Dysregulation of D₂-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure

Abstract

Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D₂ receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D₂-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D₂-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D₂-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D₂-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.

Figure 1.

D₂-like receptor availability in the caudate nucleus (A), putamen (B), ventral striatum (C), and ventral mesencephalon (D) in saline-exposed (open circles) and methamphetamine-exposed (closed circles) monkeys at baseline, 2 weeks post-drug exposure, and 7 weeks post-drug exposure. * indicates a significant change from baseline; # indicates a significant change from 2 weeks post-drug exposure. ***p < 0.001, ^###p < 0.001. SED, SE of the mean of differences.

Figure 2.

DAT availability in the caudate nucleus (A), putamen (B), ventral striatum (C), and ventral mesencephalon (D) in saline-exposed (open circles) and methamphetamine-exposed (closed circles) monkeys at baseline, 2 weeks post-drug exposure, and 7 weeks post-drug exposure. * indicates a significant change from baseline; # indicates a significant change from 2 weeks post-drug exposure. *p < 0.05, **p < 0.01, ***p < 0.001, ^###p < 0.001. SED, SE of the mean of differences.

Figure 3.

The number of trials required to reach criterion in the acquisition (A), retention (B), and reversal (C) phases between saline-exposed (open circles) and methamphetamine-exposed (closed circles) monkeys at baseline, at the 3 week assessment, at the 5 d post-drug exposure test, and at the two high difficulty sessions (1 week post-drug exposure and 3 weeks post-drug exposure). ***p < 0.001. SED, SE of the mean of differences.

Figure 4.

The relationship between changes in D₂-like receptor availability in the caudate nucleus and in the ability of monkeys to persist with a correct response following positive feedback in saline-exposed monkeys (open circles) and methamphetamine-exposed monkeys (closed circles). A, Compares the change from baseline in D₂-like receptor at the 1 week postexposure scan to change from baseline in positive-feedback sensitivity at the 5 d postexposure assessment. B, Compares the change from baseline in D₂-like receptor at the 7 week postexposure scan to change from baseline in positive-feedback sensitivity at the 3 week postexposure assessment.