The influence of high ambient temperature on thermoregulatory response to intrahypothalamic injections of noradrenaline and serotonin in the pigeon

1. Pigeons with chronically implanted injection cannula in the hypothalamus were injected with noradrenaline (NA, 10 micrograms/microliter) and 5-hydroxytryptamine (5-HT, 10 micrograms/microliter) at the ambient temperature (Ta) of 38 degrees or 42 degrees C. 2. Initial tests at cold (6 degrees C) indicated that birds responded hypothermically to NA and in most instances also to 5-HT. 3. Intrahypothalamic injection of NA (10 micrograms/microliter) had no appreciable effect on oxygen consumption (VO2), body temperature (Tb), foot temperature (Tf), or heart and respiratory rates at Ta 38 degrees C. The increase of VO2, Tb and Tf noted after similar injection at 42 degrees C was in all probability due to observed excitement and bursts of struggling rather than effects on thermoregulatory mechanisms. 4. 5-HT (10 micrograms/microliter) injected at Ta 38 degrees C depressed respiratory frequency from panting (600 breaths.min-1) to normal rate (ca. 50.min-1) within 2--4 min. The absence of panting lasted about 10 min, but only a slight increase of VO2, Tb and Tf followed. At Ta 42 degrees C, no notable changes of VO2, Tb and Tf were recorded after 5-HT injection. 5. It is concluded that 5-HT has an inhibitory action on neuronal pathway controlling panting activity in the pigeon, but NA seems to be ineffective.     

Antidepressant-like action of nicotine in forced swimming test and brain serotonin in mice

An antidepressant-like action of nicotine has been suggested in the forced swimming test. The aim of the present study was to evaluate the relationship between the antidepressant-like action of nicotine and brain serotonin (5-HT) in mice. Nicotine at a dose of 0.2 mg/kg significantly (p < 0.05) decreased the duration of immobility time in forced swimming test. However, nicotine (0.01-1 mg/kg, s.c.) had no effect on locomotor activity in open-field test. Dopamine turnover in mouse whole brain was increased by nicotine (0.01-1 mg/kg, s.c.) in a dose-dependent manner, and nicotine at a dose of 0.05 mg/kg showed a significant increases in 5-HT turnover. Nicotine at a dose of 0.05 mg/kg markedly enhanced head twitch responses induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT2A/2C receptor agonist. These findings suggest that the involvement of nicotinic and serotonergic systems in the antidepressant-like effects of nicotine.     

Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression

A number of previous studies have shown that chronic but not acute treatment with antidepressant drugs targeting the central 5-HT system, enhances mRNA expression for a number of genes including, brain-derived neurotrophic factor (BDNF) and the effector immediate early gene (IEG), activity-regulated, cytoskeletal-associated protein (Arc). The present study investigated the effects of 5-HT(6)-receptor activation on hippocampal and cortical levels of mRNA expression of BDNF and Arc in the rat. The selective 5-HT(6)-receptor agonist LY-586713 was administered acutely (0.1-10 mg/kg, s.c.) and mRNA levels of BDNF and Arc were measured 18 h later. Administration of LY-586713 caused a bell-shaped dose response on hippocampal BDNF mRNA expression, having no effect at 0.1 mg/kg, a significant up-regulation at 1 mg/kg and no effect at 10 mg/kg. The up-regulation in BDNF expression observed at 1 mg/kg was completely blocked by pre-treatment with the selective 5-HT(6)-receptor antagonist SB-271046 (10 mg/kg, s.c.). The effective dose (1 mg/kg) of LY-586713 on the induction of BDNF expression was also tested on Arc expression. Acute administration of LY-586713 at this dose caused marked increases of the Arc mRNA levels in cortical and hippocampal regions. These increases were also attenuated by SB-271046 (10 mg/kg) in all regions of the hippocampus, as well as the parietal cortex. However, in frontal cortical regions there was no attenuation by the antagonist. Moreover, SB-271046 alone increased Arc expression in these regions. The results presented here provide the first evidence for the involvement of the 5-HT(6) receptor in regulating BDNF and Arc mRNA expression, suggesting that LY-586713 has potential effects on neuronal plasticity. Overall, these findings suggest that, as opposed to more general 5-HT receptor activation by, for example, antidepressants, direct 5-HT(6)-receptor activation results in a more rapid rise in BDNF and Arc mRNA expression which does not require repeated administration.     

Selective 5HT2A and 5HT6 receptor antagonists promote sleep in rats

STUDY OBJECTIVES: Serotonin (5-HT) has long been implicated in the control of sleep and wakefulness. This study evaluated the hypnotic efficacy of the 5-HT6 antagonist RO4368554 (RO) and the 5-HT2A receptor antagonist MDL100907 (MDL) relative to zolpidem. DESIGN: A randomized, repeated-measures design was utilized in which Wistar rats received intraperitoneal injections of RO (1.0, 3.0, and 10 mg/kg), MDL (0.1, 1.0 and 3.0 mg/kg), zolpidem (10 mg/kg), or vehicle in the middle of the dark (active) period. Electroencephalogram, electromyogram, body temperature (Tb) and locomotor activity were analyzed for 6 hours after injection. MEASUREMENTS AND RESULTS: RO, MDL, and zolpidem all produced significant increases in sleep and decreases in waking, compared with vehicle control. All 3 doses of MDL produced more consolidated sleep, increased non-rapid eye movement sleep (NREM) sleep, and increased electroencephalographic delta power during NREM sleep. The highest dose of RO (10.0 mg/kg) produced significant increases in sleep and decreases in waking during hour 2 following dosing. These increases in sleep duration were associated with greater delta power during NREM sleep. ZO Zolpidem induced sleep with the shortest latency and significantly increased NREM sleep and delta power but also suppressed rapid eye movement sleep sleep; in contrast, neither RO nor MDL affected rapid eye movement sleep. Whereas RO did not affect Tb, both zolpidem and MDL reduced Tb relative to vehicle-injected controls. CONCLUSIONS: These results support a role for 5-HT2A receptor modulation in NREM sleep and suggest a previously unrecognized role for 5-HT6 receptors in sleep-wake regulation.     

Androgens and estrogens modulate 5-HT1A and 5-HT1B agonist effects on aggression

Intermale offensive aggressive behavior is facilitated by gonadal steroids and inhibited by serotonin (5-HT), presumably through its effects at 5-HT1A and 5-HT1B receptor sites. To examine the interaction between these neuroendocrine and neurochemical regulatory systems, CF-1 male mice were gonadectomized and implanted with silastic capsules containing either diethylstilbestrol (DES, a synthetic estrogen), the nonaromatizable androgens methyltrienolone (R1881) or dihydrotestosterone (DHT), or testosterone (T). Two weeks later, they were given 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A agonist; 0.1 or 1.0 mg/kg), CGS12066B (a 5-HT1B agonist; 4.0 or 8.0 mg/kg), 0.1 or 1.0 mg/kg 8-OH-DPAT + 4.0 mg/kg CGS12066B, or vehicle, and tested for aggression. In the presence of DES, the higher 8-OH-DPAT dose given in combination with CGS attenuated aggression in comparison to vehicle controls. When given nonaromatizable androgen (R1881 or DHT), all drug treatments except 0.1 mg/kg 8-OH-DPAT significantly reduced offensive attack behavior. In the presence of T, which provides estrogenic and androgenic stimulation, aggression scores were significantly reduced when males were given the high dose of 8-OH-DPAT or CGS12066B, as well as in the 1.0 mg/kg 8-OH-DPAT + CGS12066B condition. Assessments of changes in motor behavior showed significant impairment when 8.0 mg/kg CGS12066B was administered across all hormonal conditions, indicating that reductions in offensive aggression in these treatment groups were nonspecific. The results demonstrate differential effects of the steroidal environment on the ability of 5-HT1A and 5-HT1B agonists to modulate aggression, with estrogens producing a more restrictive environment than androgens for serotonergic inhibition of male-typical aggressive behavior.     

5-HT2 modulation of AY-9944 induced atypical absence seizures

We investigated the role of 5-HT(2A) and 5-HT(2C) receptors in atypical absence seizures (AAS) induced by trans-1,4-bis[2-chloro-benzylaminomethyl] cyclohexane, dihydrocholoride (AY-9944). The total duration and number and mean duration of the spontaneous bursts of slow spike-and-wave discharges (SSWD) that characterize the AY model were measured using electrocorticographic (ECoG) recordings in freely moving animals. In a randomized counterbalanced dose response design, rats were treated with either the 5-HT(2A) agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI, 0.5, 1 or 2 mg/kg), the 5-HT(2C) preferring agonist m-chlorophenylpiperazine (mCPP, 1, 2, or 4 mg/kg), the 5-HT(2A) antagonist ketanserin (2.5 or 5 mg/kg), or vehicle. DOI significantly reduced the total duration and number of SSWD. In contrast, mCPP had no effect on total duration or number of SSWD. Ketanserin exacerbated the number of SSWD at 2.5 mg/kg but produced mixed results at 5.0 mg/kg. However, none of the treatments affected the mean SSWD duration. These data support the hypothesis that 5HT(2A) receptors are involved in the pathology of experimental atypical absence seizures.     

Characterization of midbrain component of the trigger for arousal from hibernation.

The ability of the midbrain reticular formation (MRF) to trigger arousal from hibernation and to change body temperature (Tb) during euthermia was tested in golden-mantled ground squirrels (Citellus lateralis). During hibernation (ambient temperature 5-6 degrees C) microinjections of cholinomimetic compounds (acetylcholine and carbachol) triggered full arousal or produced transient increases in Tb in 15 out of 19 tests; MRF microinjections of norepinephrine (NE) and 5-hydroxytryptamine (5-HT), at the same concentrations that produced full arousal when microinjected into the preoptic/anterior hypothalamus (PO/AH) area in previous experiments, has no effect on Tb in 13 out of 16 tests. In experiments on euthermic ground squirrels tested at an ambient temperature of 25 degrees C, MRF microinjections of acetylcholine raised Tb, whereas the monoamines had no significant effects. These results show that cholinoceptive neurons in the MRF can trigger arousal from hibernation and increase Tb during euthermia. The failure of NE and 5-HT to produce any significant effects at the same doses that were reported to be effective in the PO/AH indicates that the functional organization of the MRF portion of the arousal mechanism is different from that reported for the PO/AH.     

Central versus peripheral effects on temperature preference and body temperature following alteration of 5-HT in maturing mice

Experiments were designed to distinguish between central and peripheral effects on temperature preference and body temperature of drugs injected intraperitoneally (IP) in infant mice ranging in age from 3 to 10 days postpartum. These compared a drug restricted to the periphery ("peripheral" drug) with a drug of similar action that reaches the central nervous system (CNS) as well as the periphery. Two different classes of drugs were utilized to test central versus peripheral actions independently with drugs that have different modes of action: 1-aromatic amino acid inhibitors and serotonin receptor antagonists. Although the decarboxylase inhibitor NSD 1015, which reaches the central nervous system from IP injection, can significantly decrease temperature preference (Tpref), the peripheral inhibitor carbidopa had no significant effects on Tpref or on body temperature (Tb). Furthermore, pretreatment with NSD 1015 prevented the elevation of Tpref produced by the serotonin precursor 5-hydroxytryptophan (5-HTP); however carbidopa pretreatment had no effect on the increased Tpref produced by 5-HTP. In other experiments, the peripheral serotonin antagonist BW 501C was not able to prevent elevated Tpref produced by 5-HTP, although the specific 5-HT2 antagonist pirenperone, which reaches the CNS as well as the periphery, blocks the 5-HTP elevation of Tpref. Taking all of these results together, we conclude that the changes in Tb and Tpref following these treatments require a decarboxylase inhibitor or 5-HT antagonist that reaches the CNS. However, the well known and potent peripheral vasoconstrictor action of serotonin requires that peripheral effects of drugs be considered when manipulations are not restricted to the CNS.     

The maturational onset of the 5-HT mediated head twitch in mice

The effect of elevated brain serotonin (5-hydroxytryptamine, 5-HT) on the head twitch was examined to determine an age of onset in mice for this 5-HT mediated motor activity. Two different treatments were used to elevate 5-HT: 100 mg/kg L-tryptophan with 100 mg/kg pargyline; and 100 mg/kg 5-HTP with 25 mg/kg carbidopa. Mice from ages 14 to 42 days postpartum were examined. Both treatments showed an onset of the head twitch at 15 days. Juvenile mice of 15-18 days appeared to differ in their response to the two treatments. Although 5-HTP and carbidopa stimulated head twitches, 5-HTP alone had a greater stimulatory effect at these ages, while in the other experiment only those animals receiving the combined tryptophan and pargyline treatment showed significant responses.     

Effects of repeated oral doses of dexnorfenfluramine on 5-HT levels and 5-HT uptake sites in rat brain

The effects of oral dexnorfenfluramine (DNF; 1–4 mg/kg, twice daily for 4 days), the active metabolite of dexfenfluramine, were examined on rat regional brain indole contents and [³H]citalopram binding. Two hours after the last dose, serotonin (5-HT) and 5-hydroxyindoleacet 5-hydroxyindoleacetic acid (5-HIAA) were dose-dependently lowered at doses above 1.5 mg/kg, with slight regional differences. Cortical 5-HT uptake sites were reduced onlt at the highest dose. Above 2 mg/kg DNF also caused a more lasting reduction (4 weeks) of regional indoles and cortical 5-HT uptake sites. At this longer time while the decrease in hippocampal 5-HT levels and cortical 5-HT uptake sites remained essentially constant, cortical and striatal 5-HT levels were lowered less than at 2 h, suggesting a return toward control values.     

The Roles of Different Types of Serotonin Receptors in Activation of the Hypophyseal-Testicular Complex Induced in Mice by the Presence of a Female

Placing of receptive females in the sector of a cage separated by a partition preventing physical contact but allowing sight and olfaction induced increases in blood testosterone levels in male mice. The selective agonist of 5-HT1A receptors 8-OH-DPAT (0.1 mg/kg) and the mixed 5-HT1A/1B receptor agonist eltoprazine (3.0 and 10.0 mg/kg) blocked the activatory effect of presentation of females on the hypothalamohypophyseal-testicular complex (HHTC) in males, while the 5-HT1A receptor antagonist p-MPPI (0.2 mg/kg) prevented the inhibitory effects of 8-OH-DPAT and eltoprazine. The 5-HT1B receptor agonist CGS-12066A (1.0 and 2.0 mg/kg) had no effect, while the mixed 5-HT1B/2C agonist TFMPP (5.0 mg/kg) blocked the increase in blood testosterone in males in response to presentation of females. The 5-HT2A receptor antagonist ketanserin (1.0 and 2.0 mg/kg) prevented the increase in testosterone induced by the presence of females. The 5-HT3 receptor antagonist ondansetron (0.05 and 0.1 mg/kg) increased the initial plasma testosterone level but blocked activation of the HHTC induced by the presence of receptive females. These results led to the conclusion that 5-HT receptors are involved in controlling the sexual activation of males. Different types and even subtypes of the same type of 5-HT receptor had different effects, both inhibitory and activatory, on activation of the HHTC by receptive females. Blockade of HHTC activation induced by the presence of females appears to involve 5-HT1A and 5-HT2C receptors, while activation involves 5-HT2A and 5-HT3 receptors.     

A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine ("ecstasy")

The drug 3,4 methylenedioxymethamphetamine (MDMA; ecstasy) has a widely documented ability to increase feelings of love and closeness toward others. The present study investigated whether oxytocin, a neuropeptide involved in affiliative behavior, may play a role in this effect. A moderate (5 mg/kg, i.p.) dose of MDMA increased social interaction in male Wistar rats, primarily by increasing the amount of time rats spent lying adjacent to each other. MDMA (5 mg/kg) activated oxytocin-containing neurons in the supraoptic and paraventricular nuclei of the hypothalamus, as shown by Fos immunohistochemistry. MDMA (5 mg/kg i.p.) also increased plasma oxytocin levels and this effect was prevented by pre-treatment with the 5-HT(1A) antagonist N-[2-[4-(2-methyoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100,635; 1 mg/kg i.p.). The oxytocin receptor antagonist tocinoic acid (20 microg, i.c.v.) had no effect on social behavior when given alone but significantly attenuated the facilitation of social interaction produced by MDMA (5 mg/kg). The 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)-tetraline) (8-OH-DPAT, 0.25 mg/kg, i.p.) increased social behavior in a similar way to MDMA and this effect was also significantly attenuated by tocinoic acid. Taken together, these results suggest that oxytocin release, stimulated by MDMA through 5-HT(1A) receptors, may play a key role in the prosocial effects of MDMA and underlie some of the reinforcing effects of the drug.     

Effects of the 5-HT7 receptor antagonist SB-269970 on rat hormonal and temperature responses to the 5-HT1A/7 receptor agonist 8-OH-DPAT

The physiological function of 5-HT(7) receptors is not yet fully determined. This study was designed to characterize the involvement of 5-HT(7) receptor in rat body temperature regulation and in adrenocorticotropic hormone (ACTH) and corticosterone secretion. In the first part of our study, acute administration of SB-269970 (0.1-1 mg/kg, i.p.), a potent and selective 5-HT(7) receptors antagonist, dose-dependently prevented 5-HT(1A/7) receptor agonist 8-OH-DPAT (0.1 mg/kg, s.c.)-induced hypothermia and when the 5-HT(1A) receptor antagonist WAY-100,635 was co-injected with SB-269970, a reduction of the latter hypothermia was obtained in an additive manner. In contrast, 1 mg/kg (i.p.) of SB-269970 failed to prevent 8-OH-DPAT (0.5 mg/kg, s.c.)-induced increase of ACTH and corticosterone plasma levels. In conclusion, the present results unveil an additive effect of both 5-HT(1A) and 5-HT(7) receptors in core body temperature regulation.     

Effects of chronic and acute methylphenidate hydrochloride (Ritalin) administration on locomotor activity, ultrasonic vocalizations, and neuromotor development in 3- to 11-day-old CD-1 mouse pups.

The present study examined the effects of chronic and acute treatment with methylphenidate hydrochloride (Ritalin) on isolation-induced ultrasonic vocalizations, spontaneous locomotor activity, and neuromotor coordination in 3- to 11-day-old CD-1 mouse pups. In Experiment 1, 3- to 11-day-old pups received daily injections of saline, 5 mg/kg or 20 mg/kg of methylphenidate hydrochloride, or no injection and were tested on postnatal Days 3, 5, 7, 9, and 11. Both doses of methylphenidate resulted in significant increases in locomotor activity at all ages, but had no significant effect on body weight, neuromotor development, or emission of ultrasonic vocalizations. In Experiment 2, pups were given a single dose of methylphenidate (5 or 20 mg/kg), saline, or no injection on one of postnatal Days 5, 7, 9, or 11. This acute methylphenidate treatment increased locomotor activity, but had no significant effects on ultrasonic vocalizations or neuromotor coordination. These results indicate that short-term, chronic methylphenidate treatment elevates locomotor responses, but has no immediate effects on anxietylike responses or on the development of neuromotor behavior of CD-1 mice in the first 11 days of life.     

The effects of co-administration of 3,4-methylenedioxymethamphetamine ("ecstasy") or para-methoxyamphetamine and moclobemide at elevated ambient temperatures on striatal 5-HT, body temperature and behavior in rats

We have recently demonstrated that co-administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") with the reversible monoamine oxidase type A (MAO-A) inhibitor moclobemide at an ambient temperature of 22 degrees C significantly increases striatal 5-HT outflow and 5-HT-mediated behaviors. In the present study, using microdialysis, we examined the effects of co-administration of MDMA or para-methoxyamphetamine (PMA) with moclobemide on striatal 5-HT outflow at the elevated ambient temperatures of 30 degrees C. Samples were collected every 30 min for 4 h and analyzed by high-performance liquid chromatography assay with electrochemical detection (HPLC-ED). 5-HT-mediated effects on body temperature and behavior were also recorded. Rats were treated with either saline or 20 mg/kg (i.p.) moclobemide, followed by 10 mg/kg (i.p.) MDMA, 10 mg/kg (i.p.) PMA or saline 60 min later. Both MDMA and PMA produced significant increases in 5-HT outflow (370% peak and 309% peak, respectively, P<0.05). MDMA and PMA significantly increased body temperature (+2.0 degrees C and +2.1 degrees C, respectively, P<0.01) and drug-related behaviors (P<0.05). When MDMA or PMA was co-administered with moclobemide, additional significant increases were seen in 5-HT outflow (850% peak, P<0.01 and 1450% peak, P<0.001, respectively) and only MDMA showed additional significant increase in body temperature (+5.0 degrees C, P<0.001). No additional increases were seen in behavioral activity. When moclobemide was co-administered with MDMA, sustained increases in body temperature were recorded that were significantly higher than with MDMA alone and such increases were not observed in our previous study at normal room temperature. Our results suggest greater risk of MDMA-induced adverse effects on body temperature regulation, compared with PMA, when used in combination with moclobemide at elevated ambient temperatures.     

5-HT reuptake and 5-HT2 receptors modulate capsaicin-evoked hypothermia in rats

Numerous studies support a role for the endogenous 5-hydroxytryptamine (5-HT) system in the hypothermic effect of capsaicin. None of those studies, however, selectively delineate a role for 5-HT reuptake or 5-HT receptors in this regard. In the present investigation, we determined if the blockade of 5-HT reuptake or the activation of 5-HT_1A or 5-HT₂ receptors modulates capsaicin-evoked hypothermia. The administration of capsaicin (0.2–1 mg/kg, i.m.) produced dose-related hypothermia. Fluoxetine (10 mg/kg, i.p.), a selective serotonin reuptake inhibitor (SSRI), did not affect body temperature. For combined administration, pretreatment with fluoxetine (10 mg/kg, i.p.) significantly attenuated the hypothermia caused by capsaicin (0.5 and 1 mg/kg, i.m.). For the 5-HT receptor experiments, we pretreated rats with either WAY 100635, a 5-HT_1A receptor antagonist, or mianserin, a 5-HT₂ receptor antagonist, and then administered a fixed, hypothermic dose of capsaicin (1 mg/kg, i.m.). WAY 100635 (1 mg/kg, s.c.) administration did not affect capsaicin-evoked hypothermia. This indicates that 5-HT_1A receptor activation does not play a major role in the hypothermic effect of capsaicin. In contrast, pretreatment with mianserin (10 mg/kg, i.p.) enhanced the hypothermic effect of capsaicin (1 mg/kg, i.m.). The present data reveal that capsaicin-evoked hypothermia in rats is attenuated by the blockade of 5-HT reuptake and enhanced by the antagonism of 5-HT₂ receptors.     

Serotonin type 3 receptors modulate the aggression-stimulating effects of adolescent cocaine exposure in Syrian hamsters (Mesocricetus auratus)

Repeated cocaine (0.5 mg/kg) exposure throughout adolescence stimulates offensive aggression in hamsters. These studies examined whether the cocaine-induced aggressive response was regulated by serotonin Type 3 (5-HT(3)) receptor activity and correlated with altered 5-HT(3) receptor expression. Cocaine-treated Syrian hamsters (Mesocricetus auratus) were tested for aggression after the administration of either the 5-HT(3) antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron; 0.01-1.20 mg/kg) or the 5-HT(3) agonist l-(m-chlorophenyl)-biguanide hydrochloride (mCPBG; 5.0-15.0 mg/kg), alone or in combination. Tropisetron alone dose dependently reduced cocaine-induced aggression, with a significant reduction at 0.3 mg/kg, whereas mCPBG was ineffective. mCPBG administered prior to tropisetron required a higher dose (1.2 mg/kg) of antagonist to block aggression, indicating a selective 5-HT(3) effect. Cocaine-treated hamsters showed altered 5-HT-sub-3 immunoreactivity in several brain areas implicated in aggression control. These data support a role for 5-HT(3) receptors in adolescent cocaine-induced aggression.     

Suppressive effect of vagal afferents on cervical dorsal horn neurons responding to tooth pulp electrical stimulation in the rat

The aim of the present study was to test the hypothesis that vagal afferent (VA) inputs modify the tooth pulp (TP) stimulation-evoked activity of the first cervical dorsal horn (C1) neurons via the activation of endogenous noradrenergic and serotonergic systems. In 30 anesthetized rats, the activity of 56 C1 spinal neurons and the amplitude in a digastric muscle electromyogram (dEMG, n=30) increased proportionally during TP stimulation at an intensity of 1-3.5 times the threshold for the jaw-opening reflex (JOR). The activity in 46 of these C1 neurons (82.1%) was suppressed by VA stimulation (1.0 mAx0.1 ms, 50 Hz for 30 s) of the right vagus nerve. The suppressive effects of VA stimulation on C1 spinal neuron activity were significantly reduced after intravenous administration of either the alpha-adrenergic receptor antagonist phenoxybenzamine (POB, 2.0 mg/kg and 4.0 mg/kg) or the 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonist ICS 205-930 (1.0 mg/kg and 2.0 mg/kg). But the 5-HT(1/2) receptor antagonist methysergide (1.0 mg/kg and 2.0 mg/kg) had no significant effect on VA stimulation-induced inhibition of the C1 spinal neuron activity. These results suggest that VA stimulation inhibits nociceptive transmission in the C1 spinal neuron activity via the activation of both noradrenergic and serotonergic (5-HT(3)) descending inhibitory systems.     

Body temperature responses in cats and rabbits to the monoamine oxidase inhibitor tranylcypromine

1. In unanaesthetized cats tranylcypromine (1-10 mg/kg) had scarcely any effect on rectal temperature when injected intraperitoneally, yet such injections prevented the deep and long-lasting fall in rectal temperature which normally occurs when the cat is anaesthetized by intraperitoneal pentobarbitone sodium or intravenous chloralose. The anaesthesia itself, however, was not affected. In some of the experiments with pentobarbitone sodium rectal temperature even rose to fever level.2. In anaesthetized as well as in unanaesthetized cats injections of tranylcypromine (0.1-1 mg) into the cerebral ventricles caused a rise in rectal temperature.3. In rabbits, rectal temperature was scarcely affected when surgical anaesthesia was produced by intravenous infusions of pentobarbitone sodium under the same condition in which, in cats, intraperitoneal pentobarbitone sodium produced a deep and long-lasting fall in temperature, i.e. when no external heat was applied but excessive dissipation of heat was prevented by placing the rabbit on a cotton-wool pad. However, when it was placed on the metal surface of an operating table, the anaesthesia was associated with a deep fall in rectal temperature.5. In anaesthetized and unanaesthetized rabbits tranylcypromine had no effect on rectal temperature when injected intraperitoneally (10 mg/kg) or into the cerebral ventricles (1 mg).5. These results are discussed in relation to the theory that the three monoamines in the hypothalamus, 5-hydroxytryptamine (5-HT), adrenaline and noradrenaline, act as central transmitters in temperature regulation.     

Inhibitory effect of 5-hydroxytryptamine on hyperphagia in mice with genetic overexpression of neuropeptide Y

The present study examined the effect of 5-hydroxytraptamine (5-HT) on the feeding behavior of transgenic mice with neuropeptide Y (NPY) overexpression. Solution of 5-HT (1, 2.5 or 5 mg/kg) was administered intraperitoneally into (1) NPY-overexpressing mice, and (2) wild-type mice with 2-deoxy-d-glucose (2-DG) induced hyperphagia. The NPY-overexpressing mice were further divided into five groups: (1) control mice, (2) mice treated with 5-HT (5 mg/kg), (3) mice treated with 5-HT (5 mg/kg) and ketanserin (0.5 or 1 mg/kg), a 5-HT2A receptor antagonist, (4) mice treated with insulin (1 IU/kg), and (5) mice treated with insulin (1 IU/kg) and 5-HT (5 mg/kg). Food intake and plasma glucose levels were measured. The results showed that 5-HT reduced hyperphagia in both NPY-overexpressing mice and 2-DG-treated mice in dose-dependent manner. Hyperglycemia was induced by 5-HT administration. Ketanserin antagonized the 5-HT induced hypophagia and hyperglycemia. Insulin, on the other hand, prevented 5-HT induced hyperglycemia but not the hypophagic effect. In conclusion, 5-HT reduces hyperphagia in the NPY-overexpressing rat through action on 5-HT2A receptors and this hypophagic effect of 5-HT does not depend on the hyperglycemia.