The Role of Opioids within the Striatopallidal Circuitry in Relapse to Reward Seeking

Abstract

Endogenous opioids play an important role in regulating reinstatement of extinguished drug seeking. Ten experiments investigated the neuroanatomical locus for opioid regulation of renewal, alcohol-primed reinstatement, and re-acquisition of extinguished beer seeking response. Rats were trained to nose poke for alcoholic beer in a particular context. This response was extinguished in either an alternate context or in the same context. Recovery of responding was produced in one of three ways. In renewal, rats were returned to the acquisition context. In primed reinstatement, rats were allowed to consume a small amount of beer at the commencement of test. In reacquisition, rats were allowed to respond once more for alcoholic beer. Within each of these experiments three different challenges to opioid neurotransmission were applied: a systemic injection of the general opioid receptor antagonist, naloxone, an infusion of the µ-opioid receptor antagonist CTAP into the accumbens shell, or a similar infusion into the ventral pallidum. Systemic naloxone attenuated renewal, primed reinstatement, and reacquisition. Intra-pallidal infusions of CTAP also attenuated all three forms of relapse; however intra-accumbal infusions reduced context-induced reinstatement only. In order to characterise the role of the ventral pallidum in reinstatement, active projections to this region during renewal were examined. The retrograde neuronal tracer Cholera Toxin-b subunit was injected into the pallidum of rats prior to training and testing for renewal. Retrograde-labelled neurons and c-Fos protein immunoreactivity within the accumbens shell and elsewhere in the brain were examined. Active projections specific to renewal were not found in the accumbens shell, however they were seen in the accumbens core, rostral basolateral amygdala, and the paraventricular thalamus. These findings are consistent with the hypothesis that opioid receptors mediate the hedonic impact of ethanol and ethanol associated cues. While µ-opioid receptors in the accumbens shell play a more specific role in reinstatement for context, the ventral pallidum may represent a final common locus for production of ethanol-seeking responding. The pathways recruited during context-induced reinstatement support and extend the current understanding the role of the ventral pallidum in reinstatement, showing that it is a site of convergence of striatal, thalamic and amygdala inputs.