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Vol. 305, Issue 1, 323-330, April 2003
-Opioid Receptor Antagonists in
the Forced Swim Test in Rats
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.)
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 -antagonists: 5'-guanidinonaltrindole, which was
effective after i.c.v. but not systemic treatment, and
5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective
after systemic treatment. The behavioral effects of the -antagonists
resembled those of tricyclic antidepressants (desipramine) and
selective 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]-benzenacetamide (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 impact of lateral hypothalamic brain
stimulation at a dose with strong antidepressant-like effects. These
findings are consistent 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.
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