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

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Abstract

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.

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Acknowledgements

Funded by the National Institute of Mental Health (MH63266, to WC), the National Institute on Drug Abuse (DA01533, to PSP), and an unrestricted gift from Johnson & Johnson (to W.C.). We are grateful to Cecile Beguin for comments on the manuscript.

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Correspondence to William A. Carlezon Jr.

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Todtenkopf, M.S., Marcus, J.F., Portoghese, P.S. et al. Effects of κ-opioid receptor ligands on intracranial self-stimulation in rats. Psychopharmacology 172, 463–470 (2004). https://doi.org/10.1007/s00213-003-1680-y

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  • DOI: https://doi.org/10.1007/s00213-003-1680-y

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