Effects of Tandospirone, a 5-HT1A Agonistic Anxiolytic Agent, on Haloperidol-Induced Catalepsy and Forebrain Fos Expression in Mice

Abstract

Abstract. We studied the effects of tandospirone, a 5-HT 1A agonistic anxiolytic agent, on haloperidol-induced catalepsy and forebrain Fos expression in mice. Haloperidol (0.5 mg/kg, i.p.) markedly increased the catalepsy time and enhanced Fos expression in the shell (AcS) and core (AcC) regions of the nucleus accumbens, the dorsolateral striatum (dlST), and the lateral septal nucleus (LSN). Tandospirone (0.1 -1 mg/kg, s.c.) significantly alleviated haloperidolinduced catalepsy in a dose-dependent manner, which was antagonized by WAY-100135 (a selective 5-HT 1A antagonist). The anticataleptic dose of tandospirone (1 mg/kg, s.c.) significantly reduced haloperidol-induced Fos expression in the dlST. This inhibition by tandospirone was regionally specific, and it failed to affect haloperidol-induced Fos expression either in the AcS, AcC, or LSN. In addition, the reversal of haloperidol-induced striatal Fos expression by tandospirone was antagonized by WAY-100135. These results support the notion that stimulation of 5-HT 1A receptors region-specifically counteracts the D 2 -blocking actions of haloperidol in the striatum, which may account for the ameliorative effects of 5-HT 1A agonists on antipsychoticassociated extrapyramidal disorders.

Pathophysiological Roles of Serotonergic System in Regulating Extrapyramidal Motor Functions

“…1,[3][4][5] Several studies demonstrated that activation of 5-HT 1A receptors improves antipsychotic-induced EPS and motor disabilities in animal models of Parkinson's disease. [10][11][12][13][14][15][16] In our studies, 5-HT 1A agonists (e.g., 8-hydroxy-2-(di-n-propylamino)-tetralin and tandospirone) ameliorated haloperidol-induced bradykinesia and catalepsy with potencies similar to those of antiparkisonian agents (e.g., trihexyphenidyl and L-3,4-dihydroxyphenylalanine (L-DOPA)). 13,14) Consistently with these anti-EPS actions, 5-HT 1A agonists reversed striatal Fos protein expression induced by haloperidol, indicating that 5-HT 1A receptors counteract D 2 receptor blockade by antipsychotics in the striatum.…”

“…13,14) Consistently with these anti-EPS actions, 5-HT 1A agonists reversed striatal Fos protein expression induced by haloperidol, indicating that 5-HT 1A receptors counteract D 2 receptor blockade by antipsychotics in the striatum. 14,15) Earlier studies showed that microinjection of 5-HT 1A agonists into the raphe nuclei attenuated antipsychotic-induced catalepsy, suggesting that activation of presynaptic 5-HT 1A autoreceptors can reduce EPS 11) ( Fig. 1 and Table 1).…”

Activity of serotonin 5-HT1A receptor ‘biased agonists’ in rat models of Parkinson's disease and l-DOPA-induced dyskinesia

“…In contrast, another 5-HT 1A receptor biased agonist, F13714 displays preferential presynaptic 5-HT 1A autoreceptor activation, whereas tandospirone does not discriminate between 5-HT 1A receptor sub-populations. Tandospirone has been clinically tested (Kannari et al, 2002) and investigated in rat models of PD (Matsubara et al, 2006;Ohno et al, 2009), but the activities of F13714 and F15599 have not yet been described in models of PD.…”

Effect of tandospirone, a serotonin-1A receptor partial agonist, on information processing and locomotion in dizocilpine-treated rats

“…A low dose (0.1 mg/kg) of haloperidol decreased locomotion by itself or when combined with a low, but not high, dose of tandospirone. It is well documented that 5-HT1A agonists ameliorate haloperidol-induced catalepsy (Ohno et al 2008;Ohno et al 2009). This line of evidence is consistent with our observations that a high dose of tandospirone counteracted haloperidol-induced hypolocomotion.…”

“…In other studies, 5-HT1A agonists were shown to ameliorate haloperidol-induced catalepsy (Ohno et al 2008;Ohno et al 2009). To the best of our knowledge, there is little information on whether 5-HT1A partial agonists, such as tandospirone, interact with D2 receptors in a similar way to the full agonists at 5-HT1A receptors or not.…”