Cocaine self-administration produces a persistent increase in dopamine D2 High receptors

Abstract

Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current study reports a possible resolution to this long-standing paradox. The dopamine D2 receptor exists in both a low and a high-affinity state, and dopamine exerts its effects via the more functionally relevant high-affinity D2 receptor (D2 High). We report here that cocaine self-administration experience produces a large (approximately 150%) increase in the proportion of D2 High receptors in the striatum with no change in the total number of D2 receptors, and this effect is evident both 3 and 30 days after the discontinuation of cocaine self-administration. Changes in D2 High receptors would not be evident with the probes used in human (and non-human primate) imaging studies. We suggest, therefore, that cocaine addicts and animals previously treated with cocaine may be hyper-responsive to dopaminergic drugs in part because an increase in D2 High receptors results in dopamine supersensitivity. This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine.

Figure 1

Representative experiments for the method of competition between dopamine and [³H]domperidone. The proportion of D2 receptors in the high-affinity state for dopamine in the control tissue was 17.7%, while that for the extended access rat was 49%, a 2.8-fold increase.

Figure 2

A. Mean (+/−SEM) number of cocaine infusions during the first hour of each self-administration session. By the 7th escalation session, animals allowed extended access to cocaine (6 hr session; ExtA) took significantly more infusions than animals allowed only limited access (1 hr sessions; LtdA) [main effect of group, F(1,476)=64.24, p<.0001, main effect of day, F(17,476)=6.61, p<0.0001, group by day interaction, F(17,476)=6.97, p<.0001]. B. The mean (+/−SEM) number of cocaine infusions over the entire session for ExtA (6 hr sessions) and LtdA (1 hr sessions) groups.

Figure 3

Total dopamine D2 and D2^High receptors in the dorsal striatum of no-drug control animals and animals given limited or extended access to self-administered cocaine, either 3 or 30 days after the last self-administration session. Panel a shows the total number of D2 receptors ([³H]domperidone binding) in the cocaine-treated groups expressed as a percent of the control group. There were no group differences in the total number of D2 receptors (Overall ANOVA, group, F(2,40)=.03, p=.97). Panel b shows the proportion of D2^High receptors, again with the cocaine-treated groups expressed as a percent of the control group. In control animals the proportion of D2 high affinity receptors was 18±1.4%. Cocaine self-administration experience greatly increased the proportion of D2^High receptors at both 3 and 30 days of withdrawal [main effect of group, F(2,42)=68.89, p<.0001, main effect of withdrawal time, F(1,42)=.65, p=.43, group by time interaction, F(2,32)=2.8, p=.07, *, differs from the no drug group as determined by Bonferroni’s corrected t-tests].