Role of dopamine D1- and D2-like receptor mechanisms in drug-seeking following methamphetamine self-administration in rats.

It has been suggested that dopaminergic mechanisms mediate relapse to drug-seeking behavior and both D1- and D2-like receptor mechanisms have been implicated. In contrast to self-administration of other drugs, there is a relative paucity of studies that has examined the pharmacological basis of methamphetamine (MA) seeking. Accordingly, the present study used an animal model of drug-seeking to determine the role of D1- and D2-like receptor mechanisms in relapse to MA abuse. Rats were trained to self-administer MA, and then responding was extinguished by replacing the MA solution with vehicle. Experimenter-administered injections of MA or the dopamine uptake inhibitor, GBR 12909, reinstated extinguished responding in a dose-dependent manner. The D1-like antagonist, SCH 23390 attenuated drug-seeking but the D2-like antagonist, eticlopride, was ineffective. The results suggest that MA-seeking is predominantly mediated by DA D1-like receptor mechanisms. These findings are in contrast to the literature on drug-seeking following self-administration of other drugs, and suggest that relapse to different drugs of abuse may rely upon different DA receptor mechanisms.

Methamphetamine self-administration and the effect of contingency on monoamine and metabolite tissue levels in the rat.

A number of studies have shown that exposure to high doses of methamphetamine (MA) is toxic to central dopamine (DA) and serotonin (5-HT) neurons. In most of those studies, however, high doses of MA were experimenter-administered during a short exposure time. Because contingency is a determinant for many effects of drug exposure, the present objective was to investigate the effects of self-administered MA on tissue monoamine levels following a short (24 hours) or longer (7 days) withdrawal period. As previously reported, a noncontingent "binge" high-dose treatment regimen (4 injections of 10 mg/kg MA administered every 2 hours) produced persistent depletion of cortical 5-HT and striatal DA. Effects of self-administered MA (0.1 mg/kg/infusion) were then determined following a 20-day duration where a yoked design was employed such that some rats received MA contingent on an operant lever press and others received either MA or saline dependent on the responses of the contingent rat. Self-administered MA produced a transient striatal DA depletion with a more persistent increase in DA turnover, indicating the presence of some lasting adaptations. Furthermore, the yoked design revealed that there was no effect of contingency on these parameters.

Effect of D1-like and D2-like receptor antagonists on methamphetamine and 3,4-methylenedioxymethamphetamine self-administration in rats.

It has been suggested that activation of dopamine D1-like and D2-like receptors contribute equally to the maintenance of drug self-administration. This study compared the contribution of these receptor subtypes to 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (MA) self-administration. Effects of pretreatment with the D2-like receptor antagonist, eticlopride (0.0, 0.0125, 0.025 or 0.05 mg/kg, intraperitoneal), on responding maintained by several doses of MDMA (0.5, 1.0 and 2.0 mg/kg/infusion) and MA (0.05, 0.1 and 0.2 mg/kg/infusion) were determined. As we have published data showing the effects of the D1-like receptor antagonist, SCH23390 (0.0, 0.01 or 0.02 mg/kg, subcutaneous), on MDMA self-administration, effects of this dose range on the MA dose-response curve were determined. In our previous study, 0.02 mg/kg SCH23390 produced a rightward shift in the MDMA dose response curve, whereas in the present results, this dose decreased responding maintained by most doses of MA. Eticlopride increased the responding maintained by most doses of MDMA but failed to alter MA self-administration. The present results suggest that both D1-like and D2-like receptors contribute to the maintenance of MDMA self-administration, whereas MA self-administration was more sensitive to D1-like receptor blockade.