Sleep–wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat
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.
References (62)
Depressed states and indolealkylamines
Neuronal activity in the peribrachial area: relationship to behavioral state control
Neurosci. Biobehav. Rev.
(1995)- et al.
Disposition and pharmacological effects of m-chlorophenylpiperazine in rats
Neuropharmacology
(1981) - et al.
Cholinergic receptor subtypes and REM sleep in animals and normal controls
Prog. Brain Res.
(1993) - et al.
Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression
Eur. J. Pharmacol.
(1999) - et al.
Procedure- and age-dependent hyperactivity in a new animal model of endogenous depression
Neurosci. Biobehav. Rev.
(1990) - et al.
Decreased dorsal raphe nucleus neuronal activity in adult chloral hydrate anesthetized rats following neonatal clomipramine treatment: implications for endogenous depression
Brain Res.
(1997) - et al.
A preliminary study of the effects of nighttime administration of the serotonin agonist, mCPP, on sleep architecture and behavior in healthy volunteers
Biol. Psychiatry
(1991) - et al.
Sleep electroencephalographic abnormalities in adolescent depressives: effects of scopolamine
Biol. Psychiatry
(1997) - et al.
5-Hydroxytryptamine, noradrenaline and dopamine in brain stem, hypothalamus and caudate nucleus of controls and patients committing suicide by coal gas poisoning
Lancet
(1969)
Behavioral state related changes of extracellular serotonin concentration in the dorsal raphe nucleus: a microdialysis study in the freely moving cat
Brain Res.
On-line detection of extracellular levels of serotonin in dorsal raphe nucleus and frontal cortex over the sleep/wake cycle in the freely moving rat
Neuroscience
Effects of nisoxetine, a selective noradrenaline transporter blocker, on sleep in rats
Pharmacol. Biochem. Behav.
Central administration of two 5-HT receptor agonists: effects on REM sleep initiation and PGO waves
Pharmacol. Biochem. Behav.
Effects of pharmacological treatments on the sleep of depressed patients
Biol. Psychiatry
Suppression of eltoprazine-induced REM sleep rebound by scopolamine
Neuropharmacology
Evidence of the modulatory role of serotonin in acetylcholine release from striatal interneurons
Brain Res.
Animal depression model by neonatal clomipramine: reduction of shock induced aggression
Pharmacol. Biochem. Behav.
A new animal model of endogenous depression: a summary of present findings
Neurosci. Biobehav. Rev.
Diagnostic and Statistical Manual of Mental Disorders
Intravenous administration of serotonin agonist m-chlorophenylpiperazine (mCPP) increases extracellular serotonin in the diencephalon of awake rats
Neuropharmacology
Modification of serotonergic and noradrenergic neurotransmission by repeated administration of monoamine oxidase inhibitors: electrophysiological studies in the rat central nervous system
J. Pharmacol. Exp. Ther.
Key role of 5-HT1B receptors in the regulation of paradoxical sleep as evidenced in 5-HT1B knockout mice
J. Neurosci.
Norepinephrine in depressive reactions
Arch. Gen. Psychiatry
Cellular basis of pontine ponto–geniculo–occipital wave generation and modulation
Cell. Mol. Neurobiol.
The rat as an experimental model for sleep neurophysiology
Behav. Neurosci.
Effect of application of serotonin in medial preoptic area on body temperature and sleep–wakefulness
Indian J. Exp. Biol.
Cholinergic micro-stimulation of the peribrachial nucleus in the cat: immediate and prolonged increase in ponto–geniculo–occipital waves
Arch. Ital. Biol.
Prenatal protein malnourished rats show changes in sleep–wake behavior as adults
J. Sleep Res.
Microinjection of glutamate in to the pedunculopontine tegmentum induces REM sleep and wakefulness in rat
Am. J. Physiol., Regul. Integr. Comp. Physiol.
Serotonin function and the mechanism of antidepressant action: reversal of antidepressant induced remission by rapid depletion of plasma tryptophan
Arch. Gen. Psychiatry
Cited by (8)
Enriched environment ameliorates depression-induced cognitive deficits and restores abnormal hippocampal synaptic plasticity
2016, Neurobiology of Learning and MemoryCitation Excerpt :The model does not rely on external stressors to induce depressive-like states in animals and is therefore a more accurate model to represent endogenous depression. Earlier studies in the endogenous model of depression have demonstrated behavioural depression, impaired cognition, alterations in the levels of catecholamine neurotransmitters and acetylcholine (Bhagya, Srikumar, Raju, & Shankaranarayana Rao, 2008; Bhagya et al., 2011, 2015), sleep disturbance (Mavanji, Meti, & Datta, 2002) and altered functioning of the HPA axis (Prathiba, Kumar, & Karanth, 1998) among others. There are several strategies to enhance synaptic plasticity in the adult brain and the best known among them is environmental enrichment (EE).
Rodent models of insomnia: A review of experimental procedures that induce sleep disturbances
2009, Neuroscience and Biobehavioral ReviewsMulti-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application
2006, Pharmacology and TherapeuticsCitation Excerpt :The foremost action of mCPP in animals and in man is activation of 5-HT2C receptors (Murphy et al., 1989; Gommans et al., 1998; Anderson et al., 2002; Cussac et al., 2002b; Gatch, 2003). It has been speculated that the recruitment of 5-HT2C receptors by mCPP may be associated with antidepressant properties (Mavanji et al., 2002). However, the majority of evidence suggests that direct antagonist properties of nefazodone and trazodone at 5-HT2C receptors participate in their antidepressant profiles (Section 3.2.3.3) (Murphy et al., 1989; Maes et al., 1997; Millan, 2005b).
Automated sleep staging in rat with a standard spreadsheet
2003, Journal of Neuroscience MethodsEffect of five-consecutive-day exposure to an anxiogenic stressor on sleep-wake activity in rats
2013, Frontiers in Neurology