Increased dopamine receptor activity in the nucleus accumbens shell ameliorates anxiety during drug withdrawal

Abstract

A number of lines of evidence suggest that negative emotional symptoms of withdrawal involve reduced activity in the mesolimbic dopamine system. This study examined the contribution of dopaminergic signaling in structures downstream of the ventral tegmental area to withdrawal from acute morphine exposure, measured as potentiation of the acoustic startle reflex. Systemic administration of the general dopamine receptor agonist apomorphine or a cocktail of the D1-like receptor agonist SKF82958 and the D2-like receptor agonist quinpirole attenuated potentiated startle during morphine withdrawal. This effect was replicated by apomorphine infusion into the nucleus accumbens shell. Finally, apomorphine injection was shown to relieve startle potentiation during nicotine withdrawal and conditioned place aversion to morphine withdrawal. These results suggest that transient activation of the ventral tegmental area mesolimbic dopamine system triggers the expression of anxiety and aversion during withdrawal from multiple classes of abused drugs.

Figure 1

Activation of both D1- and D2-like receptors relieves withdrawal from systemic morphine. (a) Timeline of test day for Experiments 1 and 2. (b) Withdrawal-potentiated startle was not significantly reduced by SKF82958 or quinpirole treatment, although these treatments did have effects on baseline startle. (c) A cocktail of SKF82958 and quinpirole significantly reduced startle potentiation. ^*p<0.05 compared to 0 and 10 μg/kg groups.

Figure 2

Cannula tip placements for Experiment 3. Tip locations for animals with correct placements are indicated with black circles.

Figure 3

Withdrawal from systemic morphine is dependent on dopaminergic signaling in the shell of the nucleus accumbens. (a) Timeline of test day for Experiment 3. (b) Startle potentiation was attenuated by apomorphine infusion into the NAc shell (^*p<0.05 compared to 0 and 1 μg groups). (c) Startle potentiation was not reduced by apomorphine infusion into the dorsolateral component of the bed nucleus of the stria terminal (dlBNST). (d) Startle potentiation was not reduced by apomorphine infusion into the central amygdala (CeA). (e) Startle potentiation was not reduced by apomorphine infusion into the ventral tegmental area (VTA).

Figure 4

Dopamine receptor activation prevents conditioned place aversion to morphine withdrawal. (a) Timeline of conditioning days for Experiment 4. (b) Aversion to the drug-paired side of the conditioning chamber was relieved by apomorphine injection (^*p<0.05 compared to baseline).

Figure 5

Withdrawal from systemic nicotine is dependent on dopaminergic signaling. (a) Timeline of test day for Experiment 5. (b) Startle potentiation was attenuated by apomorphine injection (^*p<0.05 compared to 0 μg/kg group). See text for discussion of significant effects in 0 mg/kg group.