Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia

Abstract

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia.

Keywords: D(3) antagonist; Dopamine D(3) receptors; Dopamine transporter; Methamphetamine; PG01037; Serotonin transporter.

Figure 1

The effects of PG01037 on methamphetamine-induced decreases in striatal DAT (A) and hyperthermia (B). Rats (n = 6–9/group) received PG010137 (4 × 32 mg/kg/injection, s.c.) or vehicle (4 × 1 ml/kg/injection, s.c.) 30 min before each administration of methamphetamine (4 × 7.5 mg/kg/injection, s.c., 2-h intervals) or vehicle (4 × 1 ml/kg/injection, s.c., 2-h intervals) and were sacrificed 7 days later. Ordinates: mean (± S.E.M.) fmol of [³H]dopamine per μg protein or body temperature. Abscissa: treatment group; V = vehicle and METH = methamphetamine or time across experiment; arrows indicate methamphetamine administration. Inset figure: mean (± S.E.M.) body temperature across time after first methamphetamine injection for each individual rat. * Methamphetamine values significantly different from respective vehicle control group (P<0.05). # PG01037/methamphetamine values significantly different from other methamphetamine group (P<0.05).

Figure 2

Methamphetamine-induced hyperthermia when methamphetamine was administered alone and with different doses of PG01037 (n = 6). Abscissa, dose in milligrams per kilogram of body weight; dashed gray line indicate body temperature across time after saline administration. Ordinate, mean (± S.E.M.) change in body temperature.

Figure 3

The effects of PG01037 on methamphetamine-induced decreases in striatal DAT (A) and hyperthermia (B) when rats were treated in a warm ambient environment. Rats (n = 6–9/group) received PG010137 (4 × 32 mg/kg/injection, s.c.) or vehicle (4 × 1 ml/kg/injection, s.c.) 30 min before each administration of methamphetamine (4 × 7.5 mg/kg/injection, s.c., 2-h intervals) or vehicle (4 × 1 ml/kg/injection, s.c., 2-h intervals) and were sacrificed 7 days later. See figure 2 for other details.