Striatal dopamine D1 and D2 receptors: Widespread influences on methamphetamine‐induced dopamine and serotonin neurotoxicity

Abstract

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

“…Findings that PG01037 attenuates the long-term methamphetamine-induced DAT deficits are similar to previous reports wherein nonselective dopamine D 1 and D 2 /D 3 receptor antagonists attenuate long-term methamphetamine-induced dopaminergic deficits by reducing the hyperthermic effects of methamphetamine (Gross et al, 2011; Broening et al, 2005; Sonsalla et al, 1986). However, and in contrast to the effect of nonselective dopamine D 2 /D 3 receptor antagonists (Broening et al, 2005; O’Dell et al, 1993), PG01037 failed to attenuate methamphetamine-induced decreases in striatal dopamine content.…”

“…Although the mechanisms underlying these long-term deficits are not completely understood, several dopamine receptor subtypes have been implicated in mediating the effects of methamphetamine. For example, nonselective dopamine D 2 /D 3 receptor antagonists can attenuate methamphetamine-induced dopamine overflow (O’Dell et al, 1993), decreases in DAT activity (Gross et al, 2011; Hadlock et al, 2010), and decreases in dopamine content (Broening et al, 2005; Sonsalla et al, 1986). However, the ability of these antagonists to attenuate the effects of methamphetamine has primarily been attributed, at least in part, to antagonism of methamphetamine-induced hyperthermia (Albers and Sonsalla, 1995).…”

Expression and Activity of Nitric Oxide Synthase Isoforms in Methamphetamine-Induced Striatal Dopamine Toxicity

“…For example, evidence suggests that NO regulates DA release in striatum (Zhu and Luo, 1992;West and Galloway, 1997;West et al, 2002), including METH-induced DA release (Bowyer et al, 1995;Inoue et al, 1996), which has been suggested to play an important role in damage to DA terminals (O'Dell et al, 1991;O'Dell et al, 1993;Gross et al, 2011). Thus, NO production during an initial exposure to a neurotoxic regimen of METH may increase DA overflow, and this DA overflow may result in the DA neuron toxicity.…”

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…Hence, pharmacological studies using D 2 -like receptor antagonists indicate a role for D 2 -like receptors in METH-induced apoptosis of striatal neurons (Xu et al, 2005) and other METH-induced toxicities. Moreover, unilateral striatal infusion of sulpiride protects against DAT loss, implicating striatal D 2 -like receptors in METH-induced neurotoxicity (Gross et al, 2011). However, D 2 -like receptors antagonists are not specific for the D 2 receptor subtype as they may also block other D 2 -like receptors (e.g.…”