Dopamine D3 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.

The dopamine D3 receptor regulates the effects of methamphetamine on LPS-induced cytokine production in murine mast cells

“…Recent studies have demonstrated that D3R mediates immune responses in activated T cells and the migration and homing of naive CD8 + T cells (Watanabe et al, 2006). Furthermore, D3R may be involved in METH-induced hyperthermia (Baladi et al, 2014). In this study, D3R inactivation blocked the METH-induced inhibition LPS-mediated cytokine production in the lungs and thymi of D3R −/− mice.…”

“…Given that D3R is involved in METH-induced hyperthermia (Baladi et al, 2014), we next sought to determine the role of D3R in LPS-induced cytokine production. We previously showed that LPS significantly increased pro-inflammatory, anti-inflammatory, and Th2 cytokines in the lungs and thymi of WT and D3R −/− (Figs.…”

“…These findings also prompted us to investigate whether D3R regulates the effect of METH on the immune response. Interestingly, a recent study indicated that the D3R was involved in METH-induced hyperthermia (Baladi et al, 2014). Previous studies showed that D3R altered the immune response of activated T cells and the migration and homing of naive CD8 + T cells (Watanabe et al, 2006;Ilani et al, 2004).…”

Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging

“…In patients with Parkinson’s disease intensive exercise leads to increased D 2 -type receptor BP ND (Fisher et al, 2013), and preliminary findings suggest a positive finding in methamphetamine users as well (Robertson et al, 2013). Future studies may also benefit from therapeutic approaches targeted at novel targets in the dopamine system, such as the D3 receptor (Baladi et al, 2014; Paterson et al, 2014), as chronic methamphetamine exposure is associated with reduced levels of D 2 receptors but elevated levels of D 3 receptors (Boileau et al, 2012; Payer et al, 2014). …”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Hypophysectomy, Drug-Induced Neuroplasticity thyroparathyroidectomy, as well as treatment with high doses of haloperidol or diazepam that reduce body temperature during amphetamine treatments, also reduce the observed toxicity Sprague et al, 2003). A large number of neurotransmitter systems appears to be involved in producing the hyperthermic effect, because blockade of receptors, including the NMDAR; D 1 R, D 2 R, and D 3 R; a1-adrenoreceptors; 5-HT 2 receptors; as well as the s and OX 1 receptors, all prevent or reduce METH-induced hyperthermia while protecting against METH toxicity (Sonsalla et al, 1991;Farfel et al, 1992;Doyle and Yamamoto, 2010;Seminerio et al, 2011Seminerio et al, , 2012Rusyniak et al, 2012;Ares-Santos et al, 2012;Kikuchi-Utsumi et al, 2013;Robson et al, 2013a;Sabol et al, 2013;Baladi et al, 2014).…”