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Long-term (21 days) treatment with imipramine, clomipramine (tricyclic antidepressants) and clorgyline (monoamine-oxidase type A inhibiting antidepressant) produced significant decreases in plasma corticosterone levels in fawn-hooded (FH) rats. In contrast, plasma adrenocorticotropic hormone (ACTH) levels were not altered by chronic imipramine or clorgyline treatment but were significantly higher in chronic clomipramine-treated FH rats. These findings demonstrate a differential effect of chronic antidepressant treatment on plasma ACTH and corticosterone concentrations in FH rats and, furthermore, support the results of earlier studies suggesting that the FH rat strain may represent a genetic model of depression.

Signal-transducing G proteins are central to the coordination of receptor-effector communication. We have explored the effects of long-term fluoxetine administration of G alpha s, G alpha i1, G alpha i2, G alpha o, G alpha q and G alpha 12 mRNA expression in various rat brain regions using reverse transcriptase-polymerase chain reaction (RT-PCR)-mediated cross-species partial cDNA cloning. Northern blot analysis, and RNase protection assay techniques. Fluoxetine decreased G alpha s mRNA in midbrain, while mRNA expression of the novel G protein alpha subunits, G alpha q and G alpha 12, was increased in neostriatum and frontal cortex. We conclude that in addition to post-translational modification, regulation of G protein function by antidepressant drugs may occur at the level of gene expression.

Expression of the N-methyl-D-aspartate receptor gene during long-term administration of competitive and non-competitive NMDA antagonists was studied in rat brain using antisense cRNA transcribed from reverse transcriptase-polymerase chain reaction (RT-PCR)-generated rat NMDA receptor cDNA. Unlike non-competitive antagonists, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) markedly decreased NMDA receptor mRNA steady-state concentrations in frontal cortex and hippocampus. Our results are consistent with a regulation of the NMDA receptor at the level of gene expression.

The G protein subunits, Gs alpha, Gi alpha, and Go alpha, have been quantitated in various rat brain regions using enzyme-linked immunosorbent assay (ELISA) techniques. Chronic (3-week) treatment with carbamazepine decreased Gs alpha in several brain regions reaching significance in the neostriatum, while chronic lithium treatment had no unequivocal effect. Lithium significantly increased Gi alpha in the hypothalamus and hippocampus, whereas carbamazepine decreased Gi alpha in the frontal cortex. Both treatments had no consistent effects on Go alpha. We conclude that long-term treatment with lithium and carbamazepine exerts differential effects on G protein alpha subunits, and that this modification of signal transduction represents a potential mechanism of antibipolar drug-induced neural plasticity.

The effect of long-term (3-week) administration of various antidepressant drugs on the steady-state concentrations of G protein alpha subunits, Gs alpha, Gi alpha, and Go alpha, has been investigated in rat brain using an enzyme-linked immunosorbent assay. Tricyclic antidepressants and clorgyline decreased Gs alpha and, to a lesser extent, Gi alpha in several brain regions, while Go alpha was increased by tricyclics but not clorgyline. We conclude that long-term treatment with antidepressant drugs exerts differential effects on G protein alpha subunits, and that antidepressant efficacy may potentially be based on functional modifications of signal transduction.

Administration of 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT) to rats produced dose-dependent decreases in food intake and hypothermia, increases in plasma prolactin and corticosterone, and a decrease in plasma growth hormone. 8-OHDPAT administration also induced the serotonin behavioral syndrome at all doses. Pretreatment with metergoline did not affect the 8-OHDPAT-induced behavioral syndrome or decrease in food intake but attenuated the prolactin increase and, furthermore, potentiated 8-OHDPAT-induced hypothermia. Pretreatment with ritanserin or naloxone did not modify 8-OHDPAT-induced changes in food intake, temperature or prolactin. Similarly, pretreatment with phenoxybenzamine, propranolol, clonidine, haloperidol and methiothepin also did not attenuate 8-OHDPAT-induced decreases in food intake. Administration of pindolol alone produced hyperthermia, decreased food intake and enhanced prolactin secretion. Pindolol thus appears to act as a partial 5-HT agonist in addition to being an antagonist at central 5-HT receptors.

Intravenous administration of 8-hydroxy-2(di-n-propylamino) tetralin (8-OHDPAT) to rats produced increases in plasma prolactin and corticosterone concentrations. Long-term or short-term treatment with the MAO type A inhibiting antidepressant, clorgyline, or tricyclic antidepressants (imipramine and clomipramine), did not change baseline levels of either prolactin or corticosterone. Long-term but not short-term clorgyline treatment attenuated 8-OHDPAT's effect on plasma prolactin but not on corticosterone. On the other hand, long-term but not short-term treatment with clomipramine and to some extent imipramine also, accentuated 8-OHDPAT's effect on plasma prolactin but not on corticosterone. These findings demonstrate that long-term antidepressant treatment in rats produces a differential effect on 8-OHDPAT-induced increases in plasma prolactin and corticosterone, which is consistent with other clinical and animal studies demonstrating a differential effect of long-term antidepressant treatment on two different 5-HT-mediated neuroendocrine functions.

Intravenous administration of the 5-HT1B agonist, m-chlorophenylpiperazine (m-CPP) to rats produced increases in plasma prolactin (peak effect at 15 min), corticosterone (peak effect at 30 min) and a decrease in plasma growth hormone (peak effect at 15 min) concentrations. Short-term or long-term clorgyline treatment did not affect baseline levels of prolactin, corticosterone or growth hormone. Short-term clorgyline treatment attenuated m-CPP's effect on corticosterone but not on prolactin or growth hormone. On the other hand, long-term clorgyline treatment attenuated m-CPP's effect on prolactin but not on corticosterone or growth hormone. These findings are compatible with development of functional subsensitivity of 5-HT1B receptors mediating prolactin release following long-term clorgyline treatment. Attenuation of m-CPP's effect on corticosterone following short-term clorgyline treatment suggests either early adaptational changes in a 5-HT receptor subtype mediating corticosterone release, or clorgyline-induced increases in other neurotransmitters such as norepinephrine which may be responsible for attenuating m-CPP's effect on corticosterone.