Role of Somatodendritic 5‐HT Autoreceptors in Modulating 5‐HT Neurotransmission^a

Abstract

A very important element controlling serotonin (5-HT) release throughout the brain is the 5-HT1A autoreceptor present on the soma and dendrites of 5-HT neurons since it exerts a negative feedback influence on their firing activity. This 5-HT1A autoreceptor receives an increased activation by endogenous 5-HT at the beginning of a treatment with a selective 5-HT reuptake inhibitor (SSRI) and, consequently, a decreased 5-HT neuronal firing activity is obtained. As the SSRI treatment is prolonged, the 5-HT1A autoreceptor desensitizes and firing activity is restored in the presence of the SSRI. That this adaptive change underlies, at least in part, the delayed therapeutic effect of SSRI in major depression is supported by the acceleration of the antidepressant response by the concomitant administration of the 5-HT1A autoreceptor antagonist pindolol with SSRIs.

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

“…Downregulation of the 5-HT 1A receptor was proposed to underlie the increase in 5-HT transmission and therapeutic action of SSRIs (Artigas et al, 1996a;Le Poul et al, 2000). Moreover, coapplication of a 5-HT 1A receptor antagonist and SSRIs was shown to accelerate antidepressant responses in patients (see Artigas et al, 1996b;Blier et al, 1998). In view of these findings, antagonistic interaction of galanin and the 5-HT 1A receptor in the DR (see Ö gren et al, 2006) may seem paradoxical, since galanin, in contrast to SSRIs, downregulates the 5-HT 1A autoreceptor (Razani et al, 2000), but at the same time reduces 5-HT transmission (see above).…”

Depletion of 5-HT Disrupts Prepulse Inhibition in Rats Dependence on the Magnitude of Depletion, and Reversal by a 5-HT Precursor

“…Based on their finding that 8-OH-DPAT significantly attenuated PPI when administered in the raphe nuclei of rats, Sipes and Geyer (1995) hypothesized that its effects were due to its ability to decrease 5-HT neuronal activity (e.g., Sharp and Hjorth 1990;Blier et al 1998). However, as mentioned by the authors (Sipes and Geyer 1995), this hypothesis was only partly supported by the data because: (1) Systemic 8-OH-DPAT produced a greater disruption of PPI than its local administration in the raphe.…”

“…More than one subtype of 5-HT receptor may be involved in these effects as selective stimulation of 5-HT 2A (Sipes and Geyer 1995;Padich et al 1996), 5-HT 1B Geyer 1994, 1996), and 5-HT 1A receptors (Rigdon and Weatherspoon 1992;Sipes and Geyer 1995) disrupts PPI in the rat. In contrast to the extensive examination of increased function, the effects of de- (Sharp and Hjorth 1990;Blier et al 1998). The finding that the 5-HT 1A agonist 8-OH-DPAT disrupts PPI after local administration in the raphe nuclei (Sipes and Geyer 1995), the main 5-HT neuron-containing nuclei, suggests that it acts on 5-HT 1A somatodendritic receptors, i.e., via a decrease in 5-HT neurotransmission.…”

“…Indeed, d-norfenfluramine, not d-fenfluramine, is known to persist relatively long (Clineschmidt et al 1978), and it has affinity for several 5-HT receptors (e.g., Garattini et al 1987). It is conceivable that interactions between body weight loss, 5-HT depletion, and direct effects of d-fenfluramine metabolites underlie the effects of the combination treatment on startle reactivity.Based on their finding that 8-OH-DPAT significantly attenuated PPI when administered in the raphe nuclei of rats, Sipes and Geyer (1995) hypothesized that its effects were due to its ability to decrease 5-HT neuronal activity (e.g., Sharp and Hjorth 1990;Blier et al 1998). However, as mentioned by the authors (Sipes and Geyer 1995), this hypothesis was only partly supported by the data because: (1) Systemic 8-OH-DPAT produced a greater disruption of PPI than its local administration in the raphe.…”

“…Nevertheless, indirect evidence for such effects exists. That is, 5-HT 1A agonist-induced disruption of PPI can reflect the actions of these drugs either at postsynaptic 5-HT 1A receptors, or at somatodendritic receptors, which inhibit 5-HT neuronal firing and release (Sharp and Hjorth 1990;Blier et al 1998). The finding that the 5-HT 1A agonist 8-OH-DPAT disrupts PPI after local administration in the raphe nuclei (Sipes and Geyer 1995), the main 5-HT neuron-containing nuclei, suggests that it acts on 5-HT 1A somatodendritic receptors, i.e., via a decrease in 5-HT neurotransmission.…”