Tricyclic Antidepressants: Long-Term Treatment Increases Responsivity of Rat Forebrain Neurons to Serotonin

Abstract

Long-term treatment of rats with clinically effective tricyclic antidepressant drugs induced a selective increase in the inhibitory response of forebrain neurons to serotonin applied by microiontophoresis. Long-term administration of some related drugs which lack antidepressant efficacy failed to induce such a change. The enhanced response to serotonin induced by the clinically active tricyclic drugs took 1 to 2 weeks to develop, a time course which correlates with the delayed onset of therapeutic effects in humans.

Effects of the Selective Norepinephrine Reuptake Inhibitor Reboxetine on Norepinephrine and Serotonin Transmission in the Rat Hippocampus

“…Prior to the advent of reboxetine, the lack of selective NE reuptake blocking drugs used clinically without a TCA moiety made it impossible to rule out structural versus NE components of such drugs in delineating the clinical impact of these properties. The present results on reboxetine are thus similar to those reported by Lacroix et al (1991), indicating that postsynaptic ␣ 2 -adrenoceptors remained normosensitive in the hippocampus after long-term desipramine (10 mg/kg/day) treatment, but stand in opposition to an increased 5-HT 1A receptors sensitivity (de Montigny and Aghajanian 1978). In contrast, both reboxetine and desipramine have been shown to reduce the sensitivity of 5-HT 1A receptors that control the firing activity of rat LC neurons after long-term treatment Szabo and Blier 2001).…”

“…In contrast, it had been reported that 5-HT 1A receptors become supersensitive in postsynaptic structures to prolonged TCA treatment (de Montigny and Aghajanian 1978;Menkes et al 1980;Wang and Aghajanian 1980). Also, TCA drugs had been shown to alter adrenoceptor function, particularly to sensitize ␣ 1 -adrenoceptor in the facial motor nucleus and the lateral geniculate body and ␣ 2 -adrenoceptors in the amygdala after long-term treatment Menkes et al 1980;Menkes and Aghajanian 1981;Freedman and Aghajanian 1985).…”

“…For example, SSRIs induce a gradual decrease in the spontaneous firing activity of NE neurons after long-term administration (Szabo et al 1999, via a complex neuronal circuitry (Szabo and Blier 2000a), which may contribute to their beneficial and/or side effects depending on the symptomatic profile of the patients (Blier 2000). On the other hand, the selective NE reuptake inhibitor desipramine increases the synaptic availability of NE but also alters 5-HT parameters after long-term administration, such as enhancing extracellular 5-HT concentrations and the responsiveness of 5-HT receptors in postsynaptic structures (de Montigny and Aghajanian 1978;Wang and Aghajanian 1980;Menkes and Aghajanian 1981;Yoshioka et al 1995). This enhanced synaptic availability of 5-HT may be due to a decreased sensitivity of ␣ 2 -adrenergic heteroreceptors located on 5-HT terminals that normally induce a negative feedback regulation on 5-HT release (Mongeau et al 1993;Yoshioka et al 1995).…”

“…This enhanced synaptic availability of 5-HT may be due to a decreased sensitivity of ␣ 2 -adrenergic heteroreceptors located on 5-HT terminals that normally induce a negative feedback regulation on 5-HT release (Mongeau et al 1993;Yoshioka et al 1995). Interestingly, all TCA drugs, independent of their capacity to inhibit the reuptake of 5-HT and/or NE, progressively enhance the responsiveness of postsynaptic 5-HT 1A receptors with a time-course congruent to the delayed onset of action of these drugs in major depression (de Montigny and Aghajanian 1978;Heninger et al 1984;Chaput et al 1991). Due to the lack of effective antidepressant drugs selective for the NE transporter not belonging to the TCA family, it has been difficult to assess whether the effects of desipramine on 5-HT transmission is attributable to its TCA moiety (because at least one of these drugs does not block NE reuptake) or to NE blockade per se.…”

Effects of Acute and Long-Term Administration of Escitalopram and Citalopram on Serotonin Neurotransmission: an In Vivo Electrophysiological Study in Rat Brain

“…It is the product of the current (in nA) used to eject 5-HT from the micropipette and the time (in seconds) required to obtain a 50% decrease from baseline of the firing rate of the recorded neuron. The more sensitive a neuron is to 5-HT, the smaller will be the IT 50 value because the number of molecules ejected is proportional to the amount of coulombs (de Montigny and Aghajanian, 1978).…”