A role for D1 dopamine receptors in striatal methamphetamine-induced neurotoxicity

Abstract

Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 Dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Importantly, METH-induced hyperthermia is tightly associated with the neurotoxicity, such that simply cooling animals during METH exposure protects against the neurotoxicity. Therefore, it is difficult to determine whether D1 DA receptors per se play an important role in METH-induced neurotoxicity or whether the protection observed simply resulted from a mitigation of METH-induced hyperthermia. To answer this important question, the current study infused a D1 DA receptor antagonist into striatum during METH exposure while controlling for METH-induced hyperthermia. Here we found that even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia.

Recent Advances in Methamphetamine Neurotoxicity Mechanisms and Its Molecular Pathophysiology

“…One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 DA receptors. Even when METH-induced hyperthermia is maintained, the coadministration of a D1 DA receptor antagonist protects against METH-induced neurotoxicity, strongly suggesting that D1 DA receptors play an important role in METH-induced neurotoxicity apart from the mitigation of METH-induced hyperthermia [ 83 ]. Although it is well known that MATH causes DA terminal degeneration, accumulating evidence indicates that METH causes injury to cell bodies in diverse brain regions [ 84 , 85 ].…”

Effects of intrastriatal dopamine D1 or D2 antagonists on methamphetamine-induced egocentric and allocentric learning and memory deficits in Sprague–Dawley rats

“…Subsequently, the efficacy of SCH-23390 was assessed by infusion into the striatum. In this experiment, MA-induced neurotoxicity on DAT was blocked by SCH-23390 infusion while holding the body temperature of the rats at 40 °C, the body temperature often found when using a neurotoxic dosing regimen of MA (Friend and Keefe 2013). While these data support that DRD1 and DRD2 are involved in MA-induced neurotoxicity, none of these studies determined whether the neuroprotective effects of DA receptor antagonists provided protection against the cognitive deficits induced by MA.…”

“…Reductions in DA and serotonin (5-HT) transporters (DAT and SERT, respectively) (Kish et al 2009;Volkow et al 2001b) as well as changes in levels of DA receptors D1 (DRD1) and D2 (DRD2) are seen in chronic MA abusers (Volkow et al 2001a;Worsley et al 2000). Similar to human findings, after neurotoxic regimens of MA, rodents exhibit reductions in striatal DA and 5-HT and hippocampal 5-HT (Broening et al 2005;Cappon et al 2000;Friedman et al 1998;Fukumura et al 1998;Gutierrez et al 2017;Herring et al 2010;Herring et al 2008a;Herring et al 2008b;Wallace et al 2001), in DAT in the neostriatum and SERT in the hippocampus (Ares-Santos et al 2012;Friend and Keefe 2013;Gross et al 2011), and in expression of striatal DRD1 and DRD2 (McCabe et al 1987). In rodents, pharmacologically inhibiting DRD1 or DRD2 prior to MA attenuates reductions in striatal DA, 5-HT, and of DAT and SERT binding (Broening et al 2005;Gross et al 2011;Sonsalla et al 1986).…”

“…This may be because (1) the antagonists did not spread sufficiently to protect all MA-affected neurons, (2) the dose of the antagonists was not optimal, (3) MA neurotoxicity affects other brain regions the antagonist did not reach but are important for learning and memory, or (4) MA neurotoxicity involves neurotransmitters and receptors other than those of DA (e.g., 5-HT, glutamate, GABA), thereby limiting the range of protection possible from DA antagonists alone. Previous studies testing the effects of DA antagonists used smaller doses of MA divided over several hours (Friend and Keefe 2013;Gross et al 2011;Gross and Marshall 2009), whereas we used a single dose. How other divided antagonist dosing regimens might affect learning and memory is not known.…”

NeuroHIV and Use of Addictive Substances

“…As a result of its neurotoxicity, METH may also induce persistent mood disorders, such as depression (Sekine et al, 2006). In addition, METH damages nigrostriatal dopaminergic terminals and induces hyperthermia, which exacerbates METH neurotoxicity (Friend & Keefe, 2013;Kikuchi-Utsumi et al, 2013).…”