals subchronically treated with cocaine. Animals exposed to repeated cocaine exposure required an acute cocaine concentration of 5.46 +/- 0.5 muM (N = 5) to inhibit cell basal firing rates by 50% versus concentrations of 2.43 +/- 0.35 muM (N = 5) for saline controls. Concentrations of 20 muM cocaine typically produced complete inhibition of firing in cocaine-pretreated animals, whereas 10 muM cocaine produced complete cessation of firing in saline controls. Repeated perfusion with equal concentrations of cocaine produced dose-dependent inhibition of firing which remained consistent at each application, indicating no development of an acute tolerance effect. In addition, inhibition responses to acute applications of 5-HT showed no differences between treatment groups. Furthermore, there were no indications of a developed tolerance to 5-HT application. Finally, ligand binding studies using 8-OH-DPAT in hippocampal tissue indicate that there are no significant differences in either K(d) or B(max) between subchronically cocaine-treated or salinetreated animals. These results seem to indicate that the inhibitory effects of cocaine are not due to direct effects on the presynaptic autoreceptor but are indirectly produced due to cocaine's inhibition of the 5-HT reuptake system.
Black
E W
EW
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas 77550, USA.
Lakoski
J M
JM