Alpha-adrenergic receptor agonists prevent emotional hyperthermia.

Emotionally significant stimuli, including potential threats from the external environment, trigger an increase in body temperature, a response known as emotional hyperthermia. Sympathetically-mediated brown adipose tissue (BAT) thermogenesis contributes substantially to this hyperthermic response. The systemic administration of α-adrenergic agonists is known to inhibit both febrile and shivering responses.

Activating dopamine D2 receptors reduces brown adipose tissue thermogenesis induced by psychological stress and by activation of the lateral habenula.

Emotional hyperthermia is the increase in body temperature that occurs as a response to an animal detecting a salient, survival-relevant stimulus. Brown adipose tissue (BAT) thermogenesis, controlled via its sympathetic innervation, contributes to this temperature increase. Here, we have used an intruder rat experimental model to determine whether quinpirole-mediated activation of dopamine D receptors attenuates emotional hyperthermia in conscious rats.

Thermoregulation and the ultradian basic rest-activity cycle.

Daily life involves interactions with the external environment. In rats these apparently spontaneous interactions, often associated with the search for food, alternate with periods of rest in both the dark and light periods of the 24-hour day. Kleitman, in whose laboratory rapid eye movement sleep was discovered, referred to the temporal pattern as "the basic rest-activity cycle.

Neurons in ventral tegmental area tonically inhibit sympathetic outflow to brown adipose tissue: possible mediation of thermogenic signals from lateral habenula.

The lateral habenula (LHb), a nucleus involved in the response to salient, especially adverse, environmental events, is implicated in brown adipose tissue (BAT) thermogenesis caused by these events. LHb-elicited thermogenesis involves a neural pathway to the lower brain stem sympathetic control center in the medullary raphé. There are no direct connections from the LHb to the medullary raphé.

Clozapine, chlorpromazine and risperidone dose-dependently reduce emotional hyperthermia, a biological marker of salience.

Rationale: We 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.

Lateral habenula regulation of emotional hyperthermia: mediation via the medullary raphé.

The lateral habenula (LHb) has an important role in the behavioural response to salient, usually aversive, events. We previously demonstrated that activation of neurons in the LHb increases brown adipose tissue (BAT) thermogenesis and constricts the cutaneous vascular bed, indicating that the LHb contributes to the central control of sympathetic outflow to thermoregulatory effector organs. We have now investigated whether the LHb mediates BAT thermogenesis elicited by emotional stress, and whether the LHb modulates thermoregulatory sympathetic outflow via the rostral medullary raphé, a key integrative lower brainstem sympathetic control centre.

Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery.

The amygdala, innervated by the noradrenergic locus coeruleus, processes salient environmental events. α2-adrenoceptor-stimulating drugs (clonidine-like agents) suppress the behavioral and physiological components of the response to salient events. Activation of sympathetic outflow to the cutaneous vascular bed is part of the physiological response to salience-mediated activation of the amygdala.

Atypical antipsychotics cause an acute increase in cutaneous hand blood flow in patients with schizophrenia and schizoaffective disorder.

Objective: Clinical studies suggest resting thermoregulatory cutaneous vasomotor tone could be increased in schizophrenia, resulting in reduced hand blood flow. In animal models, atypical antipsychotics including clozapine potently inhibit sympathetic neural outflow to the thermoregulatory cutaneous vascular beds. We have now determined whether antipsychotic medication administration is associated with an acute increase in hand blood flow in patients with schizophrenia and schizoaffective disorder, and whether this increase correlates with clinical status.

SR59230A, a beta-3 adrenoceptor antagonist, inhibits ultradian brown adipose tissue thermogenesis and interrupts associated episodic brain and body heating.

Brown adipose tissue (BAT) thermogenesis occurs episodically in an ultradian manner approximately every 80-100 min during the waking phase of the circadian cycle, together with highly correlated increases in brain and body temperatures, suggesting that BAT thermogenesis contributes to brain and body temperature increases. We investigated this in conscious Sprague-Dawley rats by determining whether inhibition of BAT thermogenesis via blockade of beta-3 adrenoceptors with SR59230A interrupts ultradian episodic increases in brain and body temperatures and whether SR59230A acts on BAT itself or via sympathetic neural control of BAT. Interscapular BAT (iBAT), brain, and body temperatures, tail artery blood flow, and heart rate were measured in unrestrained rats.

Sympathetic cutaneous vasomotor alerting responses (SCVARs) are associated with hippocampal theta rhythm in non-moving conscious rats.

Alerting stimuli that cause sympathetic cutaneous vasomotor alerting responses ("SCVARs") in the thermoregulatory vascular bed of the rabbit ear pinna also induce theta (5-8 Hz) rhythm in the hippocampal EEG, a marker that the animal is engaged with the environment. The present study determines the relation between SCVARs in the thermoregulatory tail artery vascular bed and hippocampal EEG theta rhythm in Sprague-Dawley rats. A Doppler ultrasonic flow probe chronically implanted around the base of the tail artery was used to measure SCVARs.

Selective blockade of 5-HT2A receptors attenuates the increased temperature response in brown adipose tissue to restraint stress in rats.

Previous studies have demonstrated that 5-HT2A receptors may be involved in the central control of thermoregulation and of the cardiovascular system. Our aim was to test whether these receptors mediate thermogenic and tachycardiac responses induced by acute psychological stress. Three groups of adult male Hooded Wistar rats were instrumented with: (i) a thermistor in the interscapular area (for recording brown adipose tissue temperature) and an ultrasound Doppler probe (to record tail blood flow); (ii) temperature dataloggers to record core body temperature; (iii) ECG electrodes.

Fever response to intravenous prostaglandin E2 is mediated by the brain but does not require afferent vagal signaling.

PGE2 produced in the periphery triggers the early phase of the febrile response to infection and may contribute to later phases. It can be hypothesized that peripherally synthesized PGE2 transmits febrigenic signals to the brain via vagal afferent nerves. Before testing this hypothesis, we investigated whether the febrigenic effect of intravenously administered PGE2 is mediated by the brain and is not the result of a direct action of PGE2 on thermoeffectors.

Serotonin-synthesizing neurons in the rostral medullary raphé/parapyramidal region transneuronally labelled after injection of pseudorabies virus into the rat tail.

Serotonin-synthesizing raphé/parapyramidal neurons (5-HT neurons) may function as sympathetic premotor neurons regulating sympathetic outflow to the cutaneous vascular bed. In the present study a genetically engineered pseudorabies virus (PRV) expressing green fluorescent protein (GFP) was injected into the rat tail. After survival for 3-4 days the medulla oblongata was examined using double-label immunohistochemistry, with an antibody against GFP for the virus and an antibody against phenylalanine hydroxylase 8 (PH8) for 5-HT synthesis.

Activation of 5-HT1A receptors in rostral medullary raphé inhibits cutaneous vasoconstriction elicited by cold exposure in rabbits.

In both conscious and anesthetized rabbits, we determined whether microinjection of a 5-hydroxytryptamine (5-HT) 1A receptor agonist 8-hydroxy-2-(di-n-propylaminio) tetralin (8-OH-DPAT) into the medullary raphé/parapyramidal region inhibits thermoregulatory vasoconstriction and whether microinjection of a 5-HT1A receptor antagonist (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) (WAY-100635) into the raphé reverses the cutaneous vasomotor changes induced by intravenous administration of 8-OH-DPAT. In conscious rabbits with measuring ear pinna blood flow, after microinjection of 8-OH-DPAT (3-5 nmol in 300-500 nl) into the raphé, transferring the animal from a warm cage (25-28 degrees C) to a cold cage (5-10 degrees C) did not reduce the ear pinna flow (from 57 +/- 7 cm/s to 59 +/- 3 cm/s, P > 0.05, n = 5), unlike Ringer-treated animals.

Thermogenesis in brown adipose tissue: increase by 5-HT2A receptor activation and decrease by 5-HT1A receptor activation in conscious rats.

Body temperature is decreased by 5-hydroxytryptamine 1A (5-HT1A) agonists and increased by 5-HT2A agonists. The present study determined whether changes in interscapular brown adipose tissue (iBAT) thermogenesis contribute to these effects in conscious unrestrained animals. Male Sprague-Dawley rats were pre-instrumented for measurement of iBAT and core temperature and tail artery blood flow one week before experiments.

Inhibition of medullary raphé/parapyramidal neurons prevents cutaneous vasoconstriction elicited by alerting stimuli and by cold exposure in conscious rabbits.

In conscious rabbits, microinjection of muscimol into the medullary raphé/parapyramidal region decreased fluctuation (coefficient variation) of resting ear blood flow (from 62 +/- 8 to 25 +/- 4%, P < 0.01, n = 8). The muscimol injection also prevented falls in ear blood flow that normally occur in response to alerting stimuli and to cold exposure.

Clozapine increases cutaneous blood flow and reduces sympathetic cutaneous vasomotor alerting responses (SCVARs) in rats: comparison with effects of haloperidol.

Rationale: Clozapine inhibits sympathetic outflow to the cutaneous vascular bed. Clozapine reverses hyperthermia and cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) or by lipopolysaccharide (LPS). Clozapine also reverses cutaneous vasoconstriction elicited by exposure to cold.

Activation of 5-HT1A receptors in the medullary raphe reduces cardiovascular changes elicited by acute psychological and inflammatory stresses in rabbits.

The present strategy for the prevention of excessive sympathetic neural traffic to the heart relies on the use of beta-blockers, drugs that act at the heart end of the brain-heart axis. In the present study, we attempted to suppress cardiac sympathetic nerve activity by affecting the relevant cardiomotoneurons in the brain using the selective serotonin-1A (5-HT(1A)) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In conscious, unrestrained rabbits, instrumented for recordings of heart rate, arterial pressure, or cardiac output, we provoked increases in cardiac sympathetic activity by psychological (loud sound, pinprick, and air jet) or inflammatory (0.

Activation of slowly conducting medullary raphe-spinal neurons, including serotonergic neurons, increases cutaneous sympathetic vasomotor discharge in rabbit.

Neurons in the rostral medullary raphe/parapyramidal region regulate cutaneous sympathetic nerve discharge. Using focal electrical stimulation at different dorsoventral raphe/parapyramidal sites in anesthetized rabbits, we have now demonstrated that increases in ear pinna cutaneous sympathetic nerve discharge can be elicited only from sites within 1 mm of the ventral surface of the medulla. By comparing the latency to sympathetic discharge following stimulation at the ventral raphe site with the corresponding latency following stimulation of the spinal cord [third thoracic (T3) dorsolateral funiculus] we determined that the axonal conduction velocity of raphe-spinal neurons exciting ear pinna sympathetic vasomotor nerves is 0.

Spinal 5-HT2A receptors regulate cutaneous sympathetic vasomotor outflow in rabbits and rats; relevance for cutaneous vasoconstriction elicited by MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") and its reversal by clozapine.

We determined whether spinal 5-hydroxytryptamine 2A (5-HT2A) receptors contribute to resting cutaneous sympathetic vasomotor activity, and to increases in activity elicited by electrical stimulation of the medullary raphe/parapyramidal region, and whether these receptors are involved in the cutaneous vasoconstricting action of systemically administered MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") and its reversal by clozapine. Experiments were conducted in urethane-anesthetized rabbits and rats. Administration of the 5-HT2A antagonist, trans-4-((3Z)3-[(2-Dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate (SR 46349B, 0.

Clozapine and olanzapine, but not haloperidol, reverse cold-induced and lipopolysaccharide-induced cutaneous vasoconstriction.

Rationale: Reduction of body temperature is used as predictor of psychotropic drug action. The cutaneous circulation functions as a heat-loss component of temperature regulation. Clozapine and olanzapine reverse hyperthermia and sympathetically-mediated cutaneous vasoconstriction induced by MDMA (3,4-methylenedioxymethamphetamine, ecstasy), suggesting that these drugs might reverse other forms of sympathetically mediated cutaneous vasoconstriction.

Inhibition of rostral medullary raphé neurons prevents cold-induced activity in sympathetic nerves to rat tail and rabbit ear arteries.

Sympathetically-mediated vasoconstriction of cutaneous vessels is critical for thermoregulation in the cold. We determined whether cold-induced sympathetic discharge depends on activity of neurons in the rostral medullary raphé. In urethane-anesthetized rats and rabbits, cooling the trunk skin by a water jacket reproducibly increased cutaneous sympathetic discharge recorded in the tail (rats) and the ear pinna (rabbits).

Ventricular arrhythmias triggered by alerting stimuli in conscious rabbits pre-treated with dofetilide.

We tested whether normally benign alerting/arousing stimuli provoke cardiac arrhythmias in conscious rabbits with electrically unstable myocardium. Alerting stimuli (loud sound, tapping and moving the cage, pinprick, inhalation of formaldehyde vapour) were presented before and after administration of dofetilide to conscious unrestrained rabbits (New Zealand White). Dofetilide (0.

Potential role of medullary raphe-spinal neurons in cutaneous vasoconstriction: an in vivo electrophysiological study.

In rabbits, raphe magnus/pallidus neurons form a link in the CNS pathway regulating changes in cutaneous blood flow elicited by nociceptive stimulation and activation of the central nucleus of the amygdala. To characterize relevant raphe-spinal neurons, we performed extracellular recordings from the rostral medullary raphe nuclei in anesthetized, paralyzed, mechanically ventilated rabbits. All studied neurons were antidromically activated from the dorsolateral funiculus of the spinal cord (C(8)-T(2)).