Differences among conventional, atypical and novel putative D2/5-HT1A antipsychotics on catalepsy-associated behaviour in cynomolgus monkeys

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics

“…These motor disorders were consistent with reports of dyskinesias and locomotor depressant changes occurring in monkeys with various other antipsychotics (Casey, ; Fukuoka et al ., ; Goldstein & Snyder, ; Liebman & Neale, ; Peacock & Gerlach, ; Porsolt & Jalfre, ; Rehm et al ., ; Varty et al ., ; Weiss et al ., ). Catalepsy‐associated behavior in monkeys reflected by static postures and unusual positions occurring for prolonged periods of time have been described as well (Auclair et al ., ; Kumar et al ., ). Remarkably, however, JNJ‐37822681 induced EPS‐like signs in the monkey studies at low exposures.…”

“…These observations also seem to contradict the low EPS liability of JNJ‐37822681 predicted from rat pharmacology experiments (Langlois et al ., ). However, monkeys generally tend to be more sensitive than rats to the motor side effects of antipsychotics (Auclair et al ., ). In the case of JNJ‐378722681, a comparison between rats and monkeys in this respect is hampered by the lack of pharmacology data in monkeys.…”

“…JNJ‐37822681 induced complex EPS‐like signs in all four monkey toxicology studies very similar to findings reported for other antipsychotic drugs (Arnsten et al ., ; Auclair et al ., ; Casey, , ; Fukuoka et al ., ; Kumar et al ., ; Peacock & Gerlach, ). These signs included parkinsonism (rigidity, impaired mobility or bradykinesia, staggered movements and tremors), dystonia (sustained abnormal/unusual postures such as standing like a statue or being in a trance‐like state) and dyskinesias (shaking, flicking or rolling head, repetitive movements and flickering eyes).…”

“…In general, they possess a higher affinity to the serotonin 5-HT 2 receptor relative to the dopamine D 2 receptor. Atypical antipsychotics such as risperidone and olanzapine show a lower propensity for EPS than typical antipsychotic drugs, while EPS is virtually absent with clozapine and quetiapine (Auclair et al, 2009;Miyamoto et al, 2005, Pierre, 2005Seeman, 2006;Strange, 2008). Whereas typical antipsychotics raise serum prolactin levels secondary to their dopamine D 2 receptor antagonistic action, most atypicals are less prone to induce sustained hyperprolactinemia (Kapur & Remington, 2001;Kapur & Seeman, 2001).…”

Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist

“…Introduction 5-HT 1A receptors play a major role in serotonergic transmission due to their distinctive brain localization [1,2] : inhibitory presynaptic 5-HT 1A autoreceptors are located on serotonin cell bodies in the raphe nuclei, while postsynaptic 5-HT 1A heteroreceptors are expressed in other brain areas associated with the control of mood (anxiety and depression), cognition and pain . [2][3][4][5] Activation of 5-HT 1A receptors also reverses dopamine D 2 blockade-induced catalepsy, [6][7][8][9] a property exploited in recent antipsychotic drugs to prevent motor side effects. [10][11][12] Furthermore, 5-HT 1A receptor partial agonists such as buspirone, tandospirone and eltoprazine have been clinically tested as add-on therapies to control L-DOPA-induced dyskinesia (LID) in patients with Parkinson's disease (PD).…”