Effects of kappa-opioid receptor agonists on long-term cocaine use and dopamine neurotransmission

kappa -Opioid receptor agonists have been suggested as treatments for cocai ne addiction based on studies showing that they block cocaine-related behav iors. To determine the effects Of kappa -opioid receptor agonists on long-t erm behavioral effects associated with cocaine and the neurochemical bases underlying these effects, rats were treated with the selective kappa -opioi d receptor agonist U-69593 ((+)(5 alpha ,7 alpha ,8 beta)-N-methyl-N-[7-(1- pyrrolidinyl)-1 oxaspiro[4.5]dec-8-yl]-benzeneacetamide) alone or in combin ation with cocaine and locomotor activity was measured daily. In addition, dopamine transporter and dopamine receptor densities were measured using au toradiographic techniques, and tyrosine hydroxylase was measured using immu noautoradiographic techniques. Treatment with U-69593 with or without cocai ne decreased locomotor activity. When challenged with cocaine after a 5-day treatment period, the effects of cocaine were markedly reduced in rats ini tially treated with U-69593 compared to vehicle. When U-69593 was administe red five times with 3-day intervals, it alone had no effect on locomotor ac tivity but still reduced activity associated with a cocaine injection. Afte r five daily injections, U-69593 decreased dopamine transporter and dopamin e D-2 receptor densities and increased tyrosine hydroxylase levels. These c hanges were not seen after the 3-day interval regimen, even though cocaine- induced activity was greatly reduced. These findings show that the effects associated with daily U-69593 treatment are attenuated if the drug is admin istered with a greater interval, while maintaining a blockade of cocaine-in duced activity. In addition, U-69593 can block cocaine-induced locomotor ef fects without major perturbation of the dopamine system. (C) 2001 Elsevier Science B.V. All rights reserved.