Antagonism of Reserpine‐Induced Suppression of Spontaneous Motor Activity by Stimulation of 5‐HT_1A Receptors in Rats

Abstract

The 5-HT1A and the DA D2 receptor agonists 8-OH-DPAT (0.05-3.2 mg kg-1 subcutaneously, -20 min.) and quinpirole (0.08-1.25 mg kg-1 subcutaneously, -20 min.), respectively, both partially antagonized reserpine-induced (5 mg kg-1 subcutaneously, -16 hr) suppression of spontaneous motor activity in the rat. Four different aspects of the spontaneous motor activity were recorded in a photocell-equipped open-field (8 x 8 photocells, 90 mm apart, defining two horizontal planes): locomotor activity (all photocell counts at the lower level); rearing (all photocell counts at the upper level); forward locomotion (the proportion movements across the arena); peripheral activity (the proportion locomotor activity as picked up by the photocell beam closest to the wall, i.e. 25 mm). As defined by these variables, the pattern of activity produced by 8-OH-DPAT or quinpirole were indistinguishable. The effects produced by 8-OH-DPAT were fully antagonized by the 5-HT1 antagonist (-) pindolol (4 mg kg-1 subcutaneously, -30 min.), but not by the DA D2 receptor antagonist raclopride (2 mg kg-1 subcutaneously, -30 min.) nor by the 5-HT2 receptor antagonist ritanserin (2 mg kg-1 subcutaneously, -30 min.), whereas effects produced by quinpirole were fully antagonized by raclopride (2 mg kg-1 subcutaneously, -30 min.). Effects produced by quinpirole, but not 8-OH-DPAT, were potentiated by administration of the DA D1 agonist SKF-38,393 (3 mg kg-1 subcutaneously, -20 min.). It is concluded that effects by 8-OH-DPAT on spontaneous motor activity in the reserpine treated rat primarily are due to stimulation of postsynaptic 5-HT1A receptors.

Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. III. Agonist and Antagonist Properties at Serotonin, 5-HT1 and 5-HT2, Receptor Subtypes

“…Furthermore, in pilot studies with the 5-HT 1A partial agonist, buspirone, an attenuation of spontaneous and L-DOPAinduced dyskinesias was seen in Parkinson's disease patients (Bonifati et al, 1994). However, there is no compelling evidence from experimental models (Ahlenius and Salmi 1995) that selective engagement of 5-HT 1A receptors exerts clinically meaningful antiparkinson actions or that 5-HT 1A receptors are involved in the antiparkinson profiles of drugs evaluated herein. Furthermore, 5-HT 1A agonists exert a complex influence upon locomotor behavior and blunt DA release in the striatum (Barnes and Sharp, 1999;De La Garza and Cunningham, 2000;Millan, 2000): they also attenuate L-DOPA-induced DA release in the striatum from serotonergic neurons bearing 5-HT 1A autoreceptors (Arai et al, 1996;Kannari et al, 2001).…”

“…Both presynaptic 5-HT 1A autoreceptors and their postsynaptic counterparts exert a modulatory influence upon dopaminergic transmission, motor function, mood, and cognition (Wadenberg, 1996;Barnes and Sharp, 1999;Meneses, 1999;Millan, 2000). Notably, 5-HT 1A agonists reverse reserpine-induced hypoactivity (Ahlenius and Salmi, 1995) and abrogate the motor disruption elicited by agonists (dyskinesias) and antagonists (catalepsy) at dopaminergic receptors (Wadenberg, 1996;Bibbiani et al, 2001). 5-HT 1B receptors are highly expressed in the substantia nigra, striatum, and corticolimbic structures wherein they modify the activity of serotonergic, cholinergic, and glutamatergic pathways (Bruinvels et al, 1993;Barnes and Sharp, 1999).…”

Potentiation of DOI-induced forward locomotion in rats by (?)-pindolol pretreatment

“…On the other hand, it is important to note, that DOI and some structurally similar agents, have hallucinogenic potential in man (see Glennon, 1990), whereas the SSRIs, alone or in combination with (-)-pindolol, are not. Furthermore, 5-HTIA receptors are found also postsynaptically, and (-)-pindolol effectively antagonizes 8-OH-DPAT-induced behavioral effects in reserpine treated rats (Ahlenius and Salmi, 1995). Thus, the possibility should be considered that (-)-pindolol, when combined with a SSRI, produces its effects via release of 5-HT onto 5-HT receptors other than 5-HT2A/C or 5-HT1A.…”

Postsynaptic 5-HT1A receptor stimulation increases motor activity in the 6-hydroxydopamine-lesioned rat: implications for treating Parkinson’s disease

“…There has been a substantial focus on 5-HT 1A receptors and their involvement in motor control. In acute models of parkinsonism, the 5-HT 1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT), has been shown to reverse haloperidol-induced catalepsy in rats (Andersen and Kilpatrick 1996) and increase spontaneous locomotor activity in monoamine-depleted rats (Ahlenius et al 1993;Ahlenius and Salmi 1995;Mignon and Wolf 2002). 5-HT 1A receptors exist presynaptically as autoreceptors on the raphe cell bodies and can modify endogenous 5-HT synthesis and release (Sotelo et al 1990;Riad et al 2000).…”