Studies on the role of 5-HT1A autoreceptors and α1-adrenoceptors in the inhibition of 5-HT release—I. BMY7378 and prazosin

177

102

The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT 1A receptor antagonist WAY-100,635 (20-100 mg/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA 3 pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT 1A receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED 50 ¼ 58 and 254 mg/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 mg/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 mg/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT 1A autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.

Section: Discussionmentioning

confidence: 50%

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

Mansari

Sanchéz

Chouvet

et al. 2005

177

102

“…The comparable effects of 0.3 and 1 mg/kg suggest that this was a nearly maximal effect, whereas 3 mg/kg appeared to be less effective. Interestingly, a similar dose range (0.1-1 mg/kg s.c.) reduced dose-dependently the 5-HT output in ventral hippocampus to a maximum of 30% of baseline (Hjorth et al, 1995). Lower i.v.…”

Section: Modulation Of 5-ht Release By A-adrenoceptorsmentioning

confidence: 83%

Control of 5-Hydroxytryptamine Release in the Dorsal Raphe Nucleus by the Noradrenergic System in Rat Brain. Role of α-Adrenoceptors

Bortolozzi

Artigas

2002

The interactions between the brainstem serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic (NA) systems are important for the pathophysiology and treatment of affective disorders. We examined the influence of a-adrenoceptors on 5-HT and NA release in the rat dorsal raphe nucleus (DR) using microdialysis. 5-HT and NA concentrations in DR dialysates were virtually suppressed by TTX and increased by veratridine. The local and systemic administration of the a 1 -adrenoceptor antagonist prazosin reduced the DR 5-HT output but not that of NA. The maximal 5-HT reduction induced by local prazosin administration (À78% at 100 mM) was more marked than by its systemic administration (À43% at 0.3 mg/kg). The local application of NA and desipramine, to increase the tone on DR a 1 -adrenoceptors, did not enhance 5-HT release. The local (100 mM) or systemic (0.1-1 mg/kg s.c.) administration of clonidine reduced 5-HT and NA release (À48 and À79%, respectively, at 1 mg/kg), an effect reversed by RX-821002, which by itself increased both amines when given systemically. DSP-4 pretreatment prevented the effects of clonidine on 5-HT, suggesting the participation of a 2 -adrenoceptors on NA elements. Moreover, the systemic effect of clonidine on 5-HT (but not NA) was cancelled by lesion of the lateral habenula and by anesthesia, and was slightly enhanced by cortical transection. These data support the view that a 1 -adrenoceptors in the DR tonically stimulate 5-HT release, possibly at nearly maximal tone. Likewise, the 5-HT release is modulated by a 2 -adrenoceptors in NA neurons and in forebrain areas involved in the distal control of 5-HT neurons.

“…Although activation of the 5-HT 1A receptor inhibits 5-HT release, evidence suggests that there is no appreciable 5-HT 1A -receptor-mediated inhibitory tone on 5-HT firing or release under physiological conditions (Baraban and Aghajanian, 1980;Hjorth et al, 1995). Basal 5-HT firing and terminal 5-HT release in vivo are primarily controlled by a 1 adrenergicreceptor-mediated excitation Johnson et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Flattening the Corticosterone Rhythm Attenuates 5-HT1A Autoreceptor Function in the Rat: Relevance for Depression

Leitch

Ingram

Young

et al. 2003

Depression is associated with glucocorticoid abnormalities, in particular a flattening of the diurnal cortisol rhythm. Recent data suggest that an important factor in the aetiology of depression may be a deficit in the function and expression of 5-HT 1A receptors, which has been reported in depressed patients. The present study assessed the possibility that this cortisol abnormality is causal in the 5-HT 1A receptor deficits. First, a rat model of flattened glucocorticoid rhythm was developed. Controlled release corticosterone pellets implanted for 14 days flattened the corticosterone rhythm and maintained levels constant midway between the nadir and zenith levels observed in sham-operated rats. Secondly, using microdialysis to assess 5-HT release in the hippocampus, the inhibitory response to 8-OHDPAT was measured to determine the sensitivity of somatodendritic 5-HT 1A autoreceptors. Corticosterone treatment was found to induce a significant attenuation in the response to 8-OHDPAT, indicating functional desensitization of somatodendritic 5-HT 1A autoreceptors. There was no effect of corticosterone treatment on basal extracellular 5-HT levels. The data suggest that the glucocorticoid abnormalities associated with depression may impact on the functioning of 5-HT 1A receptors in the brain. These findings suggest that resolution of cortisol abnormalities may be a valuable target for pharmacotherapy in the treatment of depression.