6-hydroxydopamine Lesion of the Mesolimbic Dopamine System Alters Morphine-Induced Conditioned Reinforcement

Background: Given that the rat mesocorticolimbic system contains dopamine neurons, and enkephalin receptors modulate the inhibitory input to these neurons (i.e., originating in ventral tegmental area) and its terminals in the striatum, the interaction between these systems imply functional overlap. Indeed, dopamine denervation in the striatum augments opioid receptor number and sensitivity as well as motor response to morphine administration. Further research is needed to understand how dopamine denervation impacts opioid-related reward behavior. Objective: The following study was conducted to investigate the effects of dopamine depletion in the nucleus accumbens on morphine-induced responding for conditioned reward. Method: Two weeks following 6-hydroxydopamine (6-OHDA) double-drop lesions of the mesolimbic dopamine system, apomorphine (0.1 mg/kg, i.p.) and amphetamine (1.5 mg/kg, i.p.) were administered directly into the nucleus accumbens and activity levels were monitored. Results: Apomorphine increased locomotion in lesioned rats, whereas amphetamine enhanced sham-lesioned activity. Lesioned rats and controls received intra-accumbens morphine (0.05, 0.5 and 2.5 μg/0.5 μl, i.c.) and were tested for total bar pressing for conditioned reward. Morphine infusion in intact rats did not alter bar pressing but in lesioned rats, intra-accumbens morphine did increase reward-related responding. Conclusion: Our findings indicate that 6-OHDA lesions of the NAc may lead to a shift in opiate involvement in conditioned reward. This shift suggests that opiate involvement in dopaminerelated behaviors may be differentially impacted by the integrity of the dopamine system. Results are discussed in terms of alterations in the opiate system following dopamine depletion, which may have implications for pharmacotherapies for psychiatric disorders such as substance use disorders, depression, and neurodegenerative disorders such as Lesch-Nyhan Syndrome.