Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective κ-opioid receptor agonist
✍ Scribed by Christian A. Heidbreder; Susan Schenk; Brian Partridge; Toni S. Shippenberg
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 113 KB
- Volume
- 30
- Category
- Article
- ISSN
- 0887-4476
No coin nor oath required. For personal study only.
✦ Synopsis
Previous data have shown that the repeated administration of -opioid receptor agonists attenuates the acute behavioral effects of cocaine. The site and mechanism by which -agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microdialysis study characterized the effects of prior, repeated administration of the selective -opioid receptor agonist U69593 on basal and cocaine-evoked DA levels within the nucleus accumbens (NAC) and caudate putamen (CPU). The influence of U69593 treatment on the locomotor-activating effects of an acute cocaine challenge was also assessed. Rats received once daily injections of U69593 (0.16-0.32 mg/kg/day) or vehicle (1.0 ml/kg/day) for 3 days. The behavioral and neurochemical effects produced by an acute cocaine challenge (20 mg/kg i.p.) were assessed 2 days following treatment cessation. Administration of cocaine to control animals increased locomotor activity. This effect was attenuated in animals which had previously received U69593 (0.32 mg/kg/day ϫ 3 days). Prior administration of U69593 failed to modify basal DA levels in either the NAC or CPU. Thus, 2 days following the cessation of U69593 treatment, dialysate DA levels did not differ from that of controls. Administration of cocaine to vehicle-treated animals increased dialysate levels of DA in both brain regions. However, in animals previously exposed to U69593 (0.32 mg/kg/day ϫ 3 days), a significant enhancement in the response of DA neurons to cocaine was seen. These data demonstrate that prior, repeated administration of a selective -opioid receptor agonist attenuates the locomotoractivating effects of cocaine and increases cocaine-evoked DA overflow in terminal projection areas of mesostriatal and mesolimbic DA neurons. These findings indicate that the behavioral interactions of -agonists with cocaine observed in this and previous studies cannot be attributed to a presynaptic inhibition of DA release. Rather, they suggest that postsynaptic or non-DA mechanisms mediate the interaction of these agents with cocaine.