No abstract

Electrophysiological investigations on the mechanism of action of antidepressants have shown that both deprivation of rapid eye movement (REM) sleep and chronic treatment with antidepressants render serotoninergic (5-HT) neurons less sensitive to the inhibitory effect of 5-HT reuptake blockers in the rat. It was of interest to test whether the same mechanisms could be evidenced in a possible experimental model of depression. The latter consisted of rats which had been treated neonatally with clomipramine and exhibited at adult age behavioural and sleep alterations which resemble the human disorder. Recording the electrophysiological activity of 5-HT neurons in the nucleus raphe dorsalis (NRD) revealed that both chronic treatment with zimelidine and REM sleep deprivation induced a hyporeactivity of these neurons to the inhibitory effect of citalopram in "normal" rats. However, in rats which had been treated neonatally with clomipramine, 5-HT neurons were hyporeactive to the effect of this 5-HT reuptake blocker already under baseline conditions, and no further modification could be induced by chronic zimelidine administration or REM sleep deprivation. It can be hypothesized that adaptive phenomena at the serotoninergic NRD level are not a relevant element to explain the mechanism of action of anti-depressants in the present model of depression, while they have been considered as a crucial event in "normal" rats.

Chronic treatment with antidepressants renders serotonergic neuronal firing less sensitive to the inhibitory effect of serotonin (5-HT) reuptake blockers in the rat, and this has been considered as a major correlate of the therapeutic action of these drugs. We investigated whether the same mechanisms could be evidenced in an experimental model of depression, the learned helplessness paradigm. Rats rendered helpless by a single session of inescapable electrical footshocks exhibit, for several days, depression-like behavioural deficits which can be reversed by sub-chronic, but not acute, treatment with antidepressants. Recording of serotonergic neurons in the dorsal raphe nucleus revealed that, under baseline conditions, the spontaneous firing was similar in helpless rats and in non-helpless controls. However, neurons in the former group exhibited an enhanced sensitivity to the inhibitory action of the 5-HT reuptake blocker, citalopram (ED50 = 0.18 +/- 0.02 mg/kg IV in helpless rats versus 0.27 +/- 0.03 mg/kg IV in controls, P < 0.05). Treatment with zimeldine during 3 consecutive days induced in both helpless and control rats, a decrease in the inhibitory response of serotonergic neurons to the citalopram challenge, which resulted in a normalization of the neuronal reactivity in the helpless group (ED50 = 0.31 +/- 0.03 mg/kg IV). Since this adaptive phenomenon parallels the behavioural improvement induced by the repeated administration of zimeldine and other antidepressants in helpless rats, it might be considered as a crucial event in the mechanism of therapeutic action of these drugs.

SUMMARY Sleep deprivation (SD) for one night induces mood improvement in depressed patients.However, relapse often occurs on the day after deprivation subsequently to a sleep episode. In light of the possible involvement of central serotonin (5-hydroxytryptamine, 5-HT) neurotransmission in both depression and sleep mechanisms, we presently investigated, in the rat, the effects of SD and recovery sleep on the electrophysiological response of 5-HT neurons in the nucleus raphe dorsalis (NRD) to an acute challenge with the 5-HT reuptake blocker citalopram. In all rats, citalopram induced a dosedependent inhibition of the firing of NRD neurons recorded under chloral hydrate anaesthesia. After SD, achieved by placing rats in a slowly rotating cylinder for 24 h, the inhibitory action of citalopram was significantly reduced (with a concomitant 53% increase in its ED5,, value). After a recovery period of 4 h, a normal susceptibility of the firing to citalopram was restored. The decreased sensitivity of 5-HT neuronal firing to the inhibitory effect of citalopram after SD probably results in an enhancement of 5-HT neurotransmission. Such an adaptive phenomenon (similar to that reported after chronic antidepressant treatment), and its normalization after recovery sleep, parallel the mood improvement effect of SD and the subsequent relapse observed in depressed patients. These data suggest that the associated changes in 5-HT autocontrol of the firing of NRD serotoninergic neurons are relevant to the antidepressant action of SD.