Effects of κ-opioid receptor ligands on intracranial self-stimulation in rats

Rationale: Elevations in cAMP response element binding protein (CREB) function within the mesolimbic system of rats reduce cocaine reward in place conditioning studies and increase immobility in the forced swim test. Each of these behavioral adaptations can be interpreted as a depressive-like effect (i.e., anhedonia, despair) that may reflect reduced activity of brain reward systems. Furthermore, each effect appears due to increases in CREB-mediated expression of dynorphin, since each is attenuated by intracranial injections of the κ-opioid receptor antagonist norBNI. Objectives: Intracranial self-stimulation (ICSS) studies were conducted in rats to determine whether administration of a κ-agonist would have depressive-like effects on brain stimulation reward, and whether pretreatment with a κ-antagonist would attenuate any such effects. Conditions that have depressive effects in people (e.g., drug withdrawal) increase the threshold amounts of stimulation required to sustain ICSS in rats. Methods: Sprague-Dawley rats with lateral hypothalamic stimulating electrodes were tested in a "curve-shift" variant of the ICSS procedure after systemic administration of the κ-agonist U-69593 alone, the novel κ-antagonist 5′-acetamidinoethylnaltrindole (ANTI) alone, or co-administration of both drugs. Results: U-69593 dose dependently increased ICSS thresholds, suggesting that activation of κ-receptors reduced the rewarding impact of the brain stimulation. ANTI had no effects on its own, but it attenuated increases in ICSS thresholds caused by the agonist. Conclusions: These data provide further evidence that stimulation of brain κ-receptors may trigger certain depressive-like signs, and that κ antagonists may have efficacy as antidepressants without having reward-related actions of their own.