Interactions of dopamine D 1 and D 2 receptor antagonists with D‐methamphetamine‐induced hyperthermia and striatal dopamine and serotonin reductions

The effects of the dopamine D 1 receptor antagonist R(+)‐SCH‐23390 and D 2 receptor antagonist S(–)‐eticlopride on d‐methamphetamine‐induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10‐mg/kg doses of d‐methamphetamine or saline with a 2‐h interval between treatments; 0.5 mg/kg eticlopride or SCH‐23390 was administered 15 min before each methamphetamine or saline injection. Two ambient temperature conditions were investigated: 24 and 33°C. Methamphetamine administered at 24°C induced hyperthermia and reduced striatal dopamine content by 73%; 0.5 mg/kg eticlopride or SCH‐23390 administered in combination with methamphetamine at 24°C attenuated methamphetamine‐induced hyperthermia and prevented significant reductions in dopamine content. At 33°C, eticlopride and SCH‐23390 were ineffective in blocking methamphetamine‐induced hyperthermia and dopamine content was reduced by 65% in the SCH‐23390‐methamphetamine group. By contrast, dopamine content was reduced by only 31% in the 33°C eticlopride‐methamphetamine group. Thus, although the eticlopride‐methamphetamine treatment combination at 33°C exhibited a hyperthermic response comparable to that seen with methamphetamine alone at 24°C, reductions in dopamine content were attenuated in the combination group compared with methamphetamine alone at 24°C. Serotonin changes showed similar attenuated reductions after SCH‐23390 or eticlopride pretreatment at 24°C in combination with methamphetamine, but this attenuation was absent at 33°C. The dissociation of methamphetamine‐induced striatal dopamine reduction and hyperthermia seen after eticlopride pretreatment suggests a dopamine D 2 receptor mechanism in mediating methamphetamine‐induced dopamine depletion. However this D 2 mechanism does not apply to methamphetamine‐induced striatal serotonin reductions. Synapse 56:84–93, 2005. © 2005 Wiley‐Liss, Inc.