Differential effect of clomipramine treatment on m-chlorophenylpiperazine-induced increases in plasma prolactin and corticosterone in rats

Intravenous administration of m-chlorophenylpiperazine (m-CPP, a serotonin agonist) to rats increased plasma prolactin and corticosterone concentrations. Long-term (21-day) and short-term (3-day) treatment with the tricyclic antidepressant, clomipramine, did not have any significant effect on baseline levels of either prolactin or corticosterone. Long-term but not short-term clomipramine treatment significantly potentiated m-CPP's effect on plasma prolactin. On the other hand, both long-term and short-term clomipramine treatment significantly attenuated m-CPP's effect on plasma corticosterone. These findings are consistent with other animal and clinical studies demonstrating a differential effect of antidepressant treatment on two different serotonin-mediated neuroendocrine functions.     

Differential effects of antidepressant treatments on fenfluramine-induced increases in plasma prolactin and corticosterone in rats

Intravenous administration of 5-HT releasing agent, fenfluramine, to rats produced increases in plasma prolactin and corticosterone concentrations. Short-term or long-term treatment with either clorgyline or imipramine did not affect baseline levels of prolactin or corticosterone. On the other hand, short-term but not long-term lithium treatment significantly increased baseline levels of corticosterone but not of prolactin. Short-term treatment with lithium but not clorgyline or imipramine potentiated fenfluramine-induced increases in plasma prolactin but not corticosterone. On the other hand, long-term treatment with clorgyline but not imipramine or lithium attenuated fenfluramine's effect on plasma prolactin but not on corticosterone. These findings demonstrate differential effects of antidepressant treatments on fenfluramine-induced increases in plasma prolactin and corticosterone in rats and are consistent with several other clinical and animal studies demonstrating dissimilar actions of different antidepressant treatments on two different 5-HT-mediated neuroendocrine functions.     

Differential effects of long-term antidepressant treatments on 8-OHDPAT-induced increases in plasma prolactin and corticosterone in rats

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.     

Basic biology of clozapine: electrophysiological and neuroendocrinological studies

The effects of clozapine and other purported atypical antipsychotics were compared with those of typical antipsychotics within the neuroendocrine axis of the rat. Atypical antipsychotics (e.g., clozapine, thioridazine, melperone, setoperone and RMI 81582) differed from typical antipsychotics (e.g., haloperidol, chlorpromazine, cis-flupentixol and fluphenazine) in that they produced only a brief elevation in serum concentrations of prolactin but marked increases in serum or plasma concentrations of corticosterone and ACTH. Moreover, atypical antipsychotics, but not typical antipsychotics, acutely increased the activity of tuberoinfundibular dopamine neurons, as judged from the accumulation of DOPA in the median eminence after inhibition of decarboxylase activity. The effects of atypical antipsychotics on tuberoinfundibular dopamine neurons and corticosterone secretion were mimicked by neurotensin. It would appear that atypical antipsychotics elicit unique neuroendocrine responses that differentiate these agents from typical antipsychotic drugs.     

Selective cortical VGLUT1 increase as a marker for antidepressant activity

The two recently characterized vesicular glutamate transporters (VGLUT) presynaptically mark and differentiate two distinct excitatory neuronal populations and thus define a cortical and a subcortical glutamatergic system (VGLUT1 and VGLUT2 positive, respectively). These two systems might be differentially implicated in brain neuropathology. Still, little is known on the modalities of VGLUT1 and VGLUT2 regulations in response to pharmacological or physiological stimuli. Given the importance of cortical neuronal activity in psychosis we investigated VGLUT1 mRNA and protein expression in response to chronic treatment with commonly prescribed psychotropic medications. We show that agents with antidepressant activity, namely the antidepressants fluoxetine and desipramine, the atypical antipsychotic clozapine, and the mood stabilizer lithium increased VGLUT1 mRNA expression in neurons of the cerebral cortex and the hippocampus and in concert enhanced VGLUT1 protein expression in their projection fields. In contrast the typical antipsychotic haloperidol, the cognitive enhancers memantine and tacrine, and the anxiolytic diazepam were without effect. We suggest that VGLUT1 could be a useful marker for antidepressant activity. Furthermore, adaptive changes in VGLUT1 positive neurons could constitute a common functional endpoint for structurally unrelated antidepressants, representing promising antidepressant targets in tracking specificity, mechanism, and onset at action.     

Sedation, an unpleasant, undesirable and potentially dangerous side-effect of many psychotropic drugs

Sedation is a property of many psychotropic drugs. It can be defined as a decrease in psychomotor and cognitive performance. Many of the earlier neuroleptic, anxiolytic, antidepressant and antihistamine drugs were extremely sedative and sedation came to be considered as an integral part of the activity of these compounds. Newer, far less sedative, examples of each of these classes have shown that sedation is not required for their efficacy. Sedation is now increasingly considered as an adverse effect which should be avoided rather than a desirable effect especially when treating disorders such as anxiety or depression. This article discusses the sedative properties and mechanisms of different classes of psychotropic drugs.     

Effect of amperozide on the dopamine synthesis activity in the tuberoinfundibular neurons

The ability of amperozide (N-ethyl-4-[4,4-bis(p-fluorophenyl)butyl]-1-piperazinecarboxamide) , a potentially antipsychotic agent, to activate the tuberoinfundibular dopamine (TIDA) neurons was studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after inhibition of DOPA decarboxylase. The activity of the TIDA neurons was markedly elevated in a dose-related manner after treatment with amperozide (1 and 10 mg/kg). A significant stimulation was also found following treatment with the atypical antipsychotic agent clozapine (20 mg/kg) while the typical antipsychotic drug haloperiodol had no effect on TIDA neuron activity. The stimulatory effect of amperiozide on the TIDA neurons is suggested to be mediated by a non-dopaminergic mechanism.     

Effect of the anxiolytic drug buspirone on prolactin and corticosterone secretion in stressed and unstressed rats

Buspirone is an atypical anxiolytic drug that exerts its action at a receptor site other than the GABA-benzodiazepine-chloride ionophore complex. The present study examined the effect of buspirone on plasma prolactin and corticosterone levels in both control and stressed rats. In unstressed rats, buspirone produced dose-dependent increases in plasma prolactin and corticosterone levels. The minimal doses of buspirone which led to significant elevations in plasma prolactin and corticosterone levels were 1.0 and 2.0 mg/kg (IP), respectively. The effect of buspirone on both hormones was maximal 30 minutes after injection. The plasma levels of prolactin and corticosterone were significantly elevated in rats that were stressed using a conditioned fear paradigm. Buspirone produced a dose-dependent attenuation of the stress-induced increase in prolactin secretion. The stress-induced increase in corticosterone secretion was inhibited by the 0.5 mg/kg (IP) dose but not by the 2.0 mg/kg (IP) dose of buspirone, which increased corticosterone secretion both in stressed and unstressed rats. These data suggest that the effect of buspirone on plasma prolactin and corticosterone levels may be mediated by two different mechanisms of action.     

Further characterization of the predictive validity of the Brattleboro rat model for antipsychotic efficacy

Our laboratory and others have reported that Brattleboro (BRAT) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in prepulse inhibition (PPI) homologous to those observed in schizophrenia patients and that these deficits are reversed by antipsychotic drugs (APDs). To further evaluate the potential predictive validity of BRAT rat PPI for APDs, we compared the effects of acute subcutaneous administration of the typical APD chlorpromazine to that of three psychotropic drugs without antipsychotic efficacy, the antidepressant imipramine, the anxiolytic diazepam and the anticonvulsant mood stabilizer valproic acid on male and female BRAT rat PPI. Male and female BRAT rats exhibited baseline (saline treatment) PPI that was not different from each other (21.1% and 21.3%, respectively) and low compared with those historically exhibited by LE rats (approximately 59%). Chlorpromazine facilitated PPI in male and female BRAT rats, whereas imipramine, diazepam, and valproic acid had no significant effect on PPI. These results suggest that PPI in the BRAT rat responds specifically to drugs with APD efficacy but not psychotropic drugs of different therapeutic families.     

Prevention of the stress-induced increase in frontal cortical dopamine efflux of freely moving rats by long-term treatment with antidepressant drugs.

Use of antidepressant drugs in the treatment of anxiety disorders has recently increased due to the anxiolytic effect of some of these agents. Because dopaminergic transmission in the prefrontal cortex is sensitive to anxiogenic or stressful stimuli, the effects of two antidepressant drugs with different mechanisms of action, imipramine and mirtazapine, on the response of rat cortical dopaminergic neurons to stress were investigated. A 2-week (but not single dose) administration of imipramine (10 mg/kg, i.p., twice daily) or mirtazapine (10 mg/kg, i.p., once daily) reduced and completely antagonized, respectively, the increase in dopamine release in the prefrontal cortex elicited by footshock stress. Long-term administration of imipramine or mirtazapine had no marked effect on the stress-induced increases in the brain or plasma concentrations of neuroactive steroids or corticosterone. An attenuation of the response of mesocortical dopaminergic neurons to stress induced by long-term treatment with antidepressants might contribute to the anxiolytic effects of such drugs.     

Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways

Recently the two vesicular-glutamate-transporters VGLUT1 and VGLUT2 have been cloned and characterized. VGLUT1 and VGLUT2 together label all glutamatergic neurons, but because of their distinct expression patterns in the brain they facilitate our ability to define between a VGLUT1-positive cortical and a VGLUT2-positive subcortical glutamatergic systems. We have previously demonstrated an increased cortical VGLUT1 expression as marker of antidepressant activity. Here, we assessed the effects of different psychotropic drugs on brain VGLUT2 mRNA and protein expression. The typical antipsychotic haloperidol, and the atypicals clozapine and risperidone increased VGLUT2 mRNA selectively in the central medial/medial parafascicular, paraventricular and intermediodorsal thalamic nuclei; VGLUT2 protein was accordingly amplified in paraventricular and ventral striatum and in prefrontal cortex. The antidepressants fluoxetine and desipramine and the sedative anxiolytic diazepam had no effect. These results highlight the implication of thalamo-limbic glutamatergic pathways in the action of antipsychotics. Increased VGLUT2 expression in these neurons might constitute a marker for antipsychotic activity and subcortical glutamate neurotransmission might be a possible novel target for future generation antipsychotics.     

Involvement of l-arginine-nitric oxide pathway in the antidepressant and memory promoting effects of morin in mice

l -Arginine-nitric oxide pathway has been reported to be involved in the mediation of the psychopharmacological effects of many psychotropic drugs. Previous studies have shown that morin, a psychotropic compound isolated from mulberry leaf produces functional psychopharmacological effects indicative of antidepressant, antipsychotic, anxiolytic and nootropic properties. However, the role of l -arginine-nitric oxide pathway in the psychotropic effects of morin has not been fully investigated, hence, the need for this study. Male Swiss mice were pretreated individually or in combination with nitric oxide precursor [l -arginine (750 mg/kg, i.p.)], competitive nonselective nitric oxide synthase (NOS) inhibitor [N(G)-nitro-l -arginine methyl ester (l -NAME, i.p) (50 mg/kg)] or selective neuronal NOS inhibitor [methylene blue (3.75 mg/kg, i.p)] prior to morin (100 mg/kg, i.p.) or saline (10 mL/kg, i.p.) treatment. Psychopharmacological activities were then evaluated 30 min later using open field, Y-maze, and forced swim tests. l -Arginine significantly reversed the effects of morin on locomotion, memory and depression in mice. The reduced motor activity and enhanced memory function produced by morin were significantly attenuated by methylene blue but augmented the antimobility activity of morin in the FST. Moreover, l -NAME potentiated the psychopharmacological effects of morin in the open field and forced swim tests but reduced its memory promoting effect. Meanwhile, morin supplementation reversed the effects of l -arginine on l -NAME-treated mice in all behavioral models. The results of this study suggest that l -arginine-nitric oxide pathway might play a role in the modulation of the antidepressant and memory promoting effects of morin in mice.     

Acute effects of antipsychotic drugs on cardiovascular responses to stress

The effect of acute treatment with clozapine, risperidone and haloperidol on cardiovascular response to open field novelty stress was investigated in rats using radio-telemetry and video-tracking analysis. Pretreatment with clozapine dose-dependently inhibited the pressor response, tachycardia and increase in dP/dt and caused a marked reduction of exploratory locomotor activity. Similar effects were observed after risperidone treatment. Haloperidol treatment markedly reduced locomotor activity but its cardiovascular effects were limited to a more rapid return of heart rate towards baseline levels. These data suggest that particularly the atypical antipsychotic drugs, clozapine and risperidone, but not the typical antipsychotic, haloperidol, reduce cardiovascular stress responses, an effect that could reflect their anxiolytic action. Such anxiolytic effects could contribute to the beneficial clinical effects of atypical antipsychotic drugs in patients with schizophrenia.     

Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents

A series of novel tetracyclic tetrahydrofuran derivatives was prepared and evaluated for its potential psychotropic properties. In vitro affinities for multiple dopaminergic, serotonergic, alpha-adrenergic, and histamine receptors and for the norepinephrine transporter as well as the ED(50) values obtained in some in vivo assays for antipsychotic, anxiolytic, and antidepressant potential are reported. Compounds (-)-1, (-)-8d, and (+)-8d have been identified as potential broad-spectrum psychotropic agents.     

Characterization of the effects of the acute and repeated administration of MK-801 on the release of adrenocorticotropin, corticosterone and prolactin in the rat

In addition to its producing profound changes in behavior, phencyclidine (PCP) disrupts neuroendocrine function in the rat. Because PCP binds to PCP as well as sigma receptors, it is not known which receptor type mediates the various effects of the drug. The purpose of the present study was to characterize the effects of the acute administration of enantiomers of MK-801, a compound with a high degree of selectivity for PCP over sigma receptors, on the release of ACTH, corticosterone and prolactin in the rat. In addition, MK-801 was administered daily for eight days in order to test whether tolerance develops to MK-801-induced ACTH and corticosterone release after repeated administration. While both enantiomers of MK-801 markedly increased plasma levels of ACTH and corticosterone, the (+) enantiomer was more potent. Tolerance developed to MK-801-induced increases in ACTH and corticosterone after repeated administration. Plasma prolactin levels were not affected by either the acute or the repeated administration of MK-801. These results suggest that the decrease in plasma levels of prolactin produced by PCP-like drugs is not mediated by PCP receptors, and may be a marker for a sigma receptor-mediated effect.     

Binding of psychotropic drugs to isolated alpha-acid glycoprotein

Alpha1-acid glycoprotein (alpha1-AG) was purified from human sera, and its binding properties with respect to psychotropic drugs were examined by equilibrium dialysis methods in order to clarify the specificity of binding. Radioactive imipramine, a tricyclic antidepressant, was used as the primary ligand. Other drugs, representative of different classes, were tested as potential inhibitors of the alpha1-AG-imipramine binding. The K(a) for imipramine was 2.8 x 10(5) (+/- 0.8) M(-10 (mean +/- S.D.). Chlorpromazine, fluphenazine, thioridazine, loxapine and thiothixene, which are antipsychotic drugs, were competitive inhibitors of imipramine binding, and their K(a) values were in the same range. Propranolol, haloperidol and diazepam were also competitive inhibitors but their affinities were lower. Molindone, an indolic antipsychotic, when tested at the same concentrations as the other drugs, did not affect imipramine binding. Trihexyphenidyl, an anti-Parkinson drug, was a potent but noncompetitive inhibitor. These data identify the antidepressant and major tranquilizer drugs that exhibit high affinity for alpha1-AG and indicate that alpha1-AG may account for 40 per cent of total imipramine bound in serum. Since in psychiatric clinical practice two drugs are frequently administered together, possible competitive effects are discussed as well as the potential role of alpha1-AG in psychiatric illness.