The effect of the selective 5‐HT_1A agonists alnespirone (S‐20499) and 8‐OH‐DPAT on extracellular 5‐hydroxytryptamine in different regions of rat brain

Abstract

1 We have examined the e ects of the systemic administration of the selective 5-HT 1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated di erentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus). 2 Alnespirone (0.1 ± 3 mg kg 71 , s.c.) dose-dependently reduced extracellular 5-HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5-HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT 1A antagonist WAY-100635 (0.5 mg kg 71 , s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3 mg kg 71 , s.c.) in frontal cortex. 3 8-OH-DPAT (0.025, 0.1 and 0.3 mg kg 71 , s.c.) also reduced extracellular 5-HT in a regionallyselective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1 mg kg 71 , s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nucleus at all doses examined. 4 Doses of both compounds close to their respective ED 50 values (0.3 mg kg 71 alnespirone, 0.025 mg kg 71 8-OH-DPAT) reduced 5-HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8-OH-DPAT. 5 These data show that the reduction of 5-HT release elicited by alnespirone and 8-OH-DPAT is more important in forebrain areas innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by di erences in the sensitivity of 5-HT 1A autoreceptors controlling 5-HT release, given the dissimilar e ects of these two 5-HT 1A agonists in regions rich in cell bodies and nerve terminals. This suggests the presence of complex mechanisms of control of 5-HT release by 5-HT 1A receptors.

Idazoxan and 8-OH-DPAT Modify the Behavioral Effects Induced by Either NA, or 5-HT, or Dual NA/5-HT Reuptake Inhibition in the Rat Forced Swimming Test

“…This behavioral pattern of response is consistent with 8-OH-DPAT decreasing 5-HTrelease, as well as with increasing NA-neuronal firing and NA-release (Casanovas et al 1997;Kreiss and Lucki 1997;Piercey et al 1994).…”

Effect of Selective Serotonin Reuptake Inhibitors via 5-HT<SUB>1A</SUB> Receptors on L-DOPA-Induced Rotational Behavior in a Hemiparkinsonian Rat Model

“…In addition, this effect of fluoxetine was abolished by pre-treatment with WAY 100135. Activation of 5-HT 1A receptors reduces serotonergic nerve discharge, which consequently leads to a reduction in 5-HT release from the corresponding afferent nerve terminals, including those originating from the dorsal raphe nucleus to the striatum (32,33). Indeed, L-DOPA-derived extracellular DA contents were attenuated by treatment with fluoxetine (31).…”

Modulation of Serotonergic Function in Rat Brain by VN2222, a Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

“…However, its systemic administration reduced 5-HT ext in the same brain area. The striatum was chosen because (together with prefrontal cortex) it is one of the brain areas where the 5-HT release is more sensitive to the activation of 5-HT 1A autoreceptors by direct and indirect (eg SSRI) agonists Casanovas et al, 1997;Romero and Artigas, 1997;Casanovas et al, 2000). The discrepancy between the effects of the local (5-HT increase) and systemic administration (5-HT decrease) of VN2222 is likely accounted for by its Figure 7 Baseline firing rate of dorsal raphe serotonergic neurons in rats treated with vehicle (n ¼ 7), 6 mg/kg day VN2222 (n ¼ 5) and 20 mg/kg day VN2222 (n ¼ 2).…”