Neuronal Mechanisms Mediating Acute Food Deprivation-Induced Reinstatement of Heroin Seeking

One of the most troubling aspects of addiction is the chronic and cyclical nature of this disorder. In particular, the desire to use drugs and subsequent relapse can occur after months or even years of absence. Amongst human drug abusers, exposure to stressful life events and style of stress-coping have been shown to predict relapse. Similarly, in rodents stress can induce the reinstatement of drug seeking, a model of stress-induced relapse. In the following series of experiments the neuronal mechanisms mediating acute 21-48h food deprivation (FD)-induced reinstatement of heroin seeking are investigated. Previously, our laboratory has demonstrated that this form of reinstatement can be attenuated by systemic injection of the dopamine (DA) D1 receptor antagonist SCH 23390. Thus, in chapter 1, the neuronal circuitry mediating the role of DA, acting at the D1 receptor, in acute FD-induced reinstatement was examined. The five experiments described in the chapter reveal a significant attenuation of heroin seeking in rats infused with SCH 23390 into the nucleus accumbens (NAc) shell, dorsal medial prefrontal cortex (dmPFC) or basolateral amygdala (BLA). However, acute FD-induced reinstatement was not affected by infusions of SCH 23390 into the NAc core, or ventral medial prefrontal cortex (vmPFC). Compulsive drug seeking and the propensity to relapse have been attributed to pathological synaptic plasticity, resulting from drug-induced changes in glutamate synapses. Thus, in chapters 2 and 3 the role of glutamate in acute FD-induced reinstatement was inspected. In chapter 2, neuroadaptations in the glutamatergic projection from the ventral subiculum (vSub) of the hippocampus to the NAc shell were investigated. The vSub to NAc shell pathway is an important excitatory input, providing spatial and affective information that is modulated by DA release within the NAc. Here, acute 48h FD was shown to block the induction of long-term potentiation (LTP) in both heroin-trained and heroin-naive rats. In chapter 3, changes in the expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptor subunits were investigated in rats trained to self-administer heroin and subsequently tested for acute FD-induced reinstatement of drug seeking. The results of this study reveled a tendency toward a reduction in GluA2 and NR1 expression in the dmPFC and NAc, respectively, of heroin-trained food deprived rats, compared to heroin-trained sated rats, as well as a significant increase in GluA2 expression in the VTA of heroin-trained-sated rats compared to drug-naive sated rats. Finally, FD increased GluA2 expression, in the BLA, in drug-naive but not heroin-trained rats. Together, these findings demonstrate an important role for both DA and glutamate in acute FD-induced reinstatement. The current results support existing models that suggest a critical role for DA and glutamate transmission, and the interaction between the two systems, in the reinstatement of drug seeking.