Glycine Transporter-1 Inhibition Preceding Extinction Training Inhibits Reacquisition of Cocaine Seeking

Abstract

Cognitive enhancers that act by increasing glycine transmission might be useful adjuncts to cocaine-cue extinction training to deter relapse. The study investigated the effects of combining treatments of the glycine transporter-1 (GlyT-1) inhibitor, Org24598, with extinction training on the subsequent reacquisition of cocaine self-administration. Squirrel monkeys and rats were trained to selfadminister cocaine under a second-order schedule of intravenous drug injection in which responding was maintained by cocaine injections and a cocaine-paired visual stimulus. During three weekly extinction sessions, saline was substituted for cocaine but responding still produced the cocaine-paired stimulus. Subjects were treated with Org24598 or vehicle, either before or after each extinction session. One week later, cocaine injections were restored, and reacquisition of cocaine self-administration was evaluated over 15 sessions. Compared with vehicle, administration of Org24598 (1.0 mg/kg in monkeys; 3.0 or 7.5 mg/kg in rats) before each extinction session significantly inhibited reacquisition of cocaine self-administration in each species. In contrast, administration of Org24598 (1.0 mg/kg in monkeys) following, rather than preceding, each extinction session did not affect reacquisition compared with vehicle. When extinction training was replaced by cocaine self-administration or abstinence control conditions, treatment with the same doses of Org24598 resulted in reacquisition that was significantly more rapid than the reacquisition observed when Org24598 was administered before extinction training sessions. The results support the potential clinical utility of GlyT-1 inhibitor pretreatments combined with cocaine-cue extinction training to inhibit relapse.

Cocaine Experience Enhances Thalamo-Accumbens N-Methyl-D-Aspartate Receptor Function

“…The present data provide the first evidence for the involvement of these NAc NMDAR receptors in psychostimulant exposure, and we speculate that the incorporation of GluN2C subunits at mThal-D1(+) synapses may be a permissive step towards the development of pathological drug-seeking behaviors. One interesting caveat is that d-cycloserine acts as an NMDAR partial antagonist when extracellular glycine concentrations are elevated (51–53), raising the possibility that NAc glycinergic transmission may be involved in the actions of cocaine (54). Nonetheless, the convergent biophysical and pharmacological data presented here support a role for the GluN2C subunit in the pathophysiological effects of cocaine experience.…”

Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments

“…If the current findings are translational, substance-dependent individuals with ADHD may therefore uniquely benefit from cue-exposure therapy (Mitchell et al, 2014), which is most effective in individuals with initially high cue reactivity (Unrod et al, 2013). Research on animal models of pharmacotherapy-assisted cue-exposure therapy for enhancing extinction of cocaine-seeking behavior (e.g., Achat-Mendes et al, 2012) may therefore have relevance to ADHD treatment.…”

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

“…Based on previous reports (Achat-Mendes et al, 2012;Lido et al, 2012), Org 24598 (0.3, 1, and 3 mg/kg) was injected intraperitoneally with a volume of 5 ml/kg, 30 min before testing. d-amphetamine (1 mg/kg) was injected intraperitoneally with a volume of 5 ml/kg, 5 min before testing, based on evidence of improvement in probabilistic learning (Young, Khan and Powell; unpublished observations).…”