SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. II: Behavioral Profile Predictive of an Atypical Antipsychotic Activity

Abstract

monohydrochloride) is a novel tropanemethanamine benzodioxane that displays antagonist activity at dopamine D 2 receptors and agonist activity at 5-HT 1A receptors. SSR181507 antagonized apomorphine-induced climbing in mice and stereotypies in rats (ED 50 of 2 and 3.4 mg/kg i.p., respectively) and blocked D-amphetamine-induced hyperlocomotion in rats at lower doses (0.3-1 mg/kg i.p.). At 1-10 mg/kg, it was found to disrupt active avoidance in mice. SSR181507 did not induce catalepsy in rats (MED460 mg/kg i.p.) and antagonized (3-10 mg/kg i.p.) haloperidol-induced catalepsy. SSR181507 was also active in two models sensitive to antidepressant/ anxiolytic drugs: in a guinea-pig pup/mother separation test, it decreased (1-3 mg/kg i.p.) the time spent vocalizing during the separation episode, and in a lithium-induced taste aversion procedure in rats, it partially reversed (3 mg/kg i.p.) the decrease of intake of a saccharin solution. Furthermore, SSR181507 increased (3 mg/kg i.p.) the latency time to paradoxical sleep in rats, an effect commonly observed with antidepressants. Coadministration of the selective 5-HT 1A blocker SL88.0338 produced catalepsy and antagonized the effects of SSR181507 in the depression/anxiety tests, confirming the view that activation of 5-HT 1A receptors confers an atypical profile on SSR181507, and is responsible for its antidepressant/anxiolytic properties. Finally, SSR181507 (1-3 mg/kg) did not affect memory performance in a Morris water maze task in rats. The pharmacological profile of SSR181507 suggests that it should control the symptoms of schizophrenia, in the absence of extrapyramidal signs and cognitive deficits, with the additional benefit of antidepressant/anxiolytic activities.

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

“…The present report and its companion paper dealing with the psychopharmacological profile of SSR181507 (Depoortere et al, 2003) provide strong evidence that this dual mechanism of action results in a drug profile compatible with an original, atypical antipsychotic activity.…”

“…In addition, it should be efficacious on schizophrenia-associated mood and anxiety disorders. A companion paper dealing with the psychopharmacological profile of SSR181507 (Depoortere et al, 2003) adds further weight to these hypotheses.…”

“…In the in vitro GTPgS model, it is highly dependent on the density of recombinant 5-HT 1A receptors and in the two preceding in vivo models, it reflects the activity at presynaptic 5-HT 1A receptors (Newman-Tancredi et al, 1998). Interestingly, in an integrated functional model in rats involving 5-HT 1A postsynaptic receptors (serotonergic syndrome), SSR181507 has the profile of a partial 5-HT 1A agonist (Depoortere et al, 2003). The effects of SSR181507 on DA and 5-HT synthesis were of long duration (at least 6 h, results not shown) and persisted after repeated treatment for 20 days, demonstrating that there is no development of tolerance.…”

“…In the present study, we report on the binding profile of this compound and its intrinsic and functional activity at these two receptors, on its electrophysiological (firing of serotonergic cell bodies of dorsal raphe nucleus (DRN), number of active cells in DA cell bodies) and neurochemical (Fos expression, basal and evoked DA efflux) profile in support of the above-mentioned hypothesis. A companion paper (Depoortere et al, 2003) provides further psychopharmacological evidence to this end.…”

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

“…Besides, there is ample preclinical evidence that activation of 5-HT 1A receptors should also prove beneficial in schizophrenia (Millan, 2000;Bantick et al, 2001;Ichikawa et al, 2001). Hence, it has been repeatedly shown that 5-HT 1A receptor agonists prevent catalepsy (an animal model of EPS) produced by blockade of DA D 2 receptors (Wadenberg and Ahlenius, 1991;Wadenberg et al, 1994;Neal-Beliveau et al, 1993;Prinssen et al, 1998Prinssen et al, , 1999Depoortere et al, 2003;Kleven et al, 2005). Consistent with this idea, clinical studies have reported that buspirone and tandospirone, two partial agonists at 5-HT 1A receptors, reduce the incidence of EPS in schizophrenic patients treated with haloperidol (Sumiyoshi et al, 2001a, b).…”