Effect of the endogenous kappa opioid agonist dynorphin A(1-17) on cocaine-evoked increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice.

Rationale: Effects of synthetic kappa opioid receptor agonists on cocaine-induced reward have been studied extensively in rats but relatively few studies have used the endogenous kappa agonist dynorphin A(1-17).

Objectives: Three studies were conducted to examine the effect of the natural sequence dynorphin on cocaine-induced increases in dopamine, on the formation of conditioned place preference and on increases in locomotor activity in C57BL/6 J mice.

Methods: After implantation of guide cannulae into the caudate putamen, mice were allowed 4-5 days to recover from surgery. In the first study, dynorphin A (0, 1, 2, 4.4 nmol) was infused into the caudate putamen and dopamine levels were measured by in vivo microdialysis in that brain region. Then, the effect of dynorphin A (4.4 nmol) on increases in dopamine levels induced by 15 mg/kg cocaine i.p. was also measured with in vivo microdialysis. The third experiment examined the effect of dynorphin A (4.4 nmol) on conditioned place preference and locomotion induced by 15 mg/kg cocaine.

Results: Dynorphin A significantly decreased basal dopamine levels in a dose-dependent manner by more than 60% at the highest dose, and this effect was completely blocked by pre-injection of the kappa-opioid receptor antagonist nor-BNI (10 mg/kg). The highest dose of dynorphin (4.4 nmol) blocked increases in dopamine levels, the formation of conditioned place preference and attenuated locomotion induced by 15 mg/kg cocaine.

Conclusion: The blockade of the cocaine-induced rise in striatal dopamine may contribute to both dynorphin's ability to prevent the development of cocaine-induced conditioned place preference and to attenuate the increase in locomotor activity.