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The effects of kappa-opioid agonist treatment on kappa-opioid receptor density and on dynorphin A levels in the rat brain were studied. Rats were treated with the selective kappa-opioid agonist U-69593 or vehicle for 5 d. Dynorphin A levels and kappa-opioid receptor binding were measured on day 8 (3 d after the last injection) or 22 (17 d after the last injection). On day 8, kappa-opioid receptor density was increased in the hypothalamus of rats treated with U-69593; there were no changes in the frontal cortex or caudate putamen. In contrast, there was an increase in dynorphin A levels in the frontal cortex and no changes in hypothalamus and caudate putamen in response to U-69593. On day 22, Bmax was decreased in frontal cortex and caudate putamen of U-69593-treated rats, whereas dynorphin A levels were increased in the caudate putamen and in the frontal cortex. These findings suggest that kappa-opioid receptor agonist treatment has long-term, continually changing effects on the kappa-opioid system.

The effect of the selective serotonin uptake inhibitor fluoxetine was examined on prodynorphin gene expression. Fluoxetine or vehicle was infused continuously for 7 d via osmotic minipumps into male rats. Northern blot analysis showed significant increases in prodynorphin gene expression in the hypothalamus (171% of controls) and significant decreases in the caudate putamen and nucleus accumbens (62% and 70% of controls, respectively). There were no significant changes in the hippocampus. Thus, chronic inhibition of serotonin uptake can regulate prodynorphin gene expression in the hypothalamus, caudate putamen, and nucleus accumbens. Fluoxetine effects were also evaluated in rats treated with p-chloroamphetamine (PCA), a neurotoxin that depletes serotonin. Because we previously reported that continuous infusion of cocaine for 7 d (which inhibits dopamine, serotonin, and norepinephrine uptake), or GBR 12909 (a selective dopamine uptake inhibitor), produced significant decreases in the hypothalamus and cocaine also produced a significant increase in prodynorphin gene expression in caudate putamen, regulation of prodynorphin gene expression by fluoxetine is suggested to be different from that by cocaine. Because neither a selective dopamine uptake inhibitor nor a selective serotonin uptake inhibitor produced the same effect as cocaine in the caudate putamen, this effect is likely regulated by the inhibition of norepinephrine uptake, by a combination of effects on two or three neurotransmitter transporters, or by a mechanism unrelated to transporter inhibition.

The effects of K-opioid agonist treatment on prodynorphin mRNA expression in the rat brain were studied. Rats were treated with the selective kappa-opioid agonist U-69593 or vehicle for 5 days and prodynorphin mRNA was measured on day 8 (3 days after the last injection) or 22 (17 days after the last injection). On day 8 prodynorphin mRNA was increased in the hypothalamus and decreased in the striatum, frontal cortex, and hippocampus of rats treated with U-69593. On day 22, prodynorphin mRNA was increased in the hypothalamus, frontal cortex and striatum of U-69593 treated rats. These findings suggests that kappa-opioid receptor agonist treatment has long-term, continually changing effects on prodynorphin mRNA expression.