Intracerebroventricular infusion of CRF increases extracellular concentrations of norepinephrine in the hippocampus and cortex as determined by in vivo voltammetry

Previous studies have indicated that intracerebroventricular (i.c.v.) infusions of corticotropin-releasing factor (CRF) activate locus coeruleus (LC) noradrenergic neurons and increase the metabolism and extracellular concentrations of norepinephrine (NE) in several brain regions, suggesting increased release. To examine the temporal aspects and mechanism of the presumed release of NE, CRF was infused i.c.v. and the oxidation current was recorded using carbon fiber voltammetric electrodes placed in rat hippocampus or cortex. The CRF (1 μg, i.c.v.) caused a significant increase of oxidation current with a delay of approximately 5 min, and a peak at approximately 35 min. Similar responses were observed in the medial prefrontal cortex. The hippocampal response was markedly attenuated when CRF was infused into rats pretreated with DSP-4 to deplete NE, suggesting that the observed changes in current resulted from oxidation of NE. The increase of NE-like current did not occur when 25 μg alpha-helical CRF_9–41 (ahCRF) was injected immediately before 1 μg CRF, suggesting that the response was mediated by cerebral CRF-receptors. Subcutaneous pretreatment with the ganglionic blocker, chlorisondamine, at a dose of 3 mg/kg had no effect on the voltammetric response to CRF, but a 6 mg/kg dose completely prevented the response. The β-adrenoceptor antagonists, S-propranolol (5 mg/kg), nadolol (5 and 10 mg/kg), and timolol (5 mg/kg) attenuated the NE response to i.c.v. CRF to varying degrees. When chlorisondamine (3 μg) or nadolol (5 μg) were given i.c.v. before the CRF, the hippocampal responses were not blocked. These results suggest peripheral actions of ganglionic and β-adrenergic blockers. We conclude that peripheral autonomic mechanisms, and probably both central and peripheral β-adrenoceptors, contribute to the increased secretion of hippocampal NE in response to i.c.v. CRF.     

Memory impairment induced by IL-1β is reversed by α-MSH through central melanocortin-4 receptors

Interleukin-1beta (IL-1β) significantly influences memory consolidation. Treatments that raise the level of IL-1β in the brain, given after training, impair contextual fear conditioning. The melanocortin α-MSH exerts potent anti-inflammatory actions by physiologically antagonizing the effect of pro-inflammatory cytokines. Five subtypes of melanocortin receptors (MC1R–MC5R) have been identified, with MC3R and MC4R predominating in the central nervous system. The present experiments show that injection of IL-1β (5 ng/0.25 μl) in dorsal hippocampus up to 15 min after training decreased freezing during the contextual fear test. The treatment with IL-1β (5 ng/0.25 μl) 12 h after conditioning cause amnesia when animals were tested 7 days post training. Thus, our results also demonstrated that IL-1β can influence persistence of long-term memory. We determined that animals previously injected with IL-1β can acquire a new contextual fear memory, demonstrating that the hippocampus was not damaged. Treatment with α-MSH (0.05 μg/0.25 μl) blocked the effect of IL-1β on contextual fear memory. Administration of the MC4 receptor antagonist HS014 (0.5 μg/0.25 μl) reversed the effect of α-MSH. However, treatment with γ-MSH (0.5 μg/0.25 μl), an MC3 agonist, did not affect IL-1β-induced impairment of memory consolidation. These results suggest that α-MSH, through central MC4R can inhibit the effect of IL-1β on memory consolidation.     

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats

Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.     

Cataleptic effect of neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice: modulation by serotonergic agents

The neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) induced catalepsy in mice is modified by dopaminergic, adenosinergic and GABAergic agents. In light of serotonergic agents being implicated in antipsychotic-induced catalepsy and their ability to increase brain neurosteroid content, the present study was undertaken to investigate the effect of various 5-HT agents on catalepsy induced by 3α,5α-THP in mice. Pretreatment with selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), 5-HT releaser, fenfluramine (10 mg/kg, i.p.), 5-HT_1A receptor agonist, 8-OH-DPAT (0.3 mg/kg, s.c.), 5-HT_1B/1C receptor agonist, TFMPP (3 mg/kg, i.p.), 5-HT_2A/1C receptor agonist, DOI (1.5 mg/kg, s.c.) and 5-HT₃ agonist, 2-methylserotonin (5 mg/kg, i.p.) potentiated the catalepsy induced by exogenous administration of 3α,5α-THP. Furthermore, FGIN 1–27, an MDR agonist that increases endogenous content of 3α,5α-THP although per se failed to exhibit any cataleptic effect but enhanced the cataleptic response in combination with these serotonergic agents. The potentiating action of 5-HT_1A, 5-HT_2A/1C or 5-HT₃ receptor agonist on 3α,5α-THP induced catalepsy was not blocked by prior administration of sub-effective dose (1 mg/kg, s.c.) of their respective receptor antagonists pindolol, ritanserin or ondansetron or by pretreatment with serotonergic neurotoxin 5,7-DHT (100 μg/mouse, i.c.v.). However this effect of different serotonergic agents was antagonized by the GABA_A receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3α-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). The 5-HT agents enhance neurosteroid-induced catalepsy by increasing GABAergic tone, likely as a consequence of increased brain content of 3α,5α-THP.     

Different receptor mechanisms mediate the effects of endotoxin and interleukin-1 on female sexual behavior

Activation of the immune system by lipopolysaccharide (LPS) produces physiological, neuroendocrine and behavioral effects, some of which are mediated by cytokine production. We have previously shown that the cytokine interleukin-1 (IL-1) inhibits sexual behavior in female, but not male rats, while producing a comparable suppression of locomotion in both sexes. The present study examined the effects of LPS on sexual behavior and locomotion of male and female rats, and the involvement of IL-1 receptors in mediating the effects of IL-1 and LPS on females' behavior. Peripheral (i.p.) administration of LPS (50 or 250 μg/kg) significantly decreased sexual behavior in females, up to 6 h after administration, while it had no effect on male sexual behavior. However, locomotor activity, measured in the open-field test, was similarly reduced by LPS in both males and females. Pretreatment with the IL-1 receptor antagonist (IL-1ra) either i.p. (10 mg/kg) or intracerebroventricularly (i.c.v.) (50 μg/rat) did not prevent the inhibition of female sexual behavior and locomotion induced by either i.p. (50 μg/kg) or i.c.v. (200 or 400 ng/rat) administration of LPS, respectively. However, identical doses of IL-1ra significantly reversed the effects of IL-1β, administered either i.p. (5 μg/kg) or i.c.v. (50 ng/rat), respectively. These results demonstrate that both LPS and IL-1β produce marked inhibition of sexual behavior in female, but not in male rats. However, IL-1 receptors are not required for the effects of LPS on sexual behavior in female rats.     

Intranigral GR-113808, a selective 5-HT4 receptor antagonist, attenuates morphine-stimulated dopamine release in the rat striatum

GR-113808, a potent and selective 5-HT₄ receptor antagonist, was infused through a microdialysis probe into the striatum and nucleus accumbens of awake rats, and basal and morphine-stimulated extracellular concentrations of dopamine (DA) were measured in these regions. At 1 and 10 μM GR-113808 did not effect the extracellular concentrations of DA in either region and 100 μM significantly reduced dialysate DA only in the striatum. A subcutaneous dose of 5 mg/kg morphine significantly raised extracellular concentrations of DA in the striatum and nucleus accumbens from 60 to 120 min after injection and the effect was not modified by 10 μM GR-113808 infused through the probe 20 min before and for 60 min after morphine. Bilateral injections of GR-113808 (1, 2.5 and 10 μg/0.5 μl) in the substantia nigra pars compacta did not affect dialysate DA in the striatum, except for a significant increase 120 min after the injection of 10 μg but the highest dose of GR-113808 prevented the increase of striatal DA caused by 5 mg/kg morphine s.c. The results suggest that 5-HT₄ receptors in the substantia nigra modulate the activity of the dopaminergic nigrostriatal system only when the neurons are activated.     

Effects of serotonin synthesis blockade on interleukin-1β action in the brain of rats

The ability of the brain serotonergic system to mediate the effects of interleukin-1β (IL-1β) was investigated. Intracerebroventricular administration of IL-1β induced a significant pyrogenic reaction, depression in social behaviour, loss of body weight and reduced food intake in rats. Pre-treatment with p-chlorphenylalanine, an inhibitor of serotonin synthesis, blocked the IL-1β-induced decrease in food intake and loss of body weight, but failed to alter the temperature increase and the decrease in communicative activity.     

Blockade of angiotensin II AT1 receptors inhibits pressor action of centrally administered interleukin-1β in Sprague Dawley rats

The aim of the present study was to evaluate the influence of intraventricular administration of recombinant rat interleukin-1β (IL-1β) on regulation of resting blood pressure and heart rate and to test the hypothesis that the brain angiotensinergic system is involved in regulation of hemodynamic parameters by centrally applied IL-1β. The experiments were performed on Sprague Dawley rats, assigned to three series of experiments. In series 1 (control, n = 6), mean arterial pressure (MAP) and heart rate (HR) were recorded for 15 min under baseline conditions. This was followed by infusion of saline (0.9% sterile NaCl 5 μL/h) into the left cerebral ventricle (LCV). Measurements were continued during the next 60 min. In series 2 (n = 6) and 3 (n = 6) the experimental design was similar, except that in series 2 the animals were LCV infused with saline containing IL-1β (100 ng/h) and in series 3 with saline containing IL-1β (100 ng/h) and angiotensin type 1 (AT1) receptors antagonist (Losartan, 10 μg/h). LCV infusion of saline alone did not influence MAP and HR while administration of IL-1β elicited significant increase in MAP, but not in HR. The pressor effect was absent during combined infusion of IL-1β and Losartan. Results of the study provide evidence that centrally administered IL-1β exerts pressor effect, and reveal that this effect is mediated by stimulation of the brain angiotensin system and requires activation of AT1 receptors.     

Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and κ-opioid receptor implicated

Our previous work has demonstrated that 100-Hz electroacupuncture (EA) or 100-Hz transcutaneous electrical nerve stimulation (TENS) was very effective in ameliorating the morphine withdrawal syndrome in rats and humans. The mechanism was obscure. (1) Rats were made dependent on morphine by repeated morphine injections (5–140 mg/kg, s.c., twice a day) for eight days. They were then given 100-Hz EA for 30 min 24 h after the last injection of morphine. A marked increase in tail flick latency (TFL) was observed. This effect of 100-Hz EA could be blocked by naloxone (NX) at 20 mg/kg, but not at 1 mg/kg, suggesting that 100-Hz EA-induced analgesia observed in morphine-dependent rats is mediated by κ-opioid receptors. (2) A significant decrease of the concentration of dynorphin A (1–17) immunoreactivity (-ir) was observed in the spinal perfusate in morphine-dependent rats, that could be brought back to normal level by 100-Hz EA. (3) 100-Hz EA was very effective in suppressing NX-precipitated morphine withdrawal syndrome. This effect of EA could be prevented by intrathecal administration of nor-BNI (2.5 μg/20 μl), a κ-opioid receptor antagonist, or dynorphin A (1–13) antibodies (25 μg/20 μl) administered 10 min prior to EA. In conclusion, while the steady-state spinal dynorphin release is low in morphine-dependent rats, it can be activated by 100-Hz EA stimulation, which may be responsible for eliciting an analgesic effect and ameliorating morphine withdrawal syndrome, most probably via interacting with κ-opioid receptor at spinal level.     

The opposing effects of interleukin-1 β microinjected into the preoptic hypothalamus and the ventromedial hypothalamus on nociceptive behavior in rats

The effects of microinjections of recombinant human interleukin-1β (rhIL-1β) into the hypothalamus and neighboring basal forebrain on nociceptive behavior were studied using a hot-plate test in rats. The microinjection of rhIL-1β at doses between 5 pg/kg and 50 pg/kg into the medial part of the preoptic area (MPO) reduced the paw-withdrawal latency. The maximal reduction was obtained 30 min after the injection of rhIL-1β at 20 pg/kg. RhIL-1β (20 pg/kg)-induced hyperalgesia was completely blocked by the simultaneous injection of IL-1 receptor antagonist (IL-1ra, 20 ng/kg), Na salicylate (200 ng/kg) or α-melanocyte-stimulating hormone (α-MSH, 20 ng/kg). The intra-MPO injection of rhIL-1β at doses of less than 5 pg/kg or more than 50 pg/kg (up to 2 ng/kg) had no effect on nociceptive behavior. The microinjection of rhIL-1β (20 pg/kg) into the lateral part of the preoptic area, the median preoptic nucleus and the diagonal band of Broca also reduced the latency. On the other hand, the microinjection of rhIL-1β (20 pg/kg) into the paraventricular nucleus, the lateral hypothalamic area and the septal nucleus had no effect on nociception. The microinjection of rhIL-1β (20 pg/kg–50 pg/kg) into the ventromedial hypothalamus produced a prolongation of the paw-withdrawal latency. A maximal prolongation was obtained 10 min after the injection of rhIL-1β at 50 pg/kg. This reaction was also blocked by the simultaneous injection of IL-1ra (50 ng/kg) and Na salicylate (500 ng/kg). These findings indicate that IL-1β in the MPO and the VMH produces hyperalgesia and analgesia, respectively, while, in addition, both effects are mediated by IL-1 receptors and the synthesis of prostaglandins.     

Antinociception induced by opioid or 5-HT agonists microinjected into the anterior pretectal nucleus of the rat

The changes in the latency for tail withdrawal in response to noxious heating of the skin induced by microinjection of opioid or serotonergic agonists into the anterior pretectal nucleus (APtN) was studied in rats. The μ-opioid agonist DAMGO (78 and 156 ρmol), but not the δ-opioid agonist DADLE (70 and 140 ρmol), the κ-opioid agonist bremazocine (0.24 and 0.48 ηmol) or the σ-opioid agonist N-allylnormetazocine (0.54 ηmol), produced a dose-dependent antinociceptive effect. The 5-HT₁ agonist 5-carboxamidotryptamine (19 and 38 ηmol) and the 5-HT_1B agonist, CGS 12066B (1.12 and 2.24 ηmol), but not the non-selective 5-HT agonist m-CPP (41 to 164 ηmol), 5-HT₂ agonist α-methylserotonin (36 and 72 ηmol) and 5-HT₃ agonist 2-methylserotonin (36 and 72 ηmol), produced a dose-dependent antinociceptive effect. These results indicate that the antinociceptive effects of opioid or serotonergic agonists microinjected into the APtN depend on drug interaction with local μ or 5-HT_1B receptors, respectively.     

Modulation of brown adipose tissue-mediated thermogenesis by lesions to the nucleus tractus solitarius in the rat

Given that relatively little is known regarding the central control of brown adipose tissue (BAT)-mediated thermogenesis the present study assessed whether the direct pharmacological stimulation of β- or α-adrenergic receptors located on the brown adipocytes would result in a typical thermogenic response following electrolytic lesions to the nucleus tractus solitarius (NTS). Bilateral electrolytic lesions to the NTS in the rat effectively disrupted the baroreceptor reflex arc. It was observed that the metabolic and temperature responses to either norepinephrine (1, 5, or 25 μg/kg/min) or to the β-agonist isoproterenol (0.5 μg/kg/min) were significantly attenuated in the NTS-lesioned rats relative to the control animals with an intact baroreflex. Conversely, the cardiovascular effects of norepinephrine or of the α-agonist phenylephrine (10 μg/kg/min) were enhanced in the NTS-lesioned animals. The results suggest that the functional capacity of the brown adipocytes was reduced following NTS lesions and points to an alteration in the ability of β-receptors to respond to pharmacological stimulation with a typical thermogenic response.     

Effect of a 5-HT1A receptor agonist, flesinoxan, on the extracellular noradrenaline level in the hippocampus and on the locomotor activity of rats

We have studied effects of 5-hydroxytryptamine 1A (5-HT_1A) receptor-selective compounds on the extracellular noradrenaline (NA) level in the hippocampus of rats using microdialysis and on their locomotor activity. A selective 5-HT_1A receptor agonist, flesinoxan (5 mg/kg, i.p.) increased the extracellular NA level in the hippocampus, and increased the locomotor activity. Both responses were blocked by pretreatment with a 5-HT_1A receptor antagonist, WAY100635 (1 mg/kg, i.p.) and an α₂ adrenoceptor agonist, clonidine (50 μg/kg, i.p.). Bilateral intrahippocampal injection of flesinoxan (200 nmol in 2 μl, respectively) increased the locomotor activity of rats and the intrahippocampal perfusion of flesinoxan (1 mM, 2 μl/min) increased the extracellular NA level in the hippocampus. Bilateral intrahippocampal injections of a small amount of WAY100635 (0.1 nmol in 2 μl, respectively) blocked the flesinoxan (5 mg/kg, i.p.)-induced hyperactivity. Flesinoxan (5 mg/kg, i.p.) did not significantly influence the level of serotonin or its major metabolite in the hippocampus, or dopamine or its metabolites in the striatum. In conclusion, these behavioral as well as pharmacological results indicate that postsynaptic 5-HT_1A receptor activation by flesinoxan increase the extracellular NA level in the hippocampus, which may be the cause of the increase of the locomotor activity.     

Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice

The present study demonstrated the antidepressant-like effect of neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α, 5α THP) in mouse forced swim test of depression and its modulation by different serotonergic agents. Pretreatment with the selective serotonin reuptake inhibitor, fluoxetine (5 mg/kg, i.p.), the 5-HT releaser, fenfluramine (10 mg/kg, i.p.), the 5-HT_1A receptor agonist, 8-OH-DPAT (0.1 mg/kg, s.c.), the 5-HT_1B/1C receptor agonist, TFMPP (4 mg/kg, s.c.) and the 5-HT_2A/1C receptor agonist, DOI (2 mg/kg, s.c.) potentiated the antidepressant-like effect of 3α, 5α THP. At these doses the serotonergic agents per se did not modify the duration of immobility. However, fluoxetine (20 mg/kg, i.p.), fenfluramine (20 mg/kg, i.p.) or imipramine (5 or 20 mg/kg, i.p.) not only reduced immobility but also enhanced the antidepressant-like effect of 3α, 5α THP. Such a potentiating effect of the 5-HT_1A or the 5-HT_2A/1C receptor agonist was not antagonized by the sub-effective dose (0.1 mg/kg, s.c.) of their respective antagonists p-MPPI or ketanserin. Pretreatment with p-CPA (300×3 mg/kg, i.p.), a depleter of 5-HT neuronal store failed to block the influence of fluoxetine and fenfluramine on antidepressant-like effect of 3α, 5α THP. The accelerated effect of 3α, 5α THP in presence of serotonergic agents was antagonized by the GABA_A receptor antagonist, bicuculline (1 mg/kg, i.p.) or the 3α-hydroxysteroid oxidoreductase enzyme inhibitor, indomethacin (5 mg/kg, i.p.). These findings for the first time demonstrate that serotonergic agents potentiate the antidepressant-like action of 3α, 5α THP, by enhancing the GABAergic tone as a likely consequence of increased brain content of this neurosteroid.     

Effect of acute administration of isoproterenol and angiotensin II, separately and in combination, on water intake and blood pressure of rats

The effects of administration of isoproterenol, a β-adrenergic agonist, and angiotensin II, a peptide, separately and in combination, on water intake and blood pressure of rats were studied. The results of 6 factorially designed studies in which 4 different doses of each compound were administered revealed that water intakes increased directly with the logarithm of increasing doses of each. The effect of simultaneous administration of the 2 compounds on water intake was additive at submaximal doses of each. No interactive effects on water intake were observed when the 2 compounds were administered simultaneously in any study. Reduction in urine output appears to be a more sensitive response to administration of isoproterenol than increase in water intake since it was virtually abolished at a dose (2.5 μg/kg SC) that had no effect on water intake. The lowest doses of angiotensin II (25 and 50 μg/kg SC) had no significant effect on either water intake or urine output. The effect of simultaneous administration of both compounds on urine output was essentially the same as that accompanying administration of isoproterenol alone. Following administration of angiotensin II (150 μg/kg, SC) mean systemic blood pressure of unanesthetized, chronically cannulated rats reached maximal levels within 5 min and returned to pretreatment control level by 60 min. Following administration of isoproterenol (25 μg/kg, SC), mean systemic blood pressure decreased within 5 min, was maximally depressed by 30 min and had returned halfway to the pretreatment control level by 60 min. Simultaneous administration of isoproterenol and angiotensin II failed to induce a significant change in blood pressure. These results are of particular interest since they show that neither the pressor effect of angiotensin II nor the depressor effect of isoproterenol is essential for the induction of drinking by these 2 compounds.     

A role for presynaptic α2-adrenoceptors in angiotensin II-induced drinking in rats

Studies from this laboratory have shown that either central or peripheral administration of clonidine, the α₂-adrenoceptor agonist, can attenuate a variety of dipsogenic stimuli in rats. Further, yohimbine and tolazoline, α₂-adrenoceptor antagonists, augment the drinking response to both peripherally administered isoproterenol and angiotensin II. Studies reported here establish a dose-inhibition relationship between the dose of clonidine administered (2 to 32 μg/kg) intracerebroventricularly (IVT) and inhibition of the drinking response to peripherally administered angiotensin II (200 μg/kg, SC). DI₅₀ was approximately 4 μg/kg. Yohimbine (300 μg/kg, SC) reversed the antidipsogenic effect of centrally administered clonidine (32 μg/kg, IVT) on angiotensin II-induced (200 μg/kg, SC) water intake. Phenylephrine, an α₂-adrenoceptor agonist, administered IVT (40 and 80 μg/kg) also inhibited angiotensin II-induced drinking in a dose-related fashion. The antidipsogenic effect of phenylephrine (80 μg/kg) was blocked by administration of yohimbine (300 μg/kg, SC). Thus, this effect of phenylephrine most likely occurs by way of α₂-adrenoceptors. These results support a role for the pre-synaptic α₂-adrenoceptor in the mediation of drinking in rats. Activation of α₂-adrenoceptors is accompanied by reduced water intake while inhibition of these receptors enhances water intake.     

A biphasic regulation of receptor mRNA expressions for growth hormone, glucocorticoid and mineralocorticoid in the rat dentate gyrus during acute stress

Acute stress increases circulating ACTH and glucocorticoid levels. The hippocampus (HIP) is a target of such stress hormones as glucocorticoid and it also expresses receptors for growth hormone (GH), particularly in the dentate gyms (DG). In order to understand the interactions between glucocorticoids and functions of GH in HIP during acute stress, the mRNA levels for GH receptor (GHR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were investigated in DG in rats exposed to restraint stress in the water (RSW). Using in situ hybridization histochemistry (ISHH), high level expressions of GHR mRNA were detected in DG. These were down-regulated by 14% after 0.5 h of RSW and then up-regulated by 38% over the initial level after 4 h of RSW. This biphasic enhancement of GHR mRNA expression in DG followed the elevation of plasma glucocorticoid levels and paralleled with biphasic expressions of mRNAs for GR and MR in DG. Although circulating GH levels did not show any correlation with the hippocampal GHR mRNA expression, adrenalectomy (ADX) decreased GHR mRNA expression in DG, and the dexamethasone treatment (DEX; 20 μg/100 μl, i.p.) of ADX rats rapidly increased the GHR mRNA expression in DG. These results have suggested that the GHR mRNA expression in the DG is regulated, at least in part, by glucocorticoids and that GH may be involved in responses of the DG to acute stress.     

The peripheral nociceptive actions of intravenously administered 5-HT in the rat requires dual activation of both 5-HT2 and 5-HT3 receptor subtypes

In 16-week-old Sprague-Dawley rats lightly anesthetized with pentobarbital, 5-HT (3–96 μg/kg, i.v.;n = 6) produced distinct pseudaffective responses and a dose-dependent (slope= 17.2 ± 6.8s/log₁₀dose) inhibition of the tail-flick (TF) reflex (ED₅₀ = 32.6 ± 9.2 μg/kg). In the same rats, a 1:1 combination of α-methyl 5-HT (a 5-HT₂ receptor selective agonist) and 2-methyl 5-HT (a 5-HT₃ receptor selective agonist) (3–192 μg/kg, i.v.), produced the same profile of pseudaffective responses and also resulted in a dose-dependent (slope= 34.0± 7.0s/log₂dose) inhibition of the TF reflex (ED₅₀ = 88.4 ± 20.5 μg/kg). In contrast, administration of α-methyl 5-HT (3–192 μg/kg, i.v.) or 2-methyl 5-HT (3–192 μg/kg, i.v.) alone did not produce any pseudaffective responses or any change in TF latency from baseline. In conscious 16-week-old male Sprague-Dawley rats, administration of 5-HT (48 μg/kg, i.v.;n = 5), or a 1:1 combination of α-methyl 5-HT and 2-methyl 5-HT (total dose= 120 μg/kg, i.v.;mn = 5), resulted in a passive avoidance behavior assessed in a step-down paradigm (slopes= 139.7 ± 58.2and154.9 ± 63.9s/trial, respectively), and the same profile of distinct pseudaffective responses exhibited by the lightly pentobarbital-anesthetized rats. However, administration of either α-methyl 5-HT (96 μg/kg, i.v.;n = 4) or 2-methyl 5-HT (96 μg/kg, i.v.;n = 4), while producing significant 5-HT receptor-mediated cardiovascular responses, produced a learned behavior not different from saline (0.25 ml, i.v.;n = 6) (slopes= 7.6 ± 2.5, 6.3 ± 1.8and7.4 ± 3.6s/trial, respectively). These results are consistent with the hypothesis that the peripheral nociceptive responses to i.v. 5-HT requires dual activation of 5-HT₂ and 5-HT₃ receptor subtypes.     

Excitatory effect of dopamine on oxytocin and vasopressin reflex releases in the rat

The involvement of dopamine in the release of oxytocin and vasopressin was investigated in lactating rats during suckling or after changes in plasma osmolality. The effects of intraventricular injections of dopamine, agonists and antagonists, were tested on electrical unit activity of oxytocinergic or vasopressinergic cells in the paraventricular nucleus, on intramammary pressure (index of oxytocin release) and diuresis (index of vasopressin release).In urethane-anaesthetized lactating suckled rats, dopamine (1 μg), apomorphine (2.5 and 5 μg) facilitated the established milk-ejection reflex, increasing the frequency and the amplitude of neurosecretory bursts of oxytocinergic cells. They also triggered the reflex in lactating rats without milk-ejections during suckling. The small doses injected were in no way such as to induce an acceleration in firing rate of oxytocinergic cells or an increase in mammary pressure.In alcohol-loaded rats, during water diuresis, dopamine (2 μg) and apomorphine (5 μg) activated the depressed vasopressinergic cells and inhibited diuresis. These facilitatory effects were progressive, reaching a maximum 10–15 min after injection.Haloperidol (5 μg) and α-flupentixol (10 μg) had an inhibitory effect on both types of neurosecretory cells in urethane-anaesthetized rats. They prevented the reflex activation of oxytocinergic cells induced by suckling and of vasopressinergic cells after a hyperosmotic stimulus (1 ml i.p 9% NaCl solution). These inhibitory effects were not of the ‘all-or-none’ type.So, we can postulate that dopamine regulates the reflex release of oxytocin and vasopressin in the hypothalamus. On the one hand, dopamine permits and controls the periodic activation of oxytocinergic cells as long as the mothers are being suckled. On the other hand, it modulates the activity of vasopressinergic cells whenever the plasma osmolality changes.