Antidepressant treatment in helpless rats: effect on the electrophysiological activity of raphe dorsalis serotonergic neurons

Abstract

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.

Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression

“…Furthermore, chronic treatment with fluoxetine significantly reduced both the immobility in the TST and the sensitivity of somatodendritic 5-HT 1A autoreceptors in HL mice. These results are in accordance with previous data obtained in helpless rats (38) and represent another support to the hypothesis of a role for 5-HT 1A autoreceptors in the mode of action of antidepressants (24).…”

“…Through the action of endogenous 5-HT, such a hypersensitivity might also account for the (slightly) lower body temperature in naive HL compared with NHL mice. Supersensitivity of 5-HT 1A autoreceptors has already been reported in other animal models of depression (5,29,38) as well as in depressed patients (39). The resulting increase in 5-HT 1A -mediated inhibitory feedback on serotoninergic neuronal firing would lead to a reduction in central 5-HT neurotransmission, as actually supported by lower 5-HIAA͞ 5-HT ratio in the brain of HL mice.…”

Effects of Long-term Acetyl-L-carnitine Administration in Rats I. Increased Dopamine Output in Mesocorticolimbic Areas and Protection toward Acute Stress Exposure

“…Long-term exposure to different stress procedures impairs an animal's responsiveness to both aversive and pleasurable stimuli (Overmier and Seligman 1967;Papp et al 1991;Moreau et al 1992;Gambarana et al 1995a), and it decreases DA output in mesolimbic areas (Di Chiara et al 1999;Gambarana et al 1999a;Mangiavacchi et al 2001). Moreover, 5-HT output in the mPFC increases in response to acute exposure to unavoidable stress (Petty et al 1992), although no difference has been observed between helpless and non-helpless control rats in the spontaneous firing of serotonergic neurons in the dorsal raphe (Maudhuit et al 1997). After chronic exposure to unavoidable stress 5-HT output decreases in the mPFC and NAcS (Mangiavacchi et al 2001).…”

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

“…One of the widely discussed causes is a polymorphism of 5-HT1A receptor-encoding gene, Htr1a [32,33]. A mechanism by which SSRI exert their antidepressant effects involves the desensitization of presynaptic 5-HT1A receptors due to the rise of the extracellular 5-HT [34][35][36][37]. It has been suggested that the ability of SSRI to desensitize presynaptic 5-HT1A receptors requires certain maximal level of their expression, and that individuals with the Htr1a C(-1019)G polymorphism (referred to as G/G allele carriers), are resistant to SSRI due to the previously described normal levels of these receptors [32,38].…”