Abstract
RationaleWe recently introduced a new rat model of emotional hyperthermia in which a salient stimulus activates brown adipose tissue (BAT) thermogenesis and tail artery constriction. Antipsychotic drugs, both classical and second generation, act to reduce excessive assignment of salience to objects and events in the external environment. The close association between salient occurrences and increases in body temperature suggests that antipsychotic drugs may also reduce emotional hyperthermia.ObjectivesWe determined whether chlorpromazine, clozapine, and risperidone dose dependently reduce emotionally elicited increases in BAT thermogenesis, cutaneous vasoconstriction, and body temperature in rats.MethodsRats, chronically instrumented for measurement of BAT and body temperature and tail artery blood flow, singly housed, were confronted with an intruder rat (confined within a small wire-mesh cage) after systemic pre-treatment of the resident rat with vehicle or antipsychotic agent. BAT and body temperatures, tail blood flow, and behavioral activity were continuously measured.ResultsClozapine (30 μg–2 mg/kg), chlorpromazine (0.1–5 mg/kg), and risperidone (6.25 μg–1 mg/kg) robustly and dose-relatedly reduced intruder-elicited BAT thermogenesis and tail artery vasoconstriction, with consequent dose-related reduction in emotional hyperthermia.ConclusionsChlorpromazine, a first-generation antipsychotic, as well as clozapine and risperidone, second-generation agents, dose-dependently reduce emotional hyperthermia. Dopamine D2 receptor antagonist properties of chlorpromazine do not contribute to thermoregulatory effects. Interactions with monoamine receptors are important, and these monoamine receptor interactions may also contribute to the therapeutic effects of all three antipsychotics. Thermoregulatory actions of putative antipsychotic agents may constitute a biological marker of their therapeutic properties.
Highlights
Inappropriate attribution of salience to insignificant stimuli is a core feature of the psychotic process in schizophrenia, contributing to impaired attention and fragmented consciousness, as well as to positive symptoms, including delusions (Barkus et al 2014; Jensen and Kapur 2009; Kapur 2003; McGhie and Chapman 1961; Roiser et al 2013)
Thermoregulatory actions of putative antipsychotic agents may constitute a biological marker of their therapeutic properties
Because Brown adipose tissue (BAT) thermogenesis and cutaneous vasoconstriction are directly controlled by sympathetic outflow from the central nervous system (CNS), emotional hyperthermia is a primary physiological event, not secondary to behavioral activity triggered by the salient event
Summary
Inappropriate attribution of salience to insignificant stimuli is a core feature of the psychotic process in schizophrenia, contributing to impaired attention and fragmented consciousness, as well as to positive symptoms, including delusions (Barkus et al 2014; Jensen and Kapur 2009; Kapur 2003; McGhie and Chapman 1961; Roiser et al 2013). Effects of antipsychotic agents on salience-related biological processes have been assessed principally for pre-pulse inhibition of the startle response to a sudden unexpected sound (PPI) (Braff and Geyer 1990). An additional model in which antipsychotic agents, both classical and second generation, have consistent robust dose-dependent effects on a separate salience-related physiological process would be valuable, especially if, like PPI, the model is applicable to both laboratory animals and humans. Because BAT thermogenesis and cutaneous vasoconstriction are directly controlled by sympathetic outflow from the central nervous system (CNS), emotional hyperthermia is a primary physiological event, not secondary to behavioral activity triggered by the salient event. Threatening or frankly stressful events are more potent stimuli for BAT thermogenesis, but any novel or unexpected event increases cutaneous sympathetic discharge, as documented in humans (Delius et al 1972)
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