Vi. Chefer et al., Kappa-opioid receptor activation prevents alterations in mesocortical dopamine neurotransmission that occur during abstinence from cocaine, NEUROSCIENC, 101(3), 2000, pp. 619-627
In vivo microdialysis was used to characterize basal dopamine dynamics and
cocaine-evoked dopamine levels in the medial prefrontal cortex of male Spra
gue-Dawley rats that had previously received once daily injections of cocai
ne (days 1-5; 20 mg/kg, i.p.) in combination with the selective kappa-opioi
d receptor agonist U-69593 (days 3-5; 0.32 mg/kg, s.c.) or its vehicle. The
influence of these treatments on [H-3]dopamine uptake in medial prefrontal
cortex synaptosomes was also determined. Three days following the cessatio
n of drug treatment, animals with prior history of cocaine administration e
xhibited enhanced psychomotor stimulation in response to a subsequent cocai
ne challenge. This effect was not apparent in animals that had previously r
eceived the cocaine treatment regimen in combination with the kappa-opioid
receptor agonist U-69593. Cocaine challenge increased prefrontal dopamine l
evels in all pretreatment groups, but cocaine-pre-exposed animals had lower
cocaine-evoked dopamine levels and higher basal in vivo extraction fractio
n, indicative of an increase in basal dopamine uptake relative to controls.
Pretreatment with U-69593 prevented these effects of cocaine. Measurement
of [H-3]dopamine uptake in synaptosomes revealed a significant increase in
uptake three days after the cessation of cocaine treatment. No increase in
uptake was observed in animals that had received the cocaine treatment regi
men in combination with U-69593.
These results demonstrate that the early phase of abstinence from cocaine i
s associated with marked alterations in medial prefrontal cortex dopamine n
eurotransmission and that these neuroadaptations are prevented by the activ
ation of kappa-opioid receptors. Furthermore, they raise the possibility th
at mesocortical dopamine neurons may be an important neural substrate upon
which kappa-opioid agonists act to prevent the development of cocaine-induc
ed behavioral sensitization. (C) 2000 IBRO. Published by Elsevier Science L
td. All rights reserved.