Antidepressant-Like Effects of -Opioid Receptor Antagonists in the Forced Swim Test in Rats STEPHEN D. MAGUE, ANDREA M. PLIAKAS, MARK S. TODTENKOPF, HILARIE C. TOMASIEWICZ, YAN ZHANG, WILLIAM C. STEVENS JR., ROBERT M. JONES, PHILIP S. PORTOGHESE, and WILLIAM A. CARLEZON JR. Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts (S.D.M., A.M.P., M.S.T., H.C.T., W.A.C.); and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota (Y.Z., W.C.S., R.M.J., P.S.P.) Received November 1, 2002; accepted January 3, 2003 ABSTRACT We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at -opioid receptors) in NAc neurons, these findings raised the possibility that -receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the -antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at -receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar -an- tagonists: 5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5'-acetamidinoethylnal- trindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the -antagonists resem- bled those of tricyclic antidepressants (desipramine) and selec- tive serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the -agonist [5,7,8]-N- methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenac- etamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the -ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective -antagonist (ANTI) did not affect the rewarding im- pact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consis- tent with the hypothesis that CREB-mediated induction of dynorphin in the NAc “triggers” immobility behavior in the FST. Furthermore, they raise the possibility that -antagonists may have efficacy as antidepressants, but lack stimulant or reward- related effects. The neurobiology of depression is not understood. Because most antidepressants with clinical efficacy act upon mono- amines [primarily norepinephrine (NE) and serotonin (5HT)], much research on depression has focused upon inter- actions between these neurotransmitters and their reuptake transporters and receptor proteins. However, recent research has become progressively focused upon the intracellular mechanisms of depression and antidepressant treatments (Manji et al., 2001; Duman, 2002; Nestler et al., 2002), with the goal of developing novel therapeutics that act faster, are more efficacious, and have fewer side effects. This approach has led to the study of brain circuits typically associated with reward-related processes, including the mesolimbic dopa- mine (DA) system (Pliakas et al., 2001; Newton et al., 2002). The mesolimbic DA system projects from the ventral teg- mental area of the midbrain to the nucleus accumbens (NAc) of the basal forebrain, and is modulated directly and indi- rectly by noradrenergic and serotonergic inputs (Pasquier et al., 1977). This circuitry contributes importantly to the he- donic (rewarding) effects of food, sexual behavior, and addic- tive drugs (Carlezon and Wise, 1996b; Kreek and Koob, 1998; Wise, 1998). It has been proposed that disruption of DA function within the NAc causes anhedonia (reduced ability to experience reward) (Wise, 1982), a hallmark symptom of depression. Consistent with this notion, withdrawal from chronic amphetamine in rats causes decreases in extracellu- lar concentrations of DA within the NAc that are accompa- This study was funded by Grant MH63266 from the National Institute of Mental Health (to W.C.), Grant DA01533 from the National Institute on Drug Abuse (to P.S.P.), an unrestricted gift from Johnson and Johnson (to W.C.), and donations by John A. Kaneb (to W.C.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.046433. ABBREVIATIONS: NE, norepinephrine; 5HT, 5-hydroxytryptamine; DA, dopamine; NAc, nucleus accumbens; CREB, cAMP response element- binding protein; FST, forced swim test; norBNI, nor-binaltorphimine; GNTI, 5'-guanidinonaltrindole; ANTI, 5'-acetamidinoethylnaltrindole; U-69593, (5,7,8)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl)-benzenacetamide; ICSS, intracranial self-stimulation; DMI, desipra- mine; FLX, fluoxetine; COC, cocaine; CIT, citalopram; SSRI, selective serotonin reuptake inhibitor; ANOVA, analysis of variance; LSD, least significant difference. 0022-3565/03/3051-323–330$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 305, No. 1 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 46433/1052156 JPET 305:323–330, 2003 Printed in U.S.A. 323 at ASPET Journals on March 19, 2016 jpet.aspetjournals.org Downloaded from