Sleep–wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat

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Abstract

The present study examined the effects of meta-chlorophenyl piperazine (mCPP) and mianserin on the sleep–wake cycle of the clomipramine-induced behaviorally screened depressed rats. Six-hour polygraphic recordings were made between 06:00 and 12:00 h, after a single injection of either saline or mianserin or mCPP into the lateral cerebral ventricle (i.c.v.) of both the depressed (n=12) and control rats (n=12). The injection of mCPP in the depressed rats caused a significant reduction in the total duration and number of rapid eye movement (REM) sleep episodes while it increased the REM sleep onset latency compared to the control saline injections. The injection of mianserin in the depressed rats also caused a significant reduction in the total duration and number of REM sleep episodes without changing the REM sleep latency. These results demonstrate for the first time that the central administration of mCPP and mianserin could act as an antidepressant in the clomipramine-induced rat model of depression.

Introduction

Endogenous depression is a major psychiatric disorder, characterized by a constellation of symptoms. The symptoms of this illness include depressed mood; loss of pleasure-seeking behavior like sex; changes in appetite; changes in sleep architecture; feeling of worthlessness or guilt; difficulty in thinking, concentrating or making decisions; and recurrent thoughts of death or suicidal ideation, plans or attempts (American Psychiatric Association, 1994). Sleep in endogenous depression is characterized by prolonged sleep latency, increased intermittent wakefulness, and early morning awakenings (Sharpley and Cowen, 1995). Depressed patients also exhibit reduction in the duration of stages 3 and 4 slow-wave sleep (SWS) with increased duration of stage 1 SWS (Reynolds and Kupfer, 1987). The changes in rapid eye movement (REM) sleep include the appearance of disinhibited REM sleep with decreased latency of REM sleep onset and increased frequency of REM sleep, especially early in the night (Reynolds and Kupfer, 1987). REM sleep in depression is also characterized by higher intensity phasic REM activity Reynolds and Kupfer, 1987, Thase et al., 2001, Hans-Peter et al., 2001, McCracken et al., 1997.

Considerable progress has been made in understanding the phenomenology of endogenous depression; however, the biological basis of this psychiatric disorder remains poorly understood. Search for the biological basis of depression has been carried out for many decades, and alterations in brain serotonergic mechanisms have long been thought to play a major role in the pathophysiology of depression. There is now considerable evidence to support the hypothesis that human endogenous depression results partly from decreased central serotonergic activity Coppen, 1968, Yates et al., 1990. This hypothesis is supported by the following evidence: (1) serotonin (5-HT) levels in the brain, plasma, and platelet are low in depressed patients Pare et al., 1969, Shaw et al., 1967; (2) reserpine, a drug, which depletes both 5-HT and catecholamines in the brain, can produce depression-like symptoms in 15% of mentally normal hypertensive patients (Bunney and Davis, 1965); (3) inhibition of 5-HT synthesis with p-chlorophenylalanine (PCPA) produces relapse of depression in patients who had responded to antidepressants Shopsin et al., 1975, Shopsin et al., 1976; (4) monoamine oxidase inhibitors (MAOI), which elevate the 5-HT concentration in the brain, also act as antidepressants (Blair et al., 1986); (5) reduction of dietary l-tryptophan, a precursor of 5-HT, can induce depressive symptoms under some circumstances (Young et al., 1985); (6) in patients, tryptophan depletion reverses the antidepressant response of 5-HT uptake inhibitors (Delgado et al., 1990).

The invention of the selective serotonin reuptake inhibitors (SSRIs) has substantially affected the treatment strategy of depression. Maximum antidepressant efficacy is obtained when tricyclic antidepressants were combined with SSRIs Nelson, 1997, Pinder, 1997. Sertraline, an SSRI, acts as an antidepressant and also decreases the duration of REM sleep (Harkin et al., 1999). In the depressive patients, locomotor agitation, changes in REM sleep, sexual and cognitive dysfunctions are attributed to a low serotonin function (Kinney et al., 1997).

To understand the mechanisms involved in the pathogenesis of endogenous depression, a rat model has been developed (Vogel and Vogel, 1982). In this rat model, chronic treatment of clomipramine in neonatal rat pups for 14 days produces a myriad of behavioral deficiencies and REM sleep disturbances in adulthood, which collectively approximate the symptomatology of endogenous depression (Vogel et al., 1990). In addition to behavioral changes, one recent neurochemical study demonstrated that in the neonatally clomipramine-treated adult depressed (CLI) rats, the levels of 5-HT are significantly lower in several regions of the brain compared to adult control rats (Mavanji and Meti, 1999). As the serotonergic system is known to be involved in the regulation of the sleep–wake cycle Jouvet, 1972, Datta, 1997, Boutrel et al., 1999, Monti and Monti, 1999, in the present study, we hypothesized that the alteration of REM sleep in CLI rats is due to the reduction of 5-HT in the brain. To test this hypothesis, in the present study, we have examined the effects of intracerebroventricular (i.c.v.) administration of serotonergic drugs on the sleep–wake cycle of CLI rats.

Section snippets

Animal model

The rats (Wistar) used in this study were obtained from the breeding facility at the National Institute of Mental Health and Neurosciences (NIMHANS, Bangalore, India). All animals were treated in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and institutional guidelines. Experimental details for the development of CLI rats are described in detail elsewhere Vogel et al., 1990, Mavanji and Meti, 1999. Briefly, 4 days after the delivery, only male pups were

Effects of neonatal clomipramine treatment on aggressive behavior of adults

Based on the behavioral criteria, described in Materials and methods, 12 of the 15 CLI rats were considered as depressed. The aggressive scores of the remaining three clomipramine-treated nondepressed rats were not included in the analysis of data. Aggression scores of these 12 CLI rats were compared with aggression scores of 12 control rats. The mean aggression scores of these 12 clomipramine-treated rats (10.6±5.1; mean±S.D.) were significantly less (P<0.001) than the mean aggression scores

Discussion

The principal findings of this study are: (1) REM sleep onset latency is significantly shorter in the clomipramine-treated rats than saline-treated rats; (2) the total number of REM sleep episodes is significantly higher in the clomipramine-treated rats than in the saline-treated rats; (3) the total amount of REM sleep in the clomipramine-treated rats is significantly more than the saline-treated rats; (4) mCPP treatment in the clomipramine-treated depressed rats decreases total amount of REM

Acknowledgements

This research was supported by research grants from the National Institutes of Health Research Grants MH-59839 and NS-34004. We also thank Elissa H. Patterson and Eric E. Spoley for technical assistance and helpful comments about this manuscript.

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