Reduced glutamate immunolabeling in the nucleus accumbens following extended withdrawal from self-administered cocaine

Abstract

Alterations in the density of GABA and glutamate immunolabeling within nerve terminals in the shell region of the nucleus accumbens were assessed in rats withdrawn from intravenous cocaine exposure. Four groups of rats were used: one group self-administered cocaine (0.42 mg/kg/infusion) in daily 3-h sessions for approximately 2 weeks, two additional groups received either saline or cocaine in a noncontingent fashion, and a fourth comprised a drug-naive, age-matched control group. Immunogold electron microscopy was used to quantify presynaptic terminal GABA and glutamate density within the vesicular and mitochondrial pools approximately 18 days following the last drug or saline exposure in the treatment groups. A significant 27.7% decrease in vesicular glutamate density within asymmetrical nerve terminals was observed in animals that self-administered cocaine as compared to controls. This group also showed an 18.6% decrease in vesicular nerve terminal glutamate immunolabeling as compared to animals that were administered a similar total dose of cocaine in a response-independent fashion. No significant changes in the density of nerve terminal GABA vesicular immunolabeling were observed in any groups. For both transmitters, no differences were detected in the density of immunolabeling within the presynaptic mitochondrial (i.e., metabolic) pool. These results demonstrate that glutamate density is suppressed in the shell region of the nucleus accumbens following withdrawal from 2 weeks of cocaine exposure. The findings also suggest that the motivational aspects that accompany self-administration may participate in this reduction.

Psychomotor Stimulant Addiction: A Neural Systems Perspective

“…Furthermore, the magnitude of LTD was reduced by repeated cocaine treatment, suggesting that long-lasting depression of excitatory synaptic transmission shares expression mechanisms with LTD . Presynaptic mechanisms may also be involved, because repeated cocaine administration decreases glutamate immunolabeling in nerve terminals of the NAc shell , an effect that appears more persistent when cocaine is selfadministered (Keys et al, 1998). These findings are in accord with others suggesting that the NAc is more quiescent after long-term withdrawal from repeated stimulant administration, perhaps reflecting a combination of depressed excitatory transmission Bibb et al, 2001;, decreased AMPA receptor subunit expression (Lu and Wolf, 1999), and changes in voltage-dependent conductances (Zhang et al, 1998).…”

Acamprosate attenuates cocaine- and cue-induced reinstatement of cocaine-seeking behavior in rats

“…Basal extracellular glutamate levels are reduced during longterm withdrawal from repeated cocaine exposure, but cocaine-stimulated glutamate release is significantly elevated above that of acutely treated subjects in the nucleus accumbens (NAc) core (Bell et al 2000;Hotsenpiller et al 2001;Kalivas et al 2003;Keys et al 1998). This dichotomy in ventral forebrain glutamate transmission appears to be a critical mediator of relapse to cocaine seeking, as restoration of basal extracellular glutamate levels prevents cocaineprimed reinstatement of cocaine seeking by inhibiting additional cocaine-induced glutamate release Moran et al 2005).…”

The principles of agonist pharmacotherapy for psychostimulant dependence

“…Dysregulation of glutamate transmission in several structures of the brain in the mesolimbic system has been proposed as an important neurobiological feature of psychostimulant dependence [86 -90]. Glutamate depletion has been associated with repeated cocaine administration [89,91]. Subsequent pharmacological restoration of cocaine treatment-depleted glutamate levels prevented cocaine-primed drug-seeking in rats [89].…”