Inactivation of neuronal function in the amygdaloid region reduces tail artery blood flow alerting responses in conscious rats.

Few studies have investigated whether neuronal function in the amygdaloid complex is necessary for the occurrence of the cardiovascular response to natural (unconditioned) environmental threats. In the present investigation in conscious unrestrained Sprague-Dawley rats we inactivated neuronal function in the amygdaloid complex acutely (bilateral muscimol injections) or chronically (unilateral or bilateral ibotenic acid injections) and measured the effect on sudden falls in tail artery blood flow elicited by non-noxious salient stimuli (sympathetic cutaneous vasomotor alerting responses, SCVARs). After acute bilateral injection of vehicle (200nl Ringer's solution) the SCVAR index was 81 ± 2%, indicating that tail blood flow was reduced by 81% in response to the salient stimuli. After acute bilateral injection of muscimol (1 nmol in 200 nl of Ringer's solution) into the amygdaloid complex the SCVAR index was 49 ± 5%, indicating that tail blood flow was reduced by 49% in response to the salient stimuli (p<0.01 versus vehicle, n=7 rats for vehicle and 6 for muscimol). One week after unilateral ibotenic acid lesions, the SCVAR index was 68 ± 3%, significantly less than 90 ± 1%, the corresponding value after unilateral injection of vehicle (p<0.01, n=6 rats in each group). After bilateral ibotenic acid lesions the SCVAR index was 52 ± 4%, significantly less than 93 ± 1%, the corresponding value after bilateral injection of vehicle (p<0.001, n=6 rats in each group). Ibotenic acid caused extensive neuronal destruction of the whole amygdaloid complex, as well as lateral temporal lobe structures including the piriform cortex. Our results demonstrate that the amygdaloid complex plays an important role in mediating the tail artery vasoconstriction that occurs in rats in response to the animal's perception of a salient stimulus, redirecting blood to areas of the body with more immediate metabolic requirements.

JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow in rats: Involvement of serotonin 5-HT1A and 5-HT2A receptor mechanisms.

Clozapine is an effective atypical antipsychotic agent, with serious side effects. JL13 [5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine] is a potential new atypical antipsychotic, structurally modified from clozapine to resist oxidation so as to reduce haematological and cardiological side effects. To assess the potential clinical potency of JL13 we tested its action in a newly described animal model based on the ability of clozapine-like agents to affect brain mechanisms controlling sympathetic outflow to thermoregulatory cutaneous vascular beds. We determined whether JL13 has clozapine-like inhibitory actions on alerting-induced falls in tail artery blood flow (sympathetic cutaneous vasomotor alerting responses, SCVARs) in rats, and whether actions on dopamine D(2), and/or 5-HT(1A) receptors are involved in these effects of JL13. The tail artery Doppler flow signal was recorded in conscious freely moving Sprague-Dawley rats before and after alerting stimuli (e.g. cage tap). The percentage fall in flow in response to an alerting stimulus was quantified as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%). We used pre-treatment with spiperone and WAY100635, before JL13, to assess the role of D(2) and 5-HT(1A) receptors. In addition, the role of 5-HT(2A) receptors in the action of JL13 was assessed by determining whether JL13 prevented and reversed the CNS-mediated tail artery vasoconstricting actions of DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), an agonist at 5-HT(2A) receptors. JL13 (0.0625-5.0mg/kg s.c.) dose-dependently inhibited SCVARs, less potently than clozapine. WAY100635 but not spiperone reduced the inhibition. JL13 prevented and reversed DOI-induced vasoconstriction. Thus JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow, but the drug is 5 times less potent than clozapine. Stimulation of 5-HT(1A) and blockade of 5-HT(2A) receptors may contribute to the effects, but dopamine D(2) receptors are apparently not involved in the action of JL13.

Brown adipose tissue thermogenesis heats brain and body as part of the brain-coordinated ultradian basic rest-activity cycle.

Brown adipose tissue (BAT), body and brain temperatures, as well as behavioral activity, arterial pressure and heart rate, increase episodically during the waking (dark) phase of the circadian cycle in rats. Phase-linking of combinations of these ultradian (<24 h) events has previously been noted, but no synthesis of their overall interrelationships has emerged. We hypothesized that they are coordinated by brain central command, and that BAT thermogenesis, itself controlled by the brain, contributes to increases in brain and body temperature. We used chronically implanted instruments to measure combinations of bat, brain and body temperatures, behavioral activity, tail artery blood flow, and arterial pressure and heart rate, in conscious freely moving Sprague-Dawley rats during the 12-h dark active period. Ambient temperature was kept constant for any particular 24-h day, varying between 22 and 27 degrees C on different days. Increases in BAT temperature (> or = 0.5 degrees C) occurred in an irregular episodic manner every 94+/-43 min (mean+/-SD). Varying the temperature over a wider range (18-30 degrees C) on different days did not change the periodicity, and neither body nor brain temperature fell before BAT temperature episodic increases. These increases are thus unlikely to reflect thermoregulatory homeostasis. Episodic BAT thermogenesis still occurred in food-deprived rats. Behavioral activity, arterial pressure (18+/-5 mmHg every 98+/-49 min) and heart rate (86+/-31 beats/min) increased approximately 3 min before each increase in BAT temperature. Increases in BAT temperature (1.1+/-0.4 degrees C) were larger than corresponding increases in brain (0.8+/-0.4 degrees C) and body (0.6+/-0.3 degrees C) temperature and the BAT episodes commenced 2-3 min before body and brain episodes, suggesting that BAT thermogenesis warms body and brain. Hippocampal 5-8 Hz theta rhythm, indicating active engagement with the environment, increased before the behavioral and autonomic events, suggesting coordination by brain central command as part of the 1-2 h ultradian basic rest-activity cycle (BRAC) proposed by Kleitman.

When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: effects of pretreatment with 5-HT1A and dopamine D2 antagonists.

When given in a warm environment MDMA (3,4-methylenedioxymethamphetamine, ecstasy) causes hyperthermia by increasing interscapular brown adipose tissue (iBAT) heat production and decreasing heat loss via cutaneous vasoconstriction. When given in a cold environment, however, MDMA causes hypothermia by an unknown mechanism. This paper addresses these mechanisms and in addition examines whether antagonists at 5-HT(1A) and D(2) receptors reduce the hypothermic action of MDMA. Male Sprague-Dawley rats instrumented with a Doppler probe for measuring tail blood flow, and probes for measuring core and iBAT temperatures, were placed in a temperature-controlled chamber. The chamber temperature was reduced to 10 degrees C and vehicle (0.5 ml Ringer), the 5-HT(1A) antagonist WAY 100635 (0.5 mg/kg), the D(2) antagonist spiperone (20 mug/kg), or the combination of Way 100635 and spiperone were injected s.c. Thirty minutes later the antagonists were injected again along with MDMA (10 mg/kg) or vehicle. MDMA reduced core body temperature by preventing cold-elicited iBAT thermogenesis and by transiently reversing cold-elicited cutaneous vasoconstriction. Pretreatment with WAY 100635 prevented MDMA induced increases in tail blood flow, and briefly attenuated MDMA's effects on iBAT and core temperature. While spiperone alone failed to affect any of the parameters, the combination of spiperone and WAY 100635 decreased MDMA-mediated hypothermia by attenuating both the effects on tail blood flow and iBAT thermogenesis. MDMA's prevention of cold-induced iBAT thermogenesis appears to have a central origin as it rapidly reverses cold-induced increases in iBAT sympathetic nerve discharge in anesthetized rats. Our results demonstrate that MDMA in a cold environment reduces core body temperature by inhibiting iBAT thermogenesis and tail artery vasoconstriction and suggest that mechanisms by which this occurs include the activation of 5-HT1A and dopamine D2 receptors.

Dopamine D2 receptor stimulation inhibits cold-initiated thermogenesis in brown adipose tissue in conscious rats.

Dopamine D(2)-like receptor agonists cause hypothermia. We investigated whether inhibiting heat production by interscapular brown adipose tissue (iBAT), a major thermogenic organ in rats, contributes to hypothermia caused by dopamine D(2)-like receptor agonists. Temperature of iBAT and tail artery blood flow were measured in conscious rats. Activity in postganglionic sympathetic nerves supplying iBAT was assessed in anesthetized rats. Conscious rats were housed in a warm cage maintained at 26-28 degrees C and then transferred to a cold cage at 5-10 degrees C to induce iBAT thermogenesis. Cold exposure increased iBAT temperature (+0.7+/-0.1 degrees C, 30 min after transferring to the cold cage, P<0.01, n=54). The mixed dopamine D(2)/D(3) receptor agonist, 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT, 0.5 mg/kg s.c.) reversed the cold-induced increase in iBAT temperature (-2.8+/-0.2 degrees C at 30 min after 7-OH-DPAT treatment during cold exposure vs. +0.3+/-0.1 degrees C at 30 min after vehicle treatment during cold exposure, n=8). These temperature changes were blocked by pre-treatment with the D(2) receptor antagonists spiperone (20 microg/kg i.p.) and L-741,626 (2.5 mg/kg i.p.), but not by the selective D(3) receptor antagonist SB-277011A (10 mg/kg i.p.). Another mixed dopamine D(2)/D(3) receptor agonist, quinpirole (0.5 mg/kg s.c.) also reversed cold-induced iBAT thermogenesis, and this effect was also prevented by pre-treatment with spiperone, but not with a peripherally acting dopamine receptor antagonist, domperidone (2 mg/kg s.c.). Neither 7-OH-DPAT nor quinpirole reversed cutaneous vasoconstriction elicited by cold exposure. In anesthetized rats, quinpirole (0.5 mg/kg i.v.) abolished iBAT sympathetic nerve discharge elicited by cooling the trunk, and this change was reversed by spiperone (20 microg/kg i.v.). These results demonstrate that activation of CNS dopamine D(2) receptors inhibits sympathetically-mediated iBAT thermogenesis in response to cold exposure. Furthermore, they suggest that in rats hypothermia induced by dopamine D(2) receptor agonists in cold environments is mainly due to decreased heat production rather than to increased heat loss.

Activation of dopamine D2 receptors in the CNS inhibits sympathetic cutaneous vasomotor alerting responses (SCVARs), contributing to clozapine's SCVAR-inhibiting action.

Sympathetic neural outflow to thermoregulatory cutaneous vascular beds is selectively activated when the individual is aroused, so that cutaneous blood flow is characterized by sudden alerting-related falls to near zero levels ("SCVARs", sympathetic cutaneous vasomotor alerting responses). Our previous work shows that clozapine, an atypical antipsychotic drug used in schizophrenia, profoundly inhibits SCVARs. Clozapine, conventionally assumed to have a dopamine D(2) receptor antagonist action, also increases baseline cutaneous blood flow and lowers body temperature. However dopamine D(2) receptor agonists lower temperature, suggesting that a dopamine D(2)agonist action might also reduce SCVARs. The present study determined whether a dopamine D(2)agonist action contributes to clozapine's SCVAR-inhibiting effect. SCVARs were measured in conscious rats with a Doppler ultrasonic flow probe chronically implanted around the base of the artery, with probe wires passing subcutaneously to a headpiece. Doppler signals were monitored via a flexible connection between the headpiece and a swivel device in the roof of the cage. Apomorphine (0.1-0.5 mg/kg), quinpirole (0.05-0.25 mg/kg) and 7-OH-DPAT (0.02-0.5 mg/kg) dose-dependently reduced SCVARs. Pre-treatment with the dopamine receptor antagonist spiperone (20 microg/kg) but not the D(1) antagonist SCH-23390 or the peripheral dopamine D(2) antagonist domperidone, abolished this effect. Spiperone pre-treatment reduced the SCVAR-inhibiting action of clozapine (0.06-1.0 mg/kg). Chlorpromazine (0.1-10 mg/kg) also dose-dependently inhibited SCVARs, but this effect was not reduced by pre-treatment with spiperone. Mechanisms underlying clozapine's SCVAR-inhibiting effect include dopamine D(2) receptor agonism, not dopamine D(2) receptor antagonism, calling into question the mechanism of the drug's therapeutic action in schizophrenia.

Clozapine reverses increased brown adipose tissue thermogenesis induced by 3,4-methylenedioxymethamphetamine and by cold exposure in conscious rats.

Clozapine, an atypical antipsychotic agent important for the treatment of schizophrenia, has marked inhibitory effects on sympathetic outflow to the thermoregulatory cutaneous circulation. In rabbits clozapine reverses ear pinna vasoconstriction induced either by administration of MDMA (3,4-methylenedioxymethamphetamine, ecstasy) or by exposing the animal to a cold environment. In rats, both these procedures are known to increase sympathetic activation of interscapular brown adipose tissue (iBAT) thermogenesis, important for heat production in the rat. In the present study in conscious rats we determined whether clozapine reduces iBAT thermogenesis induced by MDMA and by exposure to cold. We designed our study so that we could also determine effects of clozapine on the acute (stress-induced) increases in iBAT thermogenesis initiated by the process of s.c. injection. MDMA increased iBAT temperature (+1.7+/-0.2 degrees C after 90 min, P<0.01, n=14 measurements from seven rats each studied on two occasions). Clozapine acutely reversed the MDMA-elicited increase in iBAT temperature (-1.3+/-0.2 degrees C 60 min after clozapine treatment following MDMA versus +0.3+/-0.2 degrees C for 60 min after vehicle treatment following MDMA, P<0.01, n=7). Clozapine also reduced stress-induced increases in iBAT temperature, as well as increases elicited by exposing rats to a cold (5 degrees C) environment. Results, taken together with our previous findings, suggest that MDMA activates the sympathetic thermoregulatory outputs (including the output to iBAT) that defend body temperature against cold exposure and that increase body temperature in response to environmental stress. Clozapine's marked inhibition of iBAT thermogenesis may provide a clue to its marked tendency to cause obesity when used to treat humans with mental disorders including schizophrenia. Our demonstration in rats that clozapine decreases sympathetically-mediated increases in iBAT temperature elicited by MDMA adds to the likelihood that clozapine and clozapine-like agents might be therapeutically effective in life threatening hyperthermia induced by MDMA in humans.

CRF1 receptor antagonist CP-154,526 reduces cardiovascular responses during acute psychological stress in rabbits.

We examined the effect of CP-154,526 on cardiovascular changes elicited in conscious rabbits by stressful stimuli (loud sound, cage move, pinprick, formaldehyde vapour and air-jet stress). CP-154,526 substantially reduced pressor and heart rate responses to these stimuli (both vagally and sympathetically mediated), and reduced QT shortening during air-jet stress. Blocking of central CRF1 receptors attenuates cardiovascular responses to environmental stimuli, presumably by affecting brain centres that control cardiovascular functions.

5-hydroxytryptamine 1A receptor activation reduces cutaneous vasoconstriction and fever associated with the acute inflammatory response in rabbits.

5-Hydroxytryptamine(1A) (5-HT1A) receptor activation reduces body temperature partially by dilating the thermoregulatory cutaneous vascular bed, thereby increasing heat transfer to the environment. Constriction of this vascular bed, with consequent reduction of heat transfer to the environment, contributes to fever associated with the acute inflammatory response. Thus activation of 5-HT1A receptors might inhibit thermoregulatory cutaneous vasoconstriction and reduce the fever associated with the acute inflammatory response. The present study tested this hypothesis in conscious unrestrained rabbits. The acute inflammatory reaction was induced with i.v. lipopolysaccharide (LPS, 0.5 microg/kg). Body temperature was measured with an i.p. telemetric probe, and ear pinna blood flow was measured with a chronically implanted Doppler ultrasonic probe. 5-HT1A receptors were activated with i.v. 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). LPS increased body temperature by +1.7+/-0.2 degrees C during the first hour after administration. The ear pinna Doppler blood flow signal fell from 69+/-11 to 5+/-1 cm/s within 15 min (n=7, P<0.01) and remained at a low level for approximately 1 h after LPS. When administered 45 min after LPS, 8-OH-DPAT (0.1 mg/kg i.v.) reversed this fall, increasing the Doppler signal from 6+/-1 to 55+/-7 cm/s (P<0.01, n=6), and reduced the rise in body temperature. Treatment with 8-OH-DPAT (0.1 mg/kg i.v.) 5 min before and 30 min after LPS entirely prevented the LPS-induced fall in ear pinna blood flow, and reduced the rise in body temperature from 1.7+/-0.2 degrees C to 0.7+/-0.2 (n=7, P<0.01). Treatment with WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride) (0.1 mg/kg i.v.) prevented and reversed the effects of 8-OH-DPAT. Thus activation of 5-HT1A receptors reduces thermoregulatory cutaneous vasoconstriction and fever occurring as part of the acute inflammatory response. Our findings elucidate the neurotransmitter mechanisms underlying expression of an important component of the febrile response, and suggest that drugs with 5-HT1A agonist properties might be therapeutically useful when it is clinically important to reduce this response.

Lower brainstem pathways regulating sympathetically mediated changes in cutaneous blood flow.

1. When the individual is alerted by painful or salient stimuli, there is a vigorous sympathetically mediated constriction of the cutaneous vascular bed. We investigated central pathways mediating this response using chronically implanted Doppler ultrasonic probes to measure cutaneous blood flow in the rabbit ear pinna and in the rat tail. 2. Blockade of neuronal function in the amygdala prevents cutaneous vasoconstriction elicited by salient stimuli, but does not prevent the response to painful stimuli. Blockade of neuronal function in raphe magnus/pallidus and the parapyramidal region in anesthetized rabbits prevents cutaneous vasoconstriction elicited by painful stimuli. A similar region of the medullary raphe regulates tail artery vasoconstriction in rats. Inhibition of neuronal function in this region reverses cutaneous vasoconstriction induced by cooling the animal. 3. Bulbospinal presympathetic neurons in the rostral medullary raphe region appear to regulate cutaneous blood flow responses occurring as part of the response to painful or dangerous environmental events and as part of the regulation of body temperature.

5-Hydroxytryptamine 1A receptors inhibit cold-induced sympathetically mediated cutaneous vasoconstriction in rabbits.

5-HT1A receptor agonists lower body temperature. We have investigated whether activation of 5-HT1A receptors inhibits cutaneous sympathetic discharge so that dilatation of the cutaneous vascular bed lowers body temperature by increasing heat transfer to the environment. We measured ear pinna blood flow in conscious rabbits (with chronically implanted Doppler ultrasound flow probes), and postganglionic sympathetic vasomotor nerve activity in anaesthetized rabbits. Recordings from conscious rabbits were made in a cage at 26 degrees C and the rabbit was then transferred to a cage at 10 degrees C. The ear pinna Doppler signal fell from 56 +/- 4 cm s-1 in the 26 degrees C cage to 4 +/- 1 cm s-1 (P < 0.0001, n = 24) after 30 min in the 10 degrees C cage, and body temperature increased from 38.8 +/- 0.2 to 39.0 +/- 0.2 degrees C (P < 0.01, n = 24). The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg kg-1 I.V.) reversed the cold-induced fall in ear pinna blood flow (Doppler signal increased from 5 +/- 1 to 55 +/- 8 cm s-1, P < 0.001, n = 7) within 5 min when administered 30 min after transfer to the 10 degrees C cage, and prevented the fall in ear pinna blood flow when administered before the rabbit was transferred to the 10 degrees C cage. Body temperature decreased after administration of 8-OH-DPAT. These changes were abolished by the specific 5-HT1A antagonist WAY-100635 (0.1 mg kg-1 I.V.). In anaesthetized rabbits, 8-OH-DPAT (0.1 mg kg-1 I.V.) reduced resting postganglionic cutaneous sympathetic vasomotor discharge, and prevented the increase normally elicited by cooling the trunk. Our experiments constitute the first demonstration that activation of 5-HT1A receptors powerfully inhibits cold-induced increases in cutaneous sympathetic vasomotor discharge, thereby dilating the cutaneous vascular bed and increasing transfer of heat to the environment.

Clozapine reverses hyperthermia and sympathetically mediated cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (ecstasy) in rabbits and rats.

Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1-5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 +/- 0.5 degrees C in 5 mg/kg clozapine-treated rabbits and 39.0 +/- 0.2 degrees C in olanzapine-treated rabbits, less than untreated animals (41.5 +/- 0.3 degrees C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 +/- 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 +/- 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 +/- 0.5 degrees C, <38.6 +/- 0.3 degrees C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 +/- 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 +/- 1 cm/sec) and the pre-MDMA level (17 +/- 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.

Electrocardiographic changes associated with the nasopharyngeal reflex in conscious rabbits: vago-sympathetic co-activation.

Electrocardiographic responses were assessed in conscious rabbits when the nasopharyngeal reflex was elicited by inhalation of formaldehyde vapour. There was a profound fall in heart rate (224+/-5 to 64+/-4 beats per min (bpm)) associated with abnormal or absent P-waves. There were no changes in the QRS complex. The R-T interval (control value 118+/-4 ms) was initially shortened to 107+/-3 ms and then prolonged to 130+/-4 ms. Heart rate and P-wave changes were prevented by muscarinic cholinergic blockade with methylscopolamine. The R-T shortening was reduced by 79+/-4% by beta-adrenergic blockade with propranolol. Methylscopolamine also unmasked small tachycardic responses (5-25 bpm) in 5/7 animals. This tachycardia was prevented by propranolol. Thus both parasympathetic vagal cardiac nerves and sympathetic cardiac nerves are activated during the nasopharyngeal reflex, with increased vagal effects in the sino-atrial node, and increased sympathetic effects in the ventricular myocardium.

5-hydroxytryptamine(2A) receptors regulate sympathetic nerves constricting the cutaneous vascular bed in rabbits and rats.

Hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is partially due to sympathetically-mediated cutaneous vasoconstriction that impairs normal heat dissipation. MDMA acts by releasing monoamines, including 5-hydroxytryptamine (5-HT), but receptor mechanisms underlying MDMA-elicited hyperthermia and cutaneous vasoconstriction are not known. The specific 5-HT2A agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is a potent hallucinogen that also causes marked hyperthermia, suggesting the possibility that DOI, via stimulation of 5-HT2A receptors, might also cause sympathetically mediated cutaneous vasoconstriction. We tested this hypothesis in conscious unrestrained rabbits and rats. Blood flow was assessed by chronically implanted Doppler ultrasonic flow probes. Body temperature was measured by i.p. telemetric probes. We compared effects of DOI on cutaneous blood flow (ear pinna in rabbits, tail in rats) with effects on mesenteric blood flow and arterial pressure.Hyperthermia induced by DOI (5-100 microgram/kg i.v. in rabbits and 100 microgram/kg s.c. in rats) was preceded and accompanied by markedly reduced blood flow to the cutaneous bed, with no change in flow to the mesenteric bed. In rabbits, DOI (5 microgram/kg i.v.) did not affect arterial pressure or heart rate. DOI (100 microgram/kg i.v.) caused a moderate rise in arterial pressure. In rabbits, the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg i.v.) and AC90179 (0.5 mg/kg i.v.) reversed the ear pinna vasoconstriction induced by DOI (5 microgram/kg i.v.). In rats, ketanserin (3 mg/kg s.c.) reversed tail vasoconstriction and hyperthermia induced by DOI (100 microgram/kg s.c.). In rabbits, the cutaneous vasoconstricting effect of DOI (5 microgram/kg i.v.) was substantially abolished in the ipsilateral ear pinna after interruption of preganglionic sympathetic nerve activity by unilateral section of the cervical sympathetic trunk. Thus hyperthermia evoked by direct stimulation of 5-HT2A receptors is associated with marked sympathetically mediated vasoconstriction, selective for the cutaneous bed. Impairment of the ability to dissipate heat following drug-induced stimulation of 5-HT2A receptors is likely to contribute to hyperthermia induced by MDMA and by hallucinogenic drugs such as LSD.

CRF1-receptor antagonist CP-154526 reduces alerting-related cutaneous vasoconstriction in conscious rabbits.

Cutaneous vasoconstrictor responses elicited by salient stimuli in conscious rabbits may be a sensitive physiological index of emotional arousal/anxiety. Ear-pinna blood flow was measured by preimplanted laser Doppler probes, and animals were exposed to situations involving different types of potentially salient stimuli before and after i.v. administration of CP-154526 (15 mg/kg) or diazepam (4 mg/kg). At rest, ear-pinna blood flow was stable (coefficient of varition=11+/-2) and remained at high level 93+/-13% of test time. Exposure to novel environment elicited flow fluctuations (coefficient of variation=79+/-8) and reduced amount of time spent at high level to 25+/-6%. Defined unconditioned stimuli caused rapid falls in ear-pinna flow, with nociceptive stimulation producing more vigorous and consistent effects (flow response index 0.66+/-0.02) compared with non-nociceptive (flow response index 0.49+/-0.04). CP-154526 slightly raised mean arterial pressure (from 81+/-2 to 93+/-3 mmHg), increased heart rate (from 198+/-1 to 220+/-4 beats/min) and produced a mild vasoconstriction in the ear-pinna bed (flow fell from 46+/-10 to 25+/-6 cm/s). CP-154526 substantially reduced cutaneous vasoconstrictor responses elicited by the exposure to novel environment and by defined non-nociceptive stimuli, with flow-response index fall from 0.53+/-0.10 to 0.17+/-0.09 and from 0.47+/-0.04 to 0.24+/-0.04, respectively, without affecting responses to nociceptive stimuli. Diazepam reduced only vasoconstrictor responses elicited by the exposure to novel environment, with flow-response index fall from 0.40+/-0.12 to 0.27+/-0.07. Sensitivity of rapid changes in rabbit ear-pinna blood flow to anxiolytic drugs supports the idea that increased cutaneous vascular tone reflects enhanced arousal in rabbits.

Cutaneous vasoconstriction contributes to hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy) in conscious rabbits.

3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") increases body temperature. This process could be associated with increased cutaneous blood flow, as normally occurs with exercise-induced hyperthermia. Alternatively, an MDMA-induced fall in cutaneous blood flow could contribute to the hyperthermia by diminishing normal heat transfer from the body to the environment. We investigated these possibilities by administering MDMA (1.5-6 mg/kg, i.v.) to conscious freely moving rabbits, determining effects on body temperature, cutaneous blood flow (measured by a Doppler ultrasonic probe that was chronically implanted around the ear pinna artery), and other cardiovascular parameters. MDMA caused a dose-dependent increase in body temperature (from 38.3 +/- 0.3 to 41.2 +/- 0.4 degrees C after 6 mg/kg; p < 0.01; n = 5), preceded and accompanied by a dose-dependent cutaneous vasoconstriction (from 29 +/- 6 to 5 +/- 1 cm/sec after 6 mg/kg; p < 0.01; n = 5). MDMA (3 mg/kg) did not change blood flow to the mesenteric vascular bed. Prior unilateral cervical sympathectomy reduced the increase in body temperature elicited by MDMA (6 mg/kg) from 2.0 +/- 0.2 to 1.3 +/- 0.2 degrees C (p < 0.01; n = 5). On the denervated side, ear pinna blood flow after MDMA injection was 13 +/- 3 cm/sec, compared with 3 +/- 1 cm/sec on the sympathetically intact side (p < 0.05; n = 5). Thus, sympathetically mediated cutaneous vasoconstriction is one mechanism whereby MDMA causes hyperthermia. Reversal of cutaneous vasoconstriction by appropriate pharmacological means could be of therapeutic benefit in humans suffering from life-threatening hyperthermia induced by MDMA.

Raphe magnus/pallidus neurons regulate tail but not mesenteric arterial blood flow in rats.

In urethane-anesthetized rats with body temperature maintained at 39-40 degrees C, electrical stimulation of raphe magnus/pallidus/parapyramidal region within 0.5 mm of the ventral medullary surface reduced arterial blood flow to the tail cutaneous bed (measured with a chronically implanted Doppler ultrasonic flowmeter) from 28+/-5 to 6+/-1 cm/s (P<0.01), without changing mesenteric arterial blood flow, and with only small, variable changes in arterial pressure. Injection of bicuculline (50 pmol in 50 nl) at the same site reduced tail flow from 19+/-2 to 3+/-1 cm/s (P<0.01), again without significantly changing mesenteric flow, but with a moderate increase in arterial pressure. When the rat was cooled to reduce basal tail blood flow, injection of muscimol (1 nmol in 100 nl) or GABA (100 nmol in 100 nl) into the raphe site restored tail blood flow to 93+/-4% of the pre-cooling level. These recordings are the first reported direct measurements of rat tail blood flow changes elicited by alteration of neuronal function in the brainstem. The rostral medullary raphe controls the tail cutaneous vascular bed in a relatively selective manner. Our findings add to evidence that raphe magnus/pallidus/parapyramidal neurons are involved in regulating cutaneous blood flow in response to changes in body temperature in the rat.