RT Journal Article
SR Electronic
T1 Withdrawal from continuous or intermittent cocaine administration: changes in D2 receptor function.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 743
OP 749
VO 269
IS 2
A1 G R King
A1 E H Ellinwood, Jr
A1 C Silvia
A1 C M Joyner
A1 Z Xue
A1 M G Caron
A1 T H Lee
YR 1994
UL http://jpet.aspetjournals.org/content/269/2/743.abstract
AB Intermittent cocaine administration produces sensitization, whereas the continuous administration of cocaine produces tolerance to the effects of subsequent cocaine administration during withdrawal. The present study examined whether the effects of these two dosing regimens are related to alterations in the functional status of dopamine (DA) D2 receptors. In all experiments, rats were withdrawn for 7 days from a 14-day pretreatment regimen involving either continuous or intermittent cocaine administration. Experiments examined changes in the behavioral response to an autoreceptor-selective dose of apomorphine, the effects of sulpiride on electrically stimulated DA release in striatal brain slices and striatal D2 receptor binding, and mRNA levels. The results indicate that the continuous administration of cocaine produces findings consistent with D2 autoreceptor supersensitivity; there was enhanced inhibition of behavior after the autoreceptor-selective dose of apomorphine, decreased electrically stimulated DA release in the absence of sulpiride, and enhanced electrically stimulated DA release in the presence of sulpiride. However, there were no changes in postsynaptic D2 receptor binding or mRNA levels. Intermittent cocaine administration did not produce evidence of D2 autoreceptor subsensitivity: there was no decrease in inhibition of behavior after the autoreceptor-selective dose of apomorphine, no changes in electrically stimulated DA release in the absence or presence of D2 receptor blockade, and no change in the levels of D2 receptor binding; however, D2 mRNA levels were decreased by 22%. Overall, the present results are consistent with the hypothesis that the expression of tolerance induced by continuous cocaine administration is associated with D2 autoreceptor supersensitivity.