Clozapine-Induced Locomotor Suppression is Mediated by 5-HT2A Receptors in the Forebrain

Abstract

The need for safer, more effective therapeutics for the treatment of schizophrenia is widely acknowledged. To optimally target novel pharmacotherapies, in addition to establishing the mechanisms responsible for the beneficial effects of antipsychotics, the pathways underlying the most severe side effects must also be elucidated. Here we investigate the role of serotonin 2A (5-HT 2A ), serotonin 2C (5-HT 2C ), and dopamine 2 receptors (D 2 ) in mediating adverse effects associated with canonical first-and second-generation antipsychotic drugs in mice. Wild-type (WT) and 5-HT 2A knockout (KO) mice treated with haloperidol, clozapine, and risperidone were assessed for locomotor activity and catalepsy. WT mice showed a marked reduction in locomotor activity following acute administration of haloperidol and high-dose risperidone, which was most likely secondary to the severe catalepsy caused by these compounds. Clozapine also dramatically reduced locomotor activity, but in the absence of catalepsy. Interestingly, 5-HT 2A KO mice were cataleptic following haloperidol and risperidone, but did not respond to clozapine's locomotor-suppressing effects. Restoration of 5-HT 2A expression to cortical glutamatergic neurons re-instated the locomotor-suppressing effects of clozapine in the open field. In sum, we confirm that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D 2 . We also demonstrate that clozapine decreases locomotor activity in a 5-HT 2A -dependent manner, in the absence of catalepsy. Moreover, we show that it is the cortical population of 5-HT 2A that mediate the locomotor-suppressing effects of clozapine.

Sleep Homeostatic and Waking Behavioral Phenotypes inEgr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits

“…11,16 This effect is shown to be mediated, at least in part, by 5-HT2A receptors, 11 and 5-HT2A receptor-deficient mice display the same phenotype. 17 If Egr3 modulates the expression of plasticity-associated genes and serotonergic signaling in a physiologically relevant manner, it may be essential for waking behavior, sleep timing, and the electroencephalographic manifestations of sleep need. It may additionally influence the electroencephalographic response to sedating agents known to act on 5-HT2 receptors, such as clozapine.…”

“…Effects on sleep regulatory mechanisms including gamma-aminobutyric acid (GABA)ergic, adenosinergic, and glutamatergic signaling may also be involved in the response to clozapine. 11,17 Egr3 regulates GABAA receptor subunit expression 29,30 in addition to 5-HT2A receptor expression and function. 8,11 Clozapine antagonizes GABAA binding and produces a functional antagonism of GABAA receptors at synapses.…”

Animal Models of Serotonergic Psychedelics

“…58,80−83 Recent findings suggest that the 5-HT 2A receptor is involved in the locomotor suppressive effects of clozapine. 84,85 Prepulse Inhibition of Startle. Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that refers to the reduction in the startle response produced by a low-intensity nonstartling stimulus (the prepulse) presented shortly before the startle stimulus.…”

Preclinical models of antipsychotic drug action

“…Although the pre-synaptic component of the serotonergic system plays an important role in the antipsychotic-like properties of clozapine (Yadav et al, 2011a), these results with knockout mice suggest that the 5-HT 2A receptor is at least involved in the therapeutic-like effects of atypical antipsychotics, using hyperlocomotor activity induced by PCP-like drugs as a rodent model of psychosis. Recent findings also point toward a role of 5-HT 2A receptors expressed in cortical glutamatergic neurons in the effects of high doses of clozapine, but not haloperidol or risperidone, on locomotor suppression (McOmish et al, 2012; Williams et al, 2012). …”

“…These findings suggest that down-regulation of 5-HT 2A receptor is one of the mechanisms underlying the therapeutic effects of chronic treatment with antipsychotic drugs. Further work is needed to understand the cellular networks responsible for down-regulation of this receptor with antagonists/inverse agonists such as clozapine and olanzapine, as well as their sedative effects (McOmish et al, 2012; Williams et al, 2012). …”