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Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective κ‐opioid receptor agonist
Author(s) -
Heidbreder Christian A.,
Schenk Susan,
Partridge Brian,
Shippenberg Toni S.
Publication year - 1998
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(199811)30:3<255::aid-syn3>3.0.co;2-a
Subject(s) - agonist , nucleus accumbens , neurochemical , dopamine , opioid , opioid receptor , microdialysis , pharmacology , self administration , medicine , endocrinology , receptor
Previous data have shown that the repeated administration of κ‐opioid receptor agonists attenuates the acute behavioral effects of cocaine. The site and mechanism by which κ‐agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microdialysis study characterized the effects of prior, repeated administration of the selective κ‐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 × 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 × 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 κ‐opioid receptor agonist attenuates the locomotor‐activating 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 κ‐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. Synapse 30:255–262, 1998. © 1998 Wiley‐Liss, Inc.