Puerarin acts through brain serotonergic mechanisms to induce thermal effects

The present study was attempted to investigate the effect of puerarin, an isoflavone compound isolated from Pueraria lobata, on both the basal body temperature and pyrogenic fever in unanesthetized, restrained rats. Intraperitoneal administration of puerarin or crude extracts of Pueraria lobata elicited hypothermia. Direct administration of a small amount of puerarin into the lateral cerebral ventricle produced the same extent of hypothermia. Systemic or central administration of puerarin causes a decrease in both colonic temperature and hypothalamic 5-HT efflux in rats. The puerarin-induced hypothermia and decreased 5-HT efflux in the hypothalamus were attenuated by selective depletion of hypothalamic 5-HT produced by intracerebroventricular injection of 5,7-dihydroxytryptamine. Furthermore, the puerarin-induced hypothermia was almost completely abolished by treatment with a 5-HT2A-receptor agonist (DOI or quipazine) or a 5-HT1A-receptor antagonist [(-)-pindolol]. A 5-HT2A-receptor antagonist (ketanserin) or a 5-HT1A-receptor agonist (8-OH-DPAT) had additive effects with puerarin. Intracerebroventricular administration of interleukin-1 caused an increase in both colonic temperature and hypothalamic 5-HT efflux. The interleukin-1-induced hyperthermia and increased 5-HT efflux in the hypothalamus were attenuated by treatment with systemic administration of puerarin. The data indicate that puerarin exerts its hypothermic and antipyretic effects by activating 5-HT1 receptor and/or antagonizing 5-HT2A receptors in the hypothalamus.     

Cholecystokinin-induced hypothermia: possible involvement of serotoninergic mechanisms in the rat hypothalamus

The thermal effects of rats which were pretreated with 5,7-dihydroxytryptamine to deplete hypothalamic 5-hydroxytryptamine (5-HT) or with a 5-HT receptor blocker to intrahypothalamic administration of cholecystokinin (CCK) were compared with those of control rats. The CCK-induced hypothermic response was attenuated by pretreatment of the rats with either hypothalamic 5-HT depletion or receptor blockade. The reduction in the CCK hypothermia in the treated rats was due to the reduction of metabolic and vasomotor response. The data indicate that CCK may act on a 5-HT pathway within the hypothalamus to induce its hypothermia by promoting a reduction in metabolic heat production and an enhancement in heat loss in rats.     

Serotonin 1A receptor activation and hypothermia in humans: lack of evidence for a presynaptic mediation.

The hypothermia produced by 5-HT1A agonists had initially been claimed to be caused by the activation of cell body 5-HT1A autoreceptors resulting in decreased 5-HT transmission in laboratory animals. In order to address this issue in humans, 12 healthy volunteers underwent a dietary tryptophan depletion paradigm to decrease 5-HT availability, under double-blind conditions, during which body temperature was monitored following oral administration of the 5-HT1A agonist buspirone (30 mg). In addition, plasma prolactin and growth hormone evaluations, two responses that are mediated via the direct activation of postsynaptic 5-HT1A receptors, were determined. The hypothesis was that if responses are mediated by decreased transmission at postsynaptic 5-HT1A receptors, resulting from dampened 5-HT release as a consequence of 5-HT1A autoreceptors activation, then responses to the exogenous 5-HT1A agonist should be attenuated when 5-HT availability has been markedly decreased beforehand. Buspirone produced the same significant increase in prolactin and growth hormone in the tryptophan-depleted state as in the control condition. Similarly, the degree of hypothermia produced by buspirone was not significantly different in the two experimental conditions. In conclusion, these results strongly suggest that the hypothermia and the increases in prolactin and growth hormone produced by buspirone are attributable to the enhanced activation of postsynaptic 5-HT1A receptors, and not to a decrease in 5-HT transmission resulting from the activation of the 5-HT1A cell body autoreceptors on 5-HT neurons.     

5-hydroxytryptamine receptors in the hypothalamus mediate thermoregulatory responses in rabbits

Summary 1. The effects of microinjection of 5-hydroxytryptamine (5-HT) or its antagonists methysergide (a 5-HT₁ receptor antagonist), cyproheptadine (a mixed 5-HT₁/5-HT₂ receptor antagonist), or ketanserin (a 5-HT₂ receptor antagonist) into the preoptic anterior hypothalamus on thermoregulatory responses were assessed in conscious rabbits at different ambient temperatures (T _a). 2. Intrahypothalamic injection of 5-HT caused dose-dependent hypothermia in rabbits when the T _a was 2°C and 22°C. At 2°C the hypothermia was due to decreased metabolism, whereas at 22°C the hypothermia was due to increased peripheral blood flow and increased respiratory evaporative heat loss. 3. In contrast, administration of either cyproheptadine, methysergide or ketanserin into the 5-HT-sensitive sites in the preoptic anterior hypothalamus caused dose-dependent hyperthermia in rabbits when the T _a was 2°C, 22°C and 32°C. At 2°C the hyperthermia was due to increased metabolism, whereas at 32°C the hyperthermia was due to decreased peripheral blood flow and decreased respiratory evaporative heat loss. At 22°C, the hyperthermia was due to increased metabolism and decreased peripheral blood flow. 4. For a given intrahypothalamic dose (e.g.15–20 g), either methysergide, cyproheptadine or ketanserin produced the same degree of rectal temperature elevation (e.g. about 1.4°C) in rabbits. Thus, there did not appear to be any association between hypothalamic 5-HT receptor types and thermoregulation. 5. However, the present results suggest that hypothalamic 5-HT receptors mediate thermoregulatory responses in the rabbit. Activation of hypothalamic 5-HT receptors decreases heat production and increases heat loss, whereas inhibition of hypothalamic 5-HT receptors increases heat production and decreases heat loss in the rabbit.This study was supported by grants from the National Science Council of the Republic of China. Send offprint requests to S. J. Won at the above address     

Mechanisms of the influence of magnolol on eicosanoid metabolism in neutrophils

We have demonstrated that magnolol suppressed thromboxane B2 (TXB2) and leukotriene B4 (LTB4) formation in A23187-stimulated rat neutrophils. Maximum inhibition was obtained with about 10 microM magnolol. Magnolol was more effective in the inhibition of cyclooxygenase (COX) activity than in the inhibition of 5-lipoxygenase (5-LO) activity as assessed by means of enzyme activity determination in vitro and COX and 5-LO metabolic capacity analyses in vivo. Magnolol alone stimulated cytosolic phospholipase A2 (cPLA2) phosphorylation and the translocation of 5-LO and cPLA2 to the membrane, and evoked arachidonic acid (AA) release. Recruitment of both 5-LO and cPLA2 to the membranes was suppressed by EGTA. Arachidonyl trifluoromethyl ketone (AACOCF3), a PLA2 inhibitor, bromoenol lactone (BEL), a Ca2+-independent PLA2 (iPLA2) inhibitor, and EGTA suppressed the magnolol-induced AA release. However, none of the follows affected magnolol-induced AA-release: 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), a p38 mitogen-activated protein kinase (MAPK) inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), a MAPK kinase (MEK) inhibitor, or 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF109203X), a protein kinase C (PKC) inhibitor. In addition, magnolol at 30 microM did not stimulate the p38 MAPK and extracellular signal-regulated kinase 2 (ERK2) enzyme activities. These results indicated that magnolol inhibits the formation of prostaglandins and leukotrienes in A23187-stimulated rat neutrophils, probably through a direct blockade of COX and 5-LO activities. The stimulatory effects of magnolol at high concentration on the membrane association of 5-LO and cPLA2 are attributable to the elevation of [Ca2+]i, and on the AA release is likely via activation of cPLA2 and iPLA2.     

Studies on As2O3-induced rabbit hypothermia and brain monoamines (author's transl)

It has been suggested that hypothermia induced in rabbits by As2O3 3 mg/kg (i.v.) depends mostly on the blocking of the thermo-regulatory center. The relationship between hypothermia induced by As2O3 and brain monoamine levels in rabbits was investigated. To clarify the mechanism of the hypothermia, the influence of pretreatment with several agents on As2O3-induced hypothermia and on monoamine levels in the hypothalamus was examined. The core temperature was measured by inserting the thermister probe into the rectum and noradrenaline(NA), 5-hydroxytryptamine(5-HT) and 5-hydroxyindoleacetic acid(5-HIAA) levels in the hypothalamus were estimated fluorometrically. Pretreatment with p-chlorophenylalanine(PCPA), alpha-methyl-p-tyrosine(alpha-MPT) or 5-hydroxytryptophan(5-HTP) did not inhibit the hypothermia induced by As2O3 but did decrease NA levels in the hypothalamus. On the contrary, pretreatment with barbital sodium, pheniprazine, 1-DOPA and 1-tyrosine significantly inhibited the hypothermia or exhibited the hyperthermia. As2O3-induced hypothermia in rabbits was followed by a decrease in NA levels and an increase in 5-HT levels in the hypothalamus. On the other hand, when the hypothermia induced by As2O3 was inhibited by pretreatment with barbital sodium, pheniprazine, 1-DOPA and 1-tyrosine, both NA and 5-HT levels in the hypothalamus were significantly increased. These results suggest that As2O3-induced hypothermia is due to a decrease in NA levels and inhibition of the hypothermia is due to an increase in NA levels, in the rabbit hypothalamus.     

Direct evidence for an important species difference in the mechanism of 8-OH-DPAT-induced hypothermia.

1. Parallel series of experiments were carried out in the rat and mouse in order to investigate the mechanism(s) underlying the hypothermia induced in rodents by the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). 2. In the mouse, lesioning of central 5-hydroxytryptaminergic neurones (by use of the neurotoxin, 5,7-dihydroxytryptamine; 5,7-DHT) abolished the hypothermic response to 8-OH-DPAT, and depletion of brain 5-hydroxytryptamine (5-HT) levels (with the 5-HT synthesis inhibitor, p-chlorophenylalanine) markedly attenuated the response in this species. These pretreatments did not significantly attenuate 8-OH-DPAT-induced hypothermia in the rat, except for a significant attenuation of the response in 5,7-DHT-lesioned rats at the top dose of 8-OH-DPAT (1.0 mg kg-1, s.c.). 3. Pharmacological pretreatments which facilitate 5-HT release (selective 5-HT uptake inhibitors, precursor (5-hydroxytryptophan) loading, or fenfluramine), markedly attenuated or abolished 8-OH-DPAT-induced hypothermia in the mouse. These pretreatments generally had no significant effect on 8-OH-DPAT-induced hypothermia in the rat. 4. The selective noradrenaline uptake inhibitor, desipramine, had no effect on the hypothermic response to 8-OH-DPAT in either species. The selective dopamine uptake inhibitor, nomifensin, significantly increased the hypothermic response to 8-OH-DPAT in the mouse, but did not affect the response in the rat except at high, motor stimulant doses, when the response was attenuated. 5. These data are consistent with the hypothesis that 8-OH-DPAT-induced hypothermia is mediated by presynaptic autoreceptors in the mouse and by postsynaptic 5-HT1A receptors in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of -fenfluramine-induced hypothermia: evidence for multiple sites of action

The effects of -fenfluramine on core body temperature has been largely investigated under conditions of either high or low ambient temperature, whereas little research has focused on this response under normal environmental conditions. Moreover, there has been neglect in research on the mechanisms underlying changes in body temperature. In this study, we demonstrate that -fenfluramine (5 and 10 mg/kg) induces a sustained decrease in body temperature in the rat under normal ambient temperatures. Pre-treatment with the selective serotonin reuptake inhibitor sertraline (5 mg/kg), the full 5-HT_1A receptor antagonist 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinyl benzamide], WAY 100635 (0.15 mg/kg) and the 5-HT_2C receptor antagonist benzofuran-2-carboxamidine, RO 43-0440 (2.5 mg/kg) blocked -fenfluramine-induced hypothermia. Depletion of 5-hydroxytryptamine (5-HT) stores following treatment with the serotonergic neurotoxin parachlorophenylalanine reversed the initial hypothermic effects of -fenfluramine but not the later effects, as -fenfluramine produced a delayed hypothermia (>120 min post-challenge) in animals pre-treated with parachlorophenylalanine. Such findings are consistent with a requirement for -fenfluramine uptake into 5-HT neurons followed by release of 5-HT from intracellular stores and stimulation of post-synaptic 5-HT receptors to reduce body temperature. The hypothermic response to -fenfluramine was potentiated by ketanserin pre-treatment 30 min post-challenge but then antagonized at later time intervals. Pre-treatment with the dopamine, D₂ antagonist, haloperidol (1 mg/kg) and sulpiride (30 mg/kg) had a similar effect in blocking the hypothermia as WAY 100635, suggesting a role for dopamine D₂ receptors in the response. Pre-treatment with the α₂-adrenoceptor antagonist yohimbine failed to block the hypothermic response. These results suggest multiple sites of action mediating -fenfluramine-induced hypothermia and may be the result of a combined effect of -fenfluramine and its active metabolite norfenfluramine affecting not only the release of 5-HT but also stimulation of post-synaptic receptors.     

Involvement of 5-HT1A and 5-HT1B receptors for citalopram-induced hypothermia in the rat

OBJECTIVES: To examine the role of 5-HT1A and 5-HT1B receptors for citalopram-induced hypothermia in the rat. METHODS: Core temperature measurements were performed in adult male Wistar rats (305-340 g) using a computer-assisted recording instrument. The temperature readings were automated and gave a printout when the core temperature had stabilised at +/- 0.1 degree C for 10 s. RESULTS: Citalopram (6.25-100.0 mumol/kg) produced a dose-dependent hypothermia. The effect was maximal within 60 min after administration, and had waned off at 120 min. The 5-HT1B receptor agonist anpirtoline (0.25-4.0 mumol/kg) produced a dose-dependent decrease in core temperature. The citalopram-induced hypothermia (25 mumol/kg) was antagonised by pretreatment with either of the 5-HT1A and the 5-HT1B receptor antagonists, WAY-100,635 (0.04 mumol/kg) and NAS-181 (1.0 mumol/kg), respectively, or by the two drugs in combination. Subchronic treatment with the SSRI zimeldine (100 mumol/kg once daily for 2 weeks) resulted in tolerance to the hypothermic effect of citalopram (100 mumol/kg). CONCLUSIONS: The hypothermia produced by acute administration of the SSRI citalopram is mediated via activation of 5-HT1A, as well as 5-HT1B receptors, and this effect is subject to the development of tolerance.     

Regulation of contractile activity by magnolol in the rat isolated gastrointestinal tracts

This study examined the pharmacological property of magnolol, a phenolic compound purified from Magnolia officinalis, on the GI motility using the rat isolated gastrointestinal (GI) strips. Magnolol (0.3–30 μM) dose-dependently stimulated the tone and amplitude of spontaneous contractions in ileum longitudinal muscles. Magnolol at 3 μM significantly increased the contractions of jejunum longitudinal and colon circular muscles, but not the longitudinal muscle contractions in fundus, antrum and colon. Pretreatment of ileum strips with either atropine (0.5 μM) or 4-diphenyllacetoxy-N(2-chloriethyl)-piperidine (4-DAMP, 0.5 μM) dramatically inhibited the acetylcholine (ACh, 0.1 μM)- and magnolol (3 μM)-induced longitudinal muscle contractions, but they were not affected by methoctramine (0.5 μM) and hexamethonium (0.5 μM). Ondansetron (0.1 μM) and GR113808 (2 μM) significantly reduced the tone of ileum longitudinal muscle contractions stimulated by 5-HT (10 μM), but not the amplitude. Magnolol (3 μM)-induced ileum longitudinal muscle contractions, both tone and amplitude, were significantly blocked by GR113808, but not by ondansetron. Taken together, magnolol differently regulates the spontaneous GI motility according to the region of GI tracts and orientation of smooth muscles, and magnolol-induced regulation of smooth muscle contractions in rat GI strips is likely to be mediated, at least in part, by activation of ACh and 5-HT receptors, possibly the M₃ and/or 5-HT₄ receptors.     

Changes induced by corticosterone and adrenalectomy in synaptosomal and platelet uptake and binding of 5-HT: The relationship to [3H]imipramine binding

A comparative study of the effect of adrenalectomy, treatment with corticosterone, and imipramine on platelet and synaptosomal uptake was undertaken. One day after adrenalectomy, uptake of 5-hydroxytryptamine (5-HT) in the platelet and the hypothalamus was significantly decreased with an increase in the apparent K_m, but the uptake of 5-HT of the cerebral synaptosomes was unchanged. In this group, the k_d) of low affinity binding of 5-HT was also increased in the hypothalamic synaptosomes and in the platelet preparations. Treatment with cortieosterone (5 $\text{mg}\text{kg}$, i.m.) restored the decrease in the uptake of 5-HT induced by adrenalectomy in the hypothalamic synaptosomes and in the platelets, and significantly increased the uptake of 5-HT of these fractions in sham-operated rats. The binding of 5-HT was unchanged by acute treatment with corticosterone. The effectiveness of imipramine varied with the preparation and treatment group. The IC₅₀ of the cerebral synaptosomal preparation was greater than that of the hypothalamic synaptosomal preparation. Using this latter preparation, the IC₅₀ for imipramine in adrenalectomised, sham-operated and corticosterone-treated rats were found to be 0.04, 0.09 and 0.25 μM, respectively. These changes in sensitivity to imipramine were not reflected in the binding of [³H]imipramine which was unchanged.     

Some biochemical effects of zona incerta lesions that interfere with the regulation of water intake

The concentration of NE, DA and 5-HT in forebrain, striatum, and hypothalamus was measured after zona incerta (ZI) lesions that have been shown to result in general hypodipsia; adipsia during periods of food deprivation; impaired or abolished drinking in response to osmotic challenges (but not polyethylene glycol); impaired drinking after systemic isoproterenol or central angiotensin; and impaired or abolished feeding in response to 2-deoxy-D-glucose. The lesions produced a significant (40–50%) depletion of forebrain NE but a correlational analysis of the behavioral and biochemical effects of the lesions failed to indicate a causal relationship. The lesions did not reliably affect (a) forebrain DA or 5-HT; (b) striatal DA or 5-HT; (c) hypothalamic DA, NE or 5-HT. The results of these experiments indicate that significant impairments in ingestive behavior can be demonstrated in animals with diencephalic lesions that do not result in striatal (or forebrain) DA depletions. This confirms previous behavioral analyses showing that ZI lesions which interfere with ingestive behavior do not produce the debilitating sensory or motor dysfunctions typical of the rat with lateral hypothalamic lesions.     

Effects on serotonin in rat hypothalamus of D-fenfluramine,aminorex, phentermine and fluoxetine

Hypothalamic 5-HT (serotonin) regulates food intake, energy expenditure and bodyweight. Using in vivo microdialysis, we determined the effects of various anorectic drugs on hypothalamic extracellular 5-HT levels during the dark phase when rats predominantly feed. Phentermine and aminorex, which were originally considered to be catecholaminergic drugs, markedly increased 5-HT efflux in rat hypothalamus. Their actions were less profound than D-fenfluramine, but considerably greater than that of the selective 5-HT reuptake inhibitor, fluoxetine. This suggests that enhanced hypothalamic 5-HT function could be involved in their anorectic actions. Pharmacological characterization revealed that D-fenfluramine, aminorex and probably also phentermine potentiate synaptic 5-HT function predominantly by release, whereas fluoxetine acts exclusively by reuptake inhibition. The results also revealed that the combined actions of phentermine and D-fenfluramine on hypothalamic extracellular 5-HT levels were additive, but not synergistic. In contrast, there was a significant negative cooperative effect on extraneuronal 5-HT of combining phentermine with fluoxetine.     

Effect of 5-hydroxy-L-tryptophan on the release of 5-HT in rat hypothalamus in vivo as measured by microdialysis.

The effect of systemic administration of the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP) on the release of 5-HT in the lateral hypothalamus of the chloral hydrate-anaesthetized rat in vivo was examined using brain microdialysis. Administration of 5-HTP caused an immediate increase of 5-HT in dialysates, which was long lasting (greater than or equal to 140 min) and dose-dependent (30-100 mg/kg i.p.). When calcium was omitted from the perfusion medium, thereby limiting exocytosis, levels of basal 5-HT were significantly decreased and the 5-HTP-induced response of 5-HT was markedly attenuated. Administration of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (0.25 mg/kg i.p.), which selectively inhibits serotoninergic neuronal activity by activation of the somatodendritic 5-HT autoreceptor, significantly decreased basal levels of 5-HT and markedly attenuated the 5-HTP-induced increase in 5-HT. The data demonstrate that systemic administration of 5-HTP caused an increase in the release of 5-HT in the hypothalamus. Furthermore, this release occurred by a calcium-dependent mechanism (probably exocytosis), was dependent on serotoninergic neuronal activity and predominantly derived from 5-HT neurones. The findings are discussed in relation to the behavioral and neuroendocrine effects of increasing availability of the 5-HT precursor.     

Dopamine in the hypothalamus of the cat: Pharmacological characterization and push-pull perfusion analysis of sites mediating hypothermia

Within the rostral diencephalon of the cat, 113 sites were examined for their reactivity to 2.33–14.0 μg dopamine (DA) or 2.33–14.0 μg norepinephrine (NE) microinjected in a volume of 0.75 μl. During each experiment, colonic temperature was monitored and additional physiological measures were recorded continuously. In contrast to CSF controls, an intrahypothalamic injection of either catecholamine at circumscribed sites evoked a dose-dependent fall in the cat's body temperature, with NE ordinarily evoking a more profound hypothermic response. The morphological sites of maximum sensitivity were localized in the anterior hypothalamic, preoptic region. At some but not all sites, a prior microinjection of 3.5–7.0 μg phentollamine attenuated the magnitude of the DA-induced hypothermia and delayed its onset. Conversely, at all loci, the pretreatment by the injection of this alpha-adrenergic antagonist markedly reduced the absolute magnitude of the NE-induced fall in the cat's temperature. Similar pretreatment of a reactive hypothalamic locus with a beta-adrenergic receptor blocking agent, practolol (3.5 μg), failed to alter the hypothermia following a microinjection of DA. Either of two DA receptor antagonists, haloperidol (0.04–7.0 μg) or d-butaclamol (0.48–1.47 μg), when given in a sufficient dose, effictively delayed the onset of the DA-hypothermia and reduced its absolute magnitude; however, the NE-induced decline in the cat's temperature was unaffected by DA receptor blockade. Endogenous stores of DA and/or NE in the cat's hypothalamus were radio-labeled with either ³H- or ¹⁴C-catecholamines or both, microinjected through the implanted guide tube into an identified amine-sensitive site. By using push-pull cannulae, the site was subsequently perfused for 5 min with artificial CSF at a rate of 25 μl/min with samples collected at 15 min intervals. During either the third or fourth perfusion, the ambient temperature of the cat's chamber of 22–24°C was elevated to 35–45°C and maintained at this level for 15 or 30 min. This environmental warming evoked a release of either DA or NE or both amines from certain circumscribed sites within the cat's rosrtal hypothalamus. Overall, these results provide pharmacological, physiological and anatomical evidence for a differential role of DA in the hypothalamic mechanism which mediates the heat loss processes.     

Role of taurine as a possible transmitter in the thermoregulatory pathways of the rat

Taurine (10 and 20 μg) injected unilaterally into the lateral ventricle of rats caused an increase in core temperature. Bilateral injection of taurine 2.5 and 5 into the preoptic region of the anterior hypothalamus induced a dose-related hyperthermia: higher doses (10 μg) caused hypothermia. Intrahypothalamically taurine-induced hyperthermia was blocked by prior injection of strychnine hydrochloride (5 and 15 μg); doses which alone had no effect on core temperature. Of the other inhibitory amino acids injected intrahypothalamically hypotaurine also induced a hyperthermia. GABA (10 μg) caused hypothermia; glycine (10 μg) had no effect. Potassium (50 mM) stimulated release of radioactivity from superfused slices of anterior hypothalamus prelabelled with [³H]taurine in a calcium-dependent manner. A high affinity uptake mechanism with a K_m of 8.5 μM was demonstrated with [³H]taurine into slices of anterior hypothalamus. Taurine may have a neurotransmitter role in the anterior hypothalamus but whether the body temperature effects represent physiological or pharmacological events remains to be established.     

Modulation of Δ9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat

1. It has been suggested that the dose of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) that induces hypothermia in the rat increases the release of brain 5-hydroxytryptamine (5-HT). In light of this, we investigated the hypothermia produced by Δ⁹-THC, and the effect the selective serotonin reuptake inhibitor fluoxetine has on this response.
2. A significant dose-dependent decrease in body temperature occurred after i.v. administration of 0.5 to 5 mg kg⁻¹ Δ⁹-THC; maximum decreases being 0.8±0.2°C to 2.9±0.3°C. This hypothermic response was attenuated by the cannabinoid CB₁ receptor antagonist SR 141716.
3. Fluoxetine (10 mg kg⁻¹ i.p.) alone caused a decrease in body temperature of 0.6±0.1°C (n=32, P<0.05) after 40 min. However, pretreatment with fluoxetine (10 mg kg⁻¹ i.p.) 40 min before Δ⁹-THC significantly reduced the Δ⁹-THC-induced hypothermia (n=7–8, P<0.05). Contrary to this antagonist-like effect, fluoxetine administered 40 min after Δ⁹-THC significantly potentiated the Δ⁹-THC-induced hypothermia, producing a maximum decrease of 3.2±0.3°C.
4. It is suggested that the effect of fluoxetine on the Δ⁹-THC-induced hypothermic response is dependent on the time of its administration relative to that of Δ⁹-THC. Pretreatment with fluoxetine increases extracellular 5-HT due to reuptake inhibition. Increased extracellular 5-HT can activate autoreceptors which may decrease serotonergic activity, thereby reducing the Δ⁹-THC-induced hypothermia. Conversely, when fluoxetine is adminstered after Δ⁹-THC, the reuptake block is thought to potentiate the already activated serotonegic system, hence potentiating the Δ⁹-THC-induced hypothermia.

     

Neural Involvement in 5-Hydroxytryptamine-induced Net Electrogenic Ion Secretion in the Rat Intestine In-vivo

5-Hydroxytryptamine (5-HT) induces active electrogenic anion secretion by both the small intestine and the colon, responses that can be detected from measurements of transmural electrical activity. This approach was adopted to examine the involvement of neural mechanisms in 5-HT-induced secretion in rat proximal jejunum, distal ileum and proximal colon in-vivo. Under control conditions, 5-HT caused maximum rises in transintestinal potential difference of 4.7 ± 0.3, 3.8 ± 0.4 and 7.6 ± 0.3 mV, respectively, with corresponding ED50 values of 28 ± 3, 38 ± 4 and 41 ± 4 nmol kg^?1 (n = 12). In each region examined a neural component in the secretory response to 5-HT was identified. Hexamethonium (22 μmol kg^?1) reduced the 5-HT response in each region; in the jejunum and colon, it also attenuated the responses to the 5-HT₃ agonist, phenylbiguanide and to 5-methoxytryptamine (5-MeOT), an agonist at all 5-HT receptors except 5-HT₃, indicating that in these regions the nicotinic pathway can be activated by more than one 5-HT receptor subtype. Atropine (0.27 and 2.7 μmol kg^?1) was found to have regional effects on the intestinal responses to 5-HT receptor agonists. In the jejunum, evidence for a pro-secretory muscarinic pathway which could be activated by more than one 5-HT receptor subtype was found. In the ileum and colon no muscarinic pro-secretory pathway was identified, indeed in the colon, an anti-secretory pathway may be present. This muscarinic anti-secretory pathway was observed with phenylbiguanide and 5-MeOT, but not 5-HT. Substance P release does not appear to be involved in mediating the intestinal secretory response to 5-HT. 5-HT-induced intestinal anion secretion may involve a direct secretory action on the enterocyte which can be modified by neurally-mediated pro-secretory and anti-secretory pathways, the balance between these processes varying down the length of the gut.     

Food intake, neuroendocrine and temperature effects of 8-OHDPAT in the rat

Administration of 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT) to rats produced dose-dependent decreases in food intake and hypothermia, increases in plasma prolactin and corticosterone, and a decrease in plasma growth hormone. 8-OHDPAT administration also induced the serotonin behavioral syndrome at all doses. Pretreatment with metergoline did not affect the 8-OHDPAT-induced behavioral syndrome or decrease in food intake but attenuated the prolactin increase and, furthermore, potentiated 8-OHDPAT-induced hypothermia. Pretreatment with ritanserin or naloxone did not modify 8-OHDPAT-induced changes in food intake, temperature or prolactin. Similarly, pretreatment with phenoxybenzamine, propranolol, clonidine, haloperidol and methiothepin also did not attenuate 8-OHDPAT-induced decreases in food intake. Administration of pindolol alone produced hyperthermia, decreased food intake and enhanced prolactin secretion. Pindolol thus appears to act as a partial 5-HT agonist in addition to being an antagonist at central 5-HT receptors.