Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation

Abstract

Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5–10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction.

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

“…On the other hand, differences in 5-HT disposition in MADR and Taar1 transgenic mice do not correspond. Taar1 − / − mice have lower basal levels of 5-HT and greater amphetamine-induced 5-HT release compared with +/+ mice (Wolinsky et al, 2007), whereas the opposite relationship is seen in MADR mice; MAHDR mice have higher basal levels of 5-HT in the NAcc and show reduced sensitivity to MA-induced increases in 5-HT (Lominac et al, 2014). Different brain regions and assay methods could explain discrepancies related to 5-HT.…”

“…Furthermore, Taar1 − / − mice exhibit lower basal levels and greater amphetamine-induced release of DA in the striatum, compared with +/+ mice (Lindemann et al, 2008;Wolinsky et al, 2007). Similarly, MAHDR mice, which carry the non-functional version of the TAAR1, also exhibit lower resting DA tone in the NAcc and medial prefrontal cortex (mPFC), and higher MA-induced DA release in the mPFC, but not in the NAcc (Lominac et al, 2014). Therefore, DA-related phenotypes may be associated with level of MA intake.…”

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly

“…Herein, we extend to mice the handful of published studies describing the effects of subtoxic (herein, ≤2 mg/kg) MA treatment or MA self-administration upon glutamate-related biochemistry within the NAC of rats (8,9,11,19,43). Replicating earlier results (8,9,11), acute MA has little impact on extracellular glutamate within mouse NAC; however, its capacity to elevate NAC glutamate levels sensitizes with the passage of time in withdrawal for mice with repeated MA experience.…”

“…Most strikingly, the NAC hyper-glutamatergic profile of MA-naïve MAHDR mice resembles that observed within the NAC of rats (8) or mice withdrawn from subchronic MA exposure (see Table 1). As discussed below, the MA-injection regimen selected for this study produces both behavioral and neurochemical (7,19,20) sensitization in rodents. Thus, genetic vulnerability to high MA-taking is associated with a “pre-sensitized” glutamate state within the NAC.…”

“…To control individual drug experience that can confound data interpretation, we employed a non-contingent, repeated MA injection regimen (10 × 2 mg/kg, IP) that elicits behavioral and dopamine sensitization (7,19,20). The functional relevance of endogenous glutamate/Homer2 scaffolding within the NACs for the manifestation of MA-preference/aversion was determined using neuropharmacological approaches and a small hairpin RNA to knock-down Homer2b expression (shRNA-Homer2b).…”