Sex differences in the effects of a combined behavioral and pharmacological treatment strategy for cocaine relapse prevention in an animal model of cue exposure therapy.

Brief interventions of environmental enrichment (EE) or the glycine transporter-1 inhibitor Org24598 administered with cocaine-cue extinction training were shown previously to inhibit reacquisition of cocaine self-administration in male rats trained to self-administer a moderate 0.3 mg/kg dose of cocaine. Determining how EE and Org24598 synergize in combination in an animal model of cue exposure therapy is novel. Important changes made in this investigation were increasing the cocaine training dose to 1.0 mg/kg and determining sex differences. Adult male and female rats self-administering 1.0 mg/kg cocaine for 35-40 daily sessions exhibited an addiction-like phenotype under a second-order schedule of cocaine delivery and cue presentation. Rats next underwent 6 weekly extinction training sessions for which treatments consisted of EE or NoEE and Vehicle or Org24598 (3.0 mg/kg in males; 3.0 or 7.5 mg/kg in females). Rats then were tested for reacquisition of cocaine self-administration for 15 daily sessions. In males, the combined EE +3.0 mg/kg Org24598 treatment facilitated extinction learning and inhibited reacquisition of cocaine self-administration to a greater extent than no treatment and to individual EE or 3.0 mg/kg Org24598 treatments. In females, EE +7.5 mg/kg Org24598 facilitated extinction learning, but did not inhibit reacquisition of cocaine self-administration. Thus, there were sex differences in the ability of EE + Org24598 administered in conjunction with extinction training to inhibit cocaine relapse in rats exhibiting an addiction-like phenotype. These findings suggest that this multimodal treatment approach might be a feasible option during cue exposure therapy in cocaine-dependent men, but not women.

Facilitative effects of environmental enrichment for cocaine relapse prevention are dependent on extinction training context and involve increased TrkB signaling in dorsal hippocampus and ventromedial prefrontal cortex.

Cocaine-cue extinction training combined with brief interventions of environmental enrichment (EE) was shown previously to facilitate extinction and attenuate reacquisition of cocaine self-administration in rats. It is unknown whether or not the usefulness of this approach would be undermined if extinction training took place in a novel rather than familiar context. Drawing on previous studies involving pharmacological interventions, we hypothesized that the facilitative effects of EE for cocaine relapse prevention would be independent of the context used for extinction training. Rats trained to self-administer cocaine underwent cocaine-cue extinction training in either the familiar self-administration context or a novel context, with or without EE. Rats then were tested for reacquisition of cocaine self-administration in the familiar context. Target brain regions were lysed and probed for memory-related changes in receptors for glutamate and BDNF by western blotting. Contrary to our hypothesis, the facilitative effects of EE for cocaine relapse prevention were dependent on the context used for extinction training. While EE facilitated extinction regardless of context used, it inhibited cocaine relapse only after extinction training in the familiar context. EE was associated with increased GluA2 in nucleus accumbens, TrkB in dorsal hippocampus and activated TrkB in ventromedial prefrontal cortex. Of these, the changes in dorsal hippocampus and ventromedial prefrontal cortex mirrored outcomes of the cocaine relapse tests in that these changes were specific to rats receiving EE plus extinction training in the familiar context. These findings support a role for hippocampal-prefrontal BDNF-TrkB signaling in extinction-based relapse prevention strategies involving EE.

Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation.

This study investigated the combination of environmental enrichment (EE) with cocaine-cue extinction training on reacquisition of cocaine self-administration. Rats were trained under a second-order schedule for which responses were maintained by cocaine injections and cocaine-paired stimuli. During three weekly extinction sessions, saline was substituted for cocaine but cocaine-paired stimuli were presented. Rats received 4-h periods of EE at strategic time points during extinction training, or received NoEE. Additional control rats received EE or NoEE without extinction training. One week later, reacquisition of cocaine self-administration was evaluated for 15 sessions, and then GluA1 expression, a cellular substrate for learning and memory, was measured in selected brain regions. EE provided both 24 h before and immediately after extinction training facilitated extinction learning and deterred reacquisition of cocaine self-administration for up to 13 sessions. Each intervention by itself (EE alone or extinction alone) was ineffective, as was EE scheduled at individual time points (EE 4 h or 24 h before, or EE immediately or 6 h after, each extinction training session). Under these conditions, rats rapidly reacquired baseline rates of cocaine self-administration. Cocaine self-administration alone decreased total GluA1 and/or pSer845GluA1 expression in basolateral amygdala and nucleus accumbens. Extinction training, with or without EE, opposed these changes and also increased total GluA1 in ventromedial prefrontal cortex and dorsal hippocampus. EE alone increased pSer845GluA1 and EE combined with extinction training decreased pSer845GluA1 in ventromedial prefrontal cortex. EE might be a useful adjunct to extinction therapy by enabling neuroplasticity that deters relapse to cocaine self-administration.

Effects of dopamine D1 receptor blockade in the prelimbic prefrontal cortex or lateral dorsal striatum on frontostriatal function in Wistar and Spontaneously Hypertensive Rats.

Attention Deficit Hyperactivity Disorder (ADHD) is associated with dysfunctional prefrontal and striatal circuitry and dysregulated dopamine neurotransmission. Spontaneously Hypertensive Rats (SHR), a heuristically useful animal model of ADHD, were evaluated against normotensive Wistar (WIS) controls to determine whether dopamine D1 receptor blockade of either prelimbic prefrontal cortex (plPFC) or lateral dorsal striatum (lDST) altered learning functions of both interconnected sites. A strategy set shifting task measured plPFC function (behavioral flexibility/executive function) and a reward devaluation task measured lDST function (habitual responding). Prior to tests, rats received bilateral infusions of SCH 23390 (1.0 µg/side) or vehicle into plPFC or lDST. Following vehicle, SHR exhibited longer lever press reaction times, more trial omissions, and fewer completed trials during the set shift test compared to WIS, indicating slower decision-making and attentional/motivational impairment in SHR. After reward devaluation, vehicle-treated SHR responded less than WIS, indicating relatively less habitual responding in SHR. After SCH 23390 infusions into plPFC, WIS expressed the same behavioral phenotype as vehicle-treated SHR during set shift and reward devaluation tests. In SHR, SCH 23390 infusions into plPFC exacerbated behavioral deficits in the set shift test and maintained the lower rate of responding in the reward devaluation test. SCH 23390 infusions into lDST did not modify set shifting in either strain, but produced lower rates of responding than vehicle infusions after reward devaluation in WIS. This research provides pharmacological evidence for unidirectional interactions between prefrontal and striatal brain regions, which has implications for the neurological basis of ADHD and its treatment.