Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

Abstract

Methamphetamine is a highly addictive psychomotor stimulant yet the neurobiological consequences of methamphetamine self-administration remain under-characterized. Thus, we employed microdialysis in rats trained to self-administer intravenous (IV) infusions of methamphetamine (METH-SA) or saline (SAL) and a group of rats receiving non-contingent IV infusions of methamphetamine (METH-NC) at 1 or 21 days withdrawal to determine the dopamine and glutamate responses in the nucleus accumbens (NAC) to a 2 mg/kg methamphetamine intraperitoneal challenge. Furthermore, basal NAC extracellular glutamate content was assessed employing no net-flux procedures in these three groups at both time points. At both 1-and 21-day withdrawal points, methamphetamine elicited a rise in extracellular dopamine in SAL animals and this effect was sensitized in METH-NC rats. However, METH-SA animals showed a much greater sensitized dopamine response to the drug challenge compared with the other groups. Additionally, acute methamphetamine decreased extracellular glutamate in both SAL and METH-NC animals at both time-points. In contrast, METH-SA rats exhibited a modest and delayed rise in glutamate at 1-day withdrawal and this rise was sensitized at 21 days withdrawal. Finally, no net-flux microdialysis revealed elevated basal glutamate and increased extraction fraction at both withdrawal time-points in METH-SA rats. Although METH-NC rats exhibited no change in the glutamate extraction fraction, they exhibited a time-dependent elevation in basal glutamate levels. These data illustrate for the first time that a history of methamphetamine self-administration produces enduring changes in NAC neurotransmission and that non-pharmacological factors have a critical role in the expression of these methamphetamine-induced neurochemical adaptations.

Dysregulation of Dopamine and Glutamate Release in the Prefrontal Cortex and Nucleus Accumbens Following Methamphetamine Self-Administration and During Reinstatement in Rats

“…The current findings not only show a similar meth-induced reduction in basal NAc GLU but also indicate that reduced basal cortical GLU levels likely contribute to the maladaptive balance in synaptic and extrasynaptic extracellular GLU activity in the corticostriatal pathway. Interestingly, a recent finding by Lominac et al (2012) reported that rats with a similar 2 h/day meth self-administration history followed by withdrawal showed an increase in basal NAc GLU levels. Notably, they measured GLU efflux following simple withdrawal at 1 day and 3 weeks, not after daily extinction sessions.…”

Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats

“…Escalating meth self-administration increased basal levels of extra synaptic glutamate in the NAcore following 1–3 weeks of forced abstinence (Lominac et al, 2012). In contrast, basal levels of extracellular glutamate in the NAcore were reduced in meth self-administration animals that have also undergone extinction of the lever response (Parsegian and See, 2014), and presentation of meth-paired cues during reinstatement increased NAcore glutamate (Parsegian and See, 2014).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…In noncontingently dosed rats the challenge decreased extracellular glutamate levels in the NAc, whereas in previously self-administering rats, an increase in glutamate levels was observed. This increase was also associated with a larger increase in DA levels (Lominac et al, 2012). Another study found reduced basal glutamate levels in both the NAc and PFC, but increased glutamate levels after reinstatement in self-administering rats compared with yoked saline controls (Parsegian and See, 2014).…”