Gr. King et al., WITHDRAWAL FROM CONTINUOUS OR INTERMITTENT COCAINE ADMINISTRATION - CHANGES IN D-2 RECEPTOR FUNCTION, The Journal of pharmacology and experimental therapeutics, 269(2), 1994, pp. 743-749
Intermittent cocaine administration produces sensitization, whereas th
e continuous administration of cocaine produces tolerance to the effec
ts of subsequent cocaine administration during withdrawal. The present
study examined whether the effects of these two dosing regimens are r
elated to alterations in the functional status of dopamine (DA) D-2 re
ceptors. In all experiments, rats were withdrawn for 7 days from a 14-
day pretreatment regimen involving either continuous or intermittent c
ocaine 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 D-2 receptor binding, and mRNA levels. The results
indicate that the continuous administration of cocaine produces findi
ngs consistent with D-2 autoreceptor supersensitivity; there was enhan
ced inhibition of behavior after the autoreceptor-selective dose of ap
omorphine, 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
D-2 receptor binding or mRNA levels. Intermittent cocaine administrati
on did not produce evidence of D-2 autoreceptor subsensitivity: there
was no decrease in inhibition of behavior after the autoreceptor-selec
tive dose of apomorphine, no changes in electrically stimulated DA rel
ease in the absence or presence of D-2 receptor blockade, and no chang
e in the levels of D-2 receptor binding; however, D-2 mRNA levels were
decreased by 22%. Overall, the present results are consistent with th
e hypothesis that the expression of tolerance induced by continuous co
caine administration is associated with D-2 autoreceptor supersensitiv
ity.