An Open Trial of Buspirone Added to Neuroleptics in Schizophrenic Patients

Combined dopamine D 2 receptor antagonism and serotonin (5-HT) 1A receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D 2/3 antagonist and 5-HT 1A agonist. SLV313 possessed high affinity at human recombinant D 2 , D 3 , D 4 , 5-HT 2B , and 5-HT 1A receptors, moderate affinity at 5-HT 7 and weak affinity at 5-HT 2A receptors, with little-no affinity at 5-HT 4 , 5-HT 6 , a 1 , and a 2 (rat), H 1 (guinea pig), M 1 , M 4 , 5-HT 3 receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT 1A receptors (pEC 50 ¼ 9.0) and full antagonist activity at hD 2 (pA 2 ¼ 9.3) and hD 3 (pA 2 ¼ 8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT 1A syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT 1A antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT 1A -dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT 1A receptor agonist and full D 2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia. Neuropsychopharmacology (2007) 32, 78-94.

Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug

McCreary

Glennon

Ashby

et al. 2006

“…Catalepsy is an animal model considered to be predictive of occurrence of EPS, and the absence of cataleptogenic activity of SSR181507 suggests that this compound should be free from motor side effects in patients. Indeed, in the clinic, there are indications that augmentation of antipsychotic therapy with the 5-HT 1A receptor partial agonists buspirone (Goff et al, 1991;Moss et al, 1993) and tandospirone (Yoshida et al, 1998) decreases EPS and/or akathisia and/or tardive dyskinesia scores. Activation of 5-HT 1A receptors has been generally associated with occurrence of the serotonergic syndrome (forepaw treading and flat body posture) in rats, seen following treatment with 5-HT 1A receptor full agonists such as 8-OH-DPAT (Goodwin et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…8-OH-DPAT, the prototypical 5-HT 1A receptor full agonist, blocked catalepsy produced by haloperidol (Broekkamp et al, 1988;Invernizzi et al, 1988) and reduced dyskinesia in monkeys chronically treated with DA D 2 blockers (Christoffersen and Meltzer, 1998;Liebman et al, 1989). In the clinic, buspirone and tandospirone, two 5-HT 1A receptor partial agonists, have been shown to decrease parkinsonian signs or tardive dyskinesia in schizophrenic patients treated with antipsychotics (Goff et al, 1991;Moss et al, 1993;Yoshida et al, 1998). In addition, when added onto antipsychotics, tandospirone improved cognition in patients (Sumiyoshi et al, 2000(Sumiyoshi et al, , 2001.…”

Section: Introductionmentioning

confidence: 99%

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

Depoortère

Boulay

Perrault

et al. 2003

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.

“…Furthermore, 5-HT 1A agonists attenuate certain DA D 2 receptormediated motor side effects: 8-OH-DPAT and ipsapirone, two prototypical 5-HT 1A receptor agonists, prevent or reduce haloperidol-induced catalepsy in rodents (Wadenberg and Ahlenius, 1991). In clinical studies, signs of Parkinsonism were improved by the addition of buspirone (Goff et al, 1991) to neuroleptic-treated schizophrenic patients. Thus, DA D 2 receptor antagonists with high affinity and agonist properties at the 5-HT 1A receptor should have a low incidence of EPS.…”

Section: Introductionmentioning

confidence: 99%

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

Claustre

Peretti

Brun

et al. 2003

monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT 1A receptors (K I ¼ 0.8, 0.2, and 0.2 nM for human D 2 , D 3 , and 5-HT 1A , respectively). In vivo, SSR181507 inhibited [ 3 H]raclopride binding to D 2 receptors in the rat (ID 50 ¼ 0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D 2 antagonist and 5-HT 1A agonist properties in the same concentration range in vitro (IC 50 ¼ 5.3 nM and EC 50 ¼ 2.3 nM, respectively, in the GTPgS model) and in the same dose range in vivo (ED 50 ¼ 1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D 2 receptor antagonism and 5-HT 1A agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.