Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist.
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Repeated withdrawals from chronic ethanol induce a persistent adaptive change. Further, stress substitutes for the initial two withdrawals of a multiple-withdrawal protocol to sensitize rats to withdrawal-induced anxiety-like behavior ('anxiety'). Therefore, it was tested whether the persistent adaptation induced by multiple-withdrawal exposures allows stress to elicit anxiety after a period of abstinence. Social interaction was used to assess the degree of anxiety induced by 45 min of restraint stress 3, 7, or 14 days after rats were exposed to multiple withdrawals from a chronic 4.5% ethanol diet. Restraint stress reduced social interaction (ie anxiety-like behavior) at 3, but not at 7 or 14 days, after the multiple withdrawals. No anxiety response was observed in animals that received multiple withdrawals without stress or in animals that received stress when exposed only to control liquid diet. Drugs (ie a CRF1-receptor antagonist, a benzodiazepine receptor antagonist, and a 5-HT1A-receptor agonist) previously demonstrated to block the cumulative adaptation, when administered during repeated withdrawals, prevented stress-induced anxiety-like behavior during abstinence. Additionally, these drugs applied prior to stress in the rats previously exposed to the repeated withdrawal protocol, likewise, minimized stress-induced anxiety. The anxiety following stress during abstinence from previous chronic ethanol exposure is indicative of an interaction of stress with the persistent adaptive change caused by repeated withdrawals. Stress eliciting anxiety-like behavior during abstinence from previous ethanol exposures in rats is consistent with stress inducing anxiety during recovery (sobriety) in the alcoholic, a circumstance that can facilitate craving and relapse. (+info)
Inhibitory effects of the 5-HT(1A) receptor agonist buspirone on stress-induced hyperglycemia in mice: involvement of insulin and a buspirone metabolite, 1-(2-pyrimidinyl)piperazine (1-PP).
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Effects of serotonergic anxiolytic buspirone on immobilization-induced hyperglycemia were studied in mice. Stress elicited hyperglycemia in mice. Pretreatment with buspirone significantly reduced immobilization-induced hyperglycemia. Buspirone increased serum insulin levels in both non- and stressed mice. The major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP) also increased and this further inhibited immobilization-induced hyperglycemia, since 1-PP increased serum insulin levels in both non-stressed and stressed mice, similar to the increases induced by buspirone. These results suggest that buspirone can reduce stress-induced hyperglycemia by facilitating insulin release. Moreover, 1-PP, a metabolite of buspirone may participate in the effects of buspirone. Since 1-PP is an antagonist of alpha(2) receptors, alpha(2) receptors may be related to effects of 1-PP. (+info)
Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome.
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OBJECTIVE: To study the dynamic function of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. DESIGN: Prospective comparison of patients with postviral fatigue syndrome with two control groups. SETTING: Department of neurology, University of Glasgow, Southern General Hospital; department of psychiatry, St James's Hospital, Dublin. SUBJECTS: 15 patients with postviral fatigue syndrome, 13 age and sex matched healthy subjects, and 13 patients with primary depression. MAIN OUTCOME MEASURES: Serum prolactin concentrations before and one, two, and three hours after administration of buspirone. RESULTS: Because of the effects of sex hormones on prolactin secretion data for men and women were analysed separately. There was no significant difference in baseline prolactin concentrations between patients with postviral fatigue syndrome and healthy subjects or those with primary depression. However, the percentage difference between peak and baseline values was significantly higher in patients with postviral fatigue syndrome than the control groups (one way analysis of variance: women, p = 0.003; men, p = 0.004). CONCLUSIONS: The results suggest upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. The buspirone challenge test may therefore be useful in distinguishing these two conditions. Larger studies are required to explore the potential value of drugs acting on central 5-hydroxytryptamine receptors in the treatment of patients with the postviral fatigue syndrome. (+info)
Differential distribution of functional alph}1-adrenergic receptor subtypes along the rat tail artery.
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The rat tail artery has been used for the study of vasoconstriction mediated by alpha(1A)-adrenoceptors (ARs). However, rings from proximal segments of the tail artery (within the initial 4 cm, PRTA) were at least 3-fold more sensitive to methoxamine and phenylephrine (n = 6-12; p < 0.05) than rings from distal parts (between the sixth and 10th cm, DRTA). Interestingly, the imidazolines N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]m ethanesulfonamide hydrobromide (A-61603) and oxymetazoline, which activate selectively alpha(1A)-ARs, were equipotent in PRTA and DRTA (n = 4-12), whereas buspirone, which activates selectively alpha(1D)-AR, was approximately 70-fold more potent in PRTA than in DRTA (n = 8; p < 0.05). The selective alpha(1D)-AR antagonist 8-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY-7378) was approximately 70-fold more potent against the contractions induced by phenylephrine in PRTA (pK(B) of approximately 8.45; n = 6) than in DRTA (pK(B) of approximately 6.58; n = 6), although the antagonism was complex in PRTA. 5-Methylurapidil, a selective alpha(1A)-antagonist, was equipotent in PRTA and DRTA (pK(B) of approximately 8.4), but the Schild slope in DRTA was 0.73 +/- 0.05 (n = 5). The noncompetitive alpha(1B)-antagonist conotoxin rho-TIA reduced the maximal contraction induced by phenylephrine in DRTA, but not in PRTA. These results indicate a predominant role for alpha(1A)-ARs in the contractions of both PRTA and DRTA but with significant coparticipations of alpha(1D)-ARs in PRTA and alpha(1B)-ARs in DRTA. Semiquantitative reverse transcription-polymerase chain reaction revealed that mRNA encoding alpha(1A)- and alpha(1B)-ARs are similarly distributed in PRTA and DRTA, whereas mRNA for alpha(1D)-ARs is twice more abundant in PRTA. Therefore, alpha(1)-ARs subtypes are differentially distributed along the tail artery. It is important to consider the segment from which the tissue preparation is taken to avoid misinterpretations on receptor mechanisms and drug selectivities. (+info)
Respiratory abnormalities resulting from midcervical spinal cord injury and their reversal by serotonin 1A agonists in conscious rats.
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Respiratory dysfunction after cervical spinal cord injury (SCI) has not been examined experimentally using conscious animals, although clinical SCI most frequently occurs in midcervical segments. Here, we report a C5 hemicontusion SCI model in rats with abnormalities that emulate human post-SCI pathophysiology, including spontaneous recovery processes. Post-C5 SCI rats demonstrated deficits in minute ventilation (Ve) responses to a 7% CO2 challenge that correlated significantly with lesion severities (no injury or 12.5, 25, or 50 mm x 10 g weight drop; New York University impactor; p < 0.001) and ipsilateral motor neuron loss (p = 0.016). Importantly, C5 SCI resulted in at least 4 weeks of respiratory abnormalities that ultimately recovered afterward. Because serotonin is involved in respiration-related neuroplasticity, we investigated the impact of activating 5-HT1A receptors on post-C5 SCI respiratory dysfunction. Treatment with the 5-HT1A agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH DPAT) (250 microg/kg, i.p.) restored hypercapnic Ve at 2 and 4 weeks after injury (i.e., approximately 39.2% increase vs post-SCI baseline; p < or = 0.033). Improvements in hypercapnic Ve response after single administration of 8-OH DPAT were dose dependent and lasted for approximately 4 h(p < or = 0.038 and p < or = 0.024, respectively). Treatment with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.), replicated the results, whereas pretreatment with a 5-HT1A-specific antagonist, 4-iodo-N-[2-[4(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.) given 20 min before 8-OH DPAT negated the effect of 8-OH DPAT. These results imply a potential clinical use of 5-HT1A agonists for post-SCI respiratory disorders. (+info)
The 5-HT1A receptor and the stimulus effects of LSD in the rat.
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RATIONALE: It has been suggested that the 5-HT1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD). OBJECTIVE: The present study sought to characterize the effects of several compounds with known affinity for the 5-HT1A receptor on the discriminative stimulus effects of LSD. METHODS: Twelve male Fischer 344 rats were trained in a two-lever, fixed-ratio (FR) 10, and food-reinforced task with LSD (0.1 mg/kg, i.p.; 15-min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT(1A) agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT1A ligands were also tested in the presence of the selective 5-HT1A receptor antagonist, WAY-100,635 (0.3 mg/kg, s.c.; 30-min pretreatment). RESULTS: In combination tests, stimulus control by LSD was increased by all 5-HT1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT1A receptor was abolished by administration of WAY-100,635. CONCLUSION: These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT1A receptor has a significant modulatory role in the stimulus effects of LSD. (+info)
Effect of modulation of serotonergic, cholinergic, and nitrergic pathways on murine fundic size and compliance measured by ultrasonomicrometry.
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Reduced fasting or postprandial gastric volumes have been implicated in the pathophysiology of functional dyspepsia. The mechanisms that underlie the control of gastric fundic volume are incompletely understood, partly because of an inability to accurately measure fundic volume in vivo in small animals. Small animals are useful models to evaluate mechanisms, e.g., in knockout animals. The aim of this study was to determine whether an ultrasonometric technique accurately monitors fundic contraction and relaxation in mice in vivo and to determine the effect of modulation of cholinergic, nitrergic, and serotonergic pathways on fundic size and compliance in the intact mouse innervated stomach. Two to four piezoelectric crystals (diameter 1 mm, 24-microm resolution) were glued to the serosal side of fundus and used to measure distance. Validation studies showed excellent correlation between measured changes and actual changes in distances between crystals and excellent reproducibility. The expected responses to pharmacological modulation with bethanechol and nitroglycerin were demonstrated. Atropine increased the distance between the crystals, suggesting a baseline cholinergic regulation of fundic volume. Bethanechol, Nomega-nitro-L-arginine, and the 5-HT1B/D agonist sumatriptan decreased the distance between the crystals, suggesting fundic contraction. Atropine, nitroglycerin, and buspirone caused an increase in intercrystal distance consistent with fundic relaxation. Fundic compliance was investigated by changing intragastric pressure via an implanted catheter. Sumatriptan increased compliance, whereas buspirone increased the distance between crystals but did not change compliance. The data suggest that ultrasonomicrometry is a useful tool that can reproducibly and accurately measure changes in fundic size and the response to pharmacological agents. (+info)
Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women.
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The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT1A) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT(1A) receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia. (+info)