Central histaminergic stimulation of corticosterone and hyperlipemic responses after chronic ethanol consumption in rats

The consumption of ethanol in a 10% solution for 3 weeks produced a negligible increase in corticosterone secretion in the rat but raised the levels of free fatty acid (FFA) in the serum. Mepyramine insignificantly antagonized and cimetidine intensified the corticosterone response. Histamine and the H1- and H2-receptor agonists, 2-pyridylethylamine (PEA) and dimaprit significantly raised the serum corticosterone levels in chronically alcoholized rats. Mepyramine antagonized and cimetidine increased the ethanol-induced hyperlipemia. Histamine, PEA and dimaprit considerably increased the serum FFA levels in alcoholized rats. After withdrawal of ethanol, histamine and dimaprit induced a marked hyperlipemic effect, whereas PEA did not increase the serum FFA concentration. These results indicate that in chronically alcoholized rats the central histaminergic system interacts with ethanol in regulation of the serum FFA level. After the ethanol withdrawal central H1-receptors do not respond to H1-agonist stimulation.     

Interference of clonidine and alpha-methyl-p-tyrosine with stress and central histaminergic stimulation of the corticosterone response in rats

In conscious rats clonidine given intracerebroventricularly 1 h prior to a mild stress of immobilization intensified the stress-induced increase of pituitary-adrenocortical response, measured indirectly through corticosterone concentration in blood serum. The corticosterone response to clonidine was abolished by i.c.v. pretreatment of rats with yohimbine, an alpha 2-adrenergic antagonist, and was antagonized by pretreatment with phenoxybenzamine, an alpha 1-adrenergic antagonist. Clonidine intensified also the corticosterone response induced in stressed rats by i.c.v. injected histamine, 2-pyridylethylamine (PEA), a H1-receptor agonist, and dimaprit, a H2-receptor agonist. The depletion of brain catecholamines by alpha-methyl-p-tyrosine (alpha-MT) considerably increased the corticosterone response to stress but did not substantially change the response to histamine, PEA and dimaprit in stressed rats. These results suggest that clonidine increases the corticosterone secretion induced by a mild stress and histamine and histamine H1 and H2 agonists mainly through the activation of central alpha 2-adrenoceptors. The increase by alpha-MT of the stress-induced corticosterone response may indicate the inhibitory role of central catecholamines in the pituitary-adrenocortical response to stress in rats.     

The interaction of ethanol with central histaminergic stimulation of the pituitary-adrenocortical and hyperlipemic activity

Ethanol introduced intragastrically (i.g.) in rats increased the pituitary-adrenocortical activity, measured indirectly through corticosterone concentration in blood serum. Since this increase reached only about 40% of the maximum hormone levels observed in that species after another stimuli, ethanol may be considered as a relatively weak stimulus. Ethanol induced also a significant decrease in serum free fatty acid (FFA) levels which was blocked totally by a prior intracerebroventricular (i.c.v.) administration of either H1- or H2-histamine receptor antagonists, mepyramine or metiamide and cimetidine. The ethanol-induced increase in serum corticosterone was insensitive to a central histamine H1- and H2-receptors blockade. Ethanol abolished the rise in serum FFA levels induced by an i.c.v. administration of histamine, pyridylethylamine (PEA)-a H1-receptor agonist, and dimaprit--a H2-receptor agonist. The histamine- and histamine-agonists induced increases of serum corticosterone were generally slightly intensified by a prior i.g. administration of ethanol.     

Naloxone antagonizes a central histaminergic stimulation of corticosterone secretion in rats

The interaction of central opioid receptors with histaminergic stimulation of the hypothalamo-pituitary-adrenocortical axis, evaluated indirectly through corticosterone secretion, was investigated in conscious unstressed rats. To avoid any possible direct action on the adrenal cortex, all drugs were given intracerebroventricularly (i.c.v.). Histamine, 2-pyridylethylamine (PEA), a histamine H1-receptor agonist, and 4-methyl-histamine (MeHA) and dimaprit, the H2-receptor agonists, considerably increased the serum corticosterone levels 1 h after administration. Naloxone, an opioid receptor antagonist, almost abolished the corticosterone response to PEA and considerably reduced the responses to MeHA, dimaprit and histamine. The maximum inhibitory effects of naloxone on corticosterone responses induced by histamine and histamine agonists were comparable with those of the H1- and H2-receptor antagonists, mepyramine and cimetidine. These results strongly suggest that a major part of the histaminergic stimulation of the hypothalamo-pituitary-adrenal axis is mediated by central opioid receptors.     

Glycemic response to stress stimulation by ether exposure in adrenalectomized rats

Stress was induced by short-term ether exposure (2 min) and tail vein puncture in normal (SO), adrenodemedullated (ADM), and adrenalectomized (ADR) rats. In ADM and SO rats stress provoked a significant hyperglycemic response with no change in plasma insulin levels. In ADR rats, on the other hand, the hyperglycemic response was not present. Actually, a significant rapid decrease in blood glucose, plasma insulin and hepatic glycogen content was observed. When the hypoglycemic effect of stress was prevented by glucose injection into ADR rats the decrease in plasma insulin and hepatic glycogen was not observed. The data suggest that the fall in plasma insulin and hepatic glycogen content observed in ADR animals result from an activation of the sympathetic nervous system induced by the decrease in blood glucose.     

Gastric acid secretory responses to cholinergic and histaminergic stimulation in chronic morphine-treated rats

The effects of chronic morphine administration on cholinergic and histaminergic activities were evaluated in rats by observing their gastric acid secretory responses to secretagogues. The responses of in-vivo perfused stomachs to 2-deoxy-D-glucose or pentagastrin, and of the isolated gastric mucosa to histamine or bethanechol, were not significantly different between naive and chronic morphine-treated animals. It is suggested that the chronic morphine-treated rats exhibit normal cholinergic and histaminergic activities as well as receptor sensitivities to acetylcholine and histamine.     

Low - frequency stimulation of histaminergic tuberomammillary nucleus facilitates basolateral amygdaloid kindling in rats

Aim： The tuberomammillary nucleus （TM）, located in the posterior hypothalamus, is the sole seat of histaminergic neurons in the brain. In this study, we investigate whether low - frequency stimulation of TM is involved in the acquisition of amygdala kindling seizure and participated in maximal electroconvulsive shock （MES） and pentylenetetrazole （PTZ） induced convulsion models in fully amygdaloid -kindled rats. Methods： The ipsilateral or contralateral TM received lowfrequency stimulation （ 15 min train of 0. 1 ms pulses at 1 HZ and 300 -400 μA） immediately after termination of once daily kindling stimulation （2 s train of 1 ms pulses at 60 HZ and 150 -300 μA） in the right amygdala. After control animals reached fully kindled state, they were divided into two groups, one group received daily LFS plus kindling stimulation and another group only received kindling stimulation. Ten days later, all of them were tested for MES as well as PTZ induced convulsions. Results： LFS of either ipsilateral or contralateral TM significantly facilitated the progression of seizure stages and increased afterdischarge duration throughout the course of amygdaloid kindling. The marked facilitation induced by LFS on either side of the TM was predominantly due to the significant promotion of progression from stage 3 to stage 5 seizures. In addition, LFS of TM significantly increased seizure severity and prolonged forelimb and hindlimb extension durations in MES model. However, no obvious changes can be observed in PTZ convulsion model.     

Role of histaminergic mechanisms in the regulation of some stress responses in rats.

The involvement of histaminergic mechanisms in the regulation of some stress responses was studied in rats. The brain neuronal histamine (HA) depletor, alpha-fluoromethyl histidine (alpha-FMH), at doses (50 or 100 mg/kg) which markedly lower brain HA, significantly attenuated the gastric ulcer formation and the elevation in plasma corticosterone in response to cold restraint stress (CRS). alpha-FMH also appreciably reduced gastric mucosal HA content. The H1-antagonist, pheniramine (25 mg/kg), attenuated both the gastric mucosal and endocrine response to CRS, while the effects of the H2-antagonist, cimetidine (200 mg/kg), were on the plasma corticosterone levels. These results are discussed in light of complex HA-ergic mechanisms in the maintenance of physiological homeostasis during stress.     

Central endothelin-B receptor stimulation does not affect morphine analgesia in rats

Several neurotransmitter mechanisms have been proposed to play a role in the actions of morphine. We reported that centrally administered endothelin A (ETA) receptor antagonists potentiate morphine analgesia in rats. It has also been reported that ETB agonist, IRL1620, has antinociceptive action mediated through opiate receptors in the periphery. The present study was conducted to determine if central ETB receptors are involved in analgesic actions of morphine. The effect of intracerebroventricular (i.c.v.) administration of ETB receptor agonist, IRL1620, on morphine-induced analgesia and hyperthermia was determined in the rat. Morphine (4 mg/kg, s.c.) produced a significant increase (84%) in tail-flick latency compared to the control group and the analgesic response lasted for 4 h. IRL1620 (30 microg, i.c.v.) did not produce any increase (16%) in tail-flick latency over the 5-hour observation period in vehicle-treated rats. Pretreatment with IRL1620 (3, 10, and 30 microg, i.c.v.) did not have any significant effect on the intensity and duration of morphine (4 mg/kg, s.c.)-induced analgesia. Morphine (4 mg/kg, s.c.) administration produced an increase in body temperature compared to the control group. In vehicle-pretreated rats, IRL1620 (30 microg, i.c.v.) did not produce any change in body temperature. The morphine-induced hyperthermic effect was not altered in IRL1620-pretreated rats. These studies demonstrate that IRL1620, a specific ETB receptor agonist, did not affect the morphine-induced analgesic and hyperthermic effect in rats. It can be concluded that central ETB receptors are not involved in modulation of pharmacological actions of morphine.     

Central cholinergic blockade of the conditioned avoidance response in rats

Summary The effects of arecoline, Tremorine and chlorpromazine were studied in conditioned rats in shuttlebox avoidance and lever-press avoidance procedures. Conditioned avoidance response (CAR) blockade produced by subtremor doses of arecoline and Tremorine was felt to result from central cholinergic stimulation since the effects of both drugs were prevented by the tertiary anticholinergic, atropine, but not by the quaternary agent, methantheline. In both avoidance procedures the observed CAR blockade produced by these cholinergics suggested not reduction in fear or anxiety drive, popularly ascribed to chlorpromazine, but rather heightened anxiety and indecision about appropriate performance for avoiding the impending danger of shock. The behavioral pattern of the trained animals under the influence of these cholinergic drugs was, in fact, remarkably similar to behavior of the unconditioned rats during the earlier stages of avoidance training. The possible implications of these findings are discussed.A portion of this paper was presented at the AAAS meetings held in Cleveland, Ohio, December, 1963. Supported in part by USPHS Grant MH 07767-01 and an equipment grant from the Smith, Kline, and French Foundation.Generously supplied by Abbott Laboratories, Chicago, Illinois.     

Hepatic sulfhydryl content under adrenergic stimulation in male rats

The influence of a series of sympathomimetic agents on the liver content of non protein bound thiol groups (NP-SH), mainly representing glutathione, has been assessed in the male rat. The rats were intravenously and/or subcutaneously infused over 6 h at different dosages either with dopamine, dobutamine, epinephrine, terbutaline, or phentolamine, or simultaneously with dopamine and phentolamine, or with epinephrine and phentolamine. Besides NP-SH, total sulfhydryl group content was measured in liver cytosol, while glucose and insulin concentrations were determined in the serum. Liver NP-SH content was significantly decreased by epinephrine. This decrease was abolished and even inverted to an increase, when appropriate doses of phentolamine were infused simultaneously. Dopamine caused a rise in NP-SH content at a dose rate of 7.5 micrograms/kg.min, while lower and higher dose rates of dopamine exerted not any influence on liver NP-SH. When phentolamine was concomitantly infused with 15 micrograms/kg.min of dopamine, NP-SH was significantly elevated. Phentolamine, when infused exclusively, increased NP-SH as well, while it was not influenced, however, by terbutaline or dobutamine at any dosage. Cytosolic total sulfhydryls were found to be unaltered across all experimental groups. When the NP-SH values are related to the corresponding serum insulin levels, a close and linear relationship becomes evident. The study demonstrates, that some sympathomimetic agents can exert a considerable influence on hepatic non protein bound thiol content. The data suggest, that the varying liver NP-SH content under adrenergic drugs is primarily related to changes in serum insulin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of histaminergic receptor mechanisms in the stimulation of NT-3 synthesis in astrocytes

Neurotrophin-3 (NT-3) is produced by astrocytes, in addition to neurons, and monoamine neurotransmitters play a role in controlling NT-3 synthesis. The impact of histamine (HA) on the regulation of NT-3 synthesis in cultured astrocytes has not been studied. We evaluated the involvement of histamine receptors and intracellular mechanisms in the regulation of NT-3 production by HA. Real-time PCR was performed to examine the expression of all known histamine receptor subtypes in cultured rat cortical astrocytes. Pharmacological tools, selective for the H?, H? and H? receptors and intracellular systems, were utilized to confirm functional properties of HA receptors in histaminergic up-regulation of astrocytic NT-3 synthesis. HA potently and transiently elevated NT-3 expression and protein levels by more than twofold. In addition to H? and H? receptors, cultured astrocytes also express H? receptors, which activate G(i/o) proteins to inhibit adenylyl cyclase and modulate MAP kinase activity. Histaminergic stimulation was partly inhibited by selective H?, H?, and H? antagonists whereas selective H?, H?, and H? agonists or mediators of the intracellular histaminergic pathways increased NT-3 levels. Inhibitors of PKA, PKC, and CaMK II significantly reduced the HA-induced increase in NT-3 cellular levels whereas the MAP kinase cascade inhibitor completely blocked the stimulatory action of HA and all selective agonists. In conclusion, the synthesis of astrocytic NT-3 stimulated by HA is a receptor-mediated process, which is fine-tuned via subtle modulation of parallel histaminergic H?, H?, and H? pathways that converge at the level of MAP kinase activity. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

Role of central histaminergic system in lorazepam withdrawal syndrome in rats.

Effects of histaminergic agonists and antagonists were investigated on withdrawal signs in lorazepam-dependent rats. Physical dependence was developed by giving lorazepam admixed with the food in the following dose schedule (in mg/kg given daily x days): 10 x 4, 20 x 4, 40 x 4, 80 x 4, and 120 x 7. The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), reaction time to pain, foot shock aggression (FSA), and audiogenic seizures. During the withdrawal period, the rats were divided into groups of 10 each. Control-withdrawal group did not receive any drug. The drugs (in mg/kg administered intramuscularly)--L-histidine (50), histamine-N-methyl (2), promethazine (10), pheniramine (10), astemizole (10), and thioperamide (1)--were given separately in other groups daily during the withdrawal period. The withdrawal signs in control group were hyperkinesia, hyperaggression, and audiogenic seizures. L-Histidine, precursor of histamine, and thioperamide, antagonist of H3 receptor, potentiated hyperkinesia, hyperaggression, and audiogenic seizures. Histamine-N-methyl, agonist of H3 receptor, and H1 receptor antagonists, promethazine and pheniramine, blocked all the withdrawal signs. Astemizole, a peripheral antagonist of H1 receptor, could not affect any withdrawal sign. It may be concluded that histamine H1 receptors are facilitatory and H3 receptors are inhibitory for benzodiazepine (BZD) withdrawal syndrome.     

Hypothalamo-limbic involvement in modulation of tooth-pump stimulation evoked nociceptive response in rats

The hypothalamo-limbic system has been implicated in recognizing the affective significance of pain and elicitation of related emotional responses. Several evidences from different studies support a role of these areas in endogenous analgesic mechanisms for pain modulation as elucidated by different pain tests in more than one animal model. In the above context, the aim of this study was to investigate the relative effectiveness of the pain modulatory action of hypothalamic and limbic structures in rat using similar stimulation parameters, and studying the effect on tooth pulp stimulation evoked jaw opening reflex (TP-JOR). To achieve the objective, unilateral stimulation of hypothalamic (lateral = LH; ventromedial = VMN; anterior = AH) and limbic areas (amygdala = AMYG; hippocampus = HIPP) was done on the TP-JOR test. A significant reduction in the amplitude of EMG recorded from the digastric muscle (dEMG) as a result of tooth-pulp stimulation was observed on stimulation of LH, VMN, AMYG and HIPP but not from AH. Also, the magnitude of this effect was almost similar from these areas. The results suggest that these areas (except AH) have an antinociceptive role in tooth-pulp stimulation evoked pain response.     

Central choline suppresses plasma renin response to graded haemorrhage in rats

Central administration of choline increases blood pressure in normotensive and hypotensive states by increasing plasma concentrations of vasopressin and catecholamines. We hypothesized that choline could also modulate the renin-angiotensin pathway, the third main pressor system in the body. Plasma renin activity (PRA), which serves as an index of the function of the peripheral renin-angiotensin system, was determined in rats subjected to graded haemorrhage following central choline administration. Intracerebroventricular (i.c.v.) injection of choline (12.5-150 microg), a precursor of the neurotransmitter acetylcholine (ACh), inhibited the increase in PRA in rats subjected to graded haemorrhage by sequential removal of 0.55 mL blood/100 g bodyweight. Choline, in the range 50-150 microg, increased blood pressure. Intraperitoneal (i.p.) administration of 150 microg choline failed to alter blood pressure and plasma renin responses to graded haemorrhage. Administration of a higher dose (90 mg/kg, i.p.) of choline decreased blood pressure and enhanced PRA in the first two blood samples obtained during the graded haemorrhage. Physostigmine (10 microg, i.c.v.), ACh (10 microg, i.c.v.), carbamylcholine (10 microg, i.c.v.) and cytidine 5'-diphosphocholine (CDP-choline; 250 microg, i.c.v.) increased blood pressure and attenuated plasma renin responses to graded haemorrhage. Inhibition of PRA by i.c.v. choline was abolished by i.c.v. pretreatment with mecamylamine (50 microg), but not atropine (10 microg). Blood pressure responses to choline (150 microg) were attenuated by pretreatment with both mecamylamine and atropine. Inhibition of PRA in response to central choline administration was associated with enhanced plasma vasopressin and catecholamine responses to graded haemorrhage. Pretreatment of rats with a vasopressin antagonist reversed central choline-induced inhibition of plasma renin responses to graded haemorrhage without altering the blood pressure response. In conclusion, central administration of choline inhibits the plasma renin response to graded haemorrhage. Nicotinic receptor activation and an increase in plasma vasopressin appear to be involved in this effect.     

The influence of repeated prestressors on single stress response in rats

The effect of various stressors of different intensity applied in random order before the final single immersion restraint stress was tested in two inbred rat strains, isoprenaline-sensitive and isoprenaline-resistant. The isoprenaline-sensitive strain revealed higher incidence of heart lesions after this single acute stress and low incidence of gastric lesions. The isoprenaline-resistant strain had the opposite characteristics. These differences were constantly reproducible when this strong stressor was used. After prestress by different stressors (tail-flick, ether anaesthesia, Porsolt swimming stress) at different time schedules, the incidence of gastric ulcer lesions, the weight of organs (heart, adrenals, spleen) changed substantially in isoprenaline-sensitive rats only. The most important result was reversal of the extent of gastric lesions. The isoprenaline-sensitive strain revealed more lesions than the isoprenaline-resistant one. The repeated different prestressors mainly changed the reactivity of animals, isoprenaline-sensitive rats becoming more similar to isoprenaline-resistant rats. These findings urged us to interpret carefully the results obtained in stress research with different and multiple stressors both in animals and humans.     

Effect of intracerebroventricular impromidine on pituitary-adrenocortical response to stress in rats

In the rats subjected to a mild stress of immobilization impromidine, and H2-receptor agonist, given 60 min prior to the stress, intensified the stress-induced increase in hypophyseal-adrenocortical response, evaluated indirectly through the corticosterone concentration in the blood serum. Impromidine was far more potent but only about half as efficient as histamine, 4-methyl histamine (4-MH) and dimaprit. The effect of impromidine was abolished by pretreatment of the rats with cimetidine. The alpha-adrenergic blockers phenoxybenzamine, phentolamine and yohimbine, almost totally antagonized the corticosterone response to impromidine in stressed rats. Propranolol, a beta-adrenergic blocker, abolished the corticosterone response to impromidine but did not antagonize the response to 4-MH and dimaprit. The effect of impromidine was not modified by i.c.v. pretreatment of the rats with atropine. The results obtained show that impromidine is far more potent but less efficient than histamine and the previously known selective H2-receptor agonists in inducing the pituitary-adrenocortical response in stressed rats. These results also suggest that impromidine may release norepinephrine but not interact with cholinergic receptors while stimulating the corticosterone response in stressed rats.     

Chlordiazepoxide and morphine reduce pressor response to brain stimulation in awake rats

The effects of intravenous as well as dorsal midbrain injections of morphine and chlordiazepoxide on the blood pressure rise induced by electrical stimulation of the dorsal periaqueductal gray matter (DPAG) were studied in unanesthetized rats. Chlordiazepoxide applied systemically or locally into the DPAG, as well as locally applied but not systemically injected morphine were found to attenuate the centrally-induced hypertension. These data together with others suggest that benzodiazepines as well as local injections of morphine into the DPAG decrease the aversive effect induced by DPAG stimulation.     

Adenosine and the bradycardiac response to vagus nerve stimulation in rats.

The effects of intracardiac infusions of adenosine on the changes in heart rate (HR), electrocardiogram (ECG) and arterial blood pressure (BP) induced by both vagal stimulation and exogenous acetylcholine (ACh) were studied in anesthetized rats. Adenosine inhibited the bradycardia induced by vagal nerve stimulation, an effect antagonized by theophylline, decreased the elongation caused by vagal stimulation of the R-R intervals of the ECG, and caused a small but consistent decrease in the hypotensive effect of vagus nerve stimulation. At the dose that reduced the bradycardiac responses to vagal stimulation, adenosine enhanced the bradycardiac effect of exogenous ACh, increased R-R intervals and the number of P waves not followed by the ECG and had little or no effect on the inhibition induced by ACh on BP. The effects of adenosine on the bradycardiac responses to vagal nerve stimulation or to ACh administration were similar in both non-reserpinized and reserpinized animals. These results suggest that exogenous adenosine can modify the vagal influences on the heart by exerting pre-junctional inhibition of the vagus nerve and post-junctional enhancement of the ACh actions, and that the adrenergic system does not contribute to these effects of adenosine.     

Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats

Some reports indicate that morphine can induce anxiolytic effects both in animal and in man. It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 microg/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 microg/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 microg/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 microg/rat), pyrilamine (50 microg/rat) and ranitidine (5 microg/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 microg/rat), pyrilamine (25, 50 and 100 microg/rat) or ranitidine (5, 10 and 20 microg/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system.