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The brain serotoninergic (5HTergic) system of epileptic subjects can influence their vulnerability to stress. We studied the putative dependency of 5HT neurotransmission parameters on emotional stress, and the presence, types and severity of seizures using rats with genetic generalized (absence and/or audiogenic) epilepsy, of WAG/Rij and Wistar strains. The animals were stressed by exposure to a short aversive noise or left without sound stimulation. Tissue concentrations of 5HT, tryptophan (TRT) and 5-hydroxyindolacetic acid (5HIAA) were assessed by HPLC. The stressor activated the 5HTergic system within thalamus (5HIAA elevated), frontal cortex (5HT, TRT elevated), hypothalamus (increased TRT) in all rats. However, the normal (non-epileptic) rats displayed the highest response in the frontal cortex and the lowest one in the thalamus, as compared to the epileptic rats. Absence-epileptic rats exhibited higher thalamic 5HIAA increase than their controls. Significant correlations existed between propensity of absence epilepsy and 5HTergic parameters measured in the cortex and hypothalamus of absence-epileptic rats. No major difference was found between groups with and without audiogenic epilepsy. The results imply that the stress response depends on the presence of epileptic pathology and the seizure type and severity. The brain 5HT may be involved in the control of the paroxysms and behaviour in absence-epileptic subjects.

The present study characterized the intensity-response functions of extracellular field responsiveness of different cortical/subcortical structures of the forebrain following the free-field presentation of tone stimuli, within a population of genetically audiogenic seizure (AGS)-prone KM-Wistar rats. The neural response properties of each case were compared to its propensity to exhibit AGSs during the continuous tone stimulation (15 kHz, 90 s at max.). The amplitudes or slope components of the evoked responses and their peak latencies showed significant positive (amplitude and slope) and negative (peak latency) Bolzmann's sigmoid relationships with the onset-latency of AGS. These relationships, with areal differences in the slopes of saturation functions, applied for the three different data sets recorded simultaneously from the stratum radiatum dendritic layer of the hippocampal CA1 area, primary auditory cortex layers II-IV, and frontal cortex surface. In addition, the similar type of functions between the evoked response variables and AGS onset latency held when all the areas were considered together. These data suggest that the neural responsiveness to acoustic stimulation of the primary sensory, multimodal and association cortices of the forebrain may altogether contribute to the seizure initiation by that modality in the genetically AGS-prone rats. It has been previously shown that there exist abundant and dispersed auditory projections from these forebrain areas to the brain stem and spinal cord, structures that are generally considered to be the key predisposing factors in the generation of AGS. Hence, the types of correlation found reflect the subject-specific stage of forebrain responsiveness, being either related or unrelated to genetic AGS-specific changes, and possibly its triggering impact upon the lower brain AGS network. Accordingly, the mere comparison of forebrain response measures of these AGS-prone animals with those of the AGS-resistant ones could not reveal the result presented.

The fasciculus retroflexus (FR) fiber bundle comprises the intense cholinergic projection from the medial division of the habenula nucleus (Hbn) of the epithalamus to the interpeduncular nucleus (IPN) of the limbic midbrain. Due to the widespread connections of the Hbn and IPN, it could be surmised that the FR is integrated in the processings of various subsystems that are known to be involved in the sleep-wake mechanisms; relevant sites include the limbic forebrain and midbrain areas and more caudal pontine structures. Consequently, the present study addressed the significance of the FR in the spontaneous sleep-wake stage-associated variations of the different activity patterns of frontal cortex and hippocampal electroencephalograms (EEGs), the electrooculogram, and body movements, in freely behaving rats that had been subjected to either bilateral electrolytic lesioning of the FR or control operations. The evolution of different state combinations was assessed by the combinatory analysis of different activity stages appearing on the 6-h records. As compared to the control-operated group, the FR lesioning substantially reduced the time spent in rapid eye movement (REM) sleep by 79%, moderately decreased the duration of the intermediate state of sleep by 29%, and quiet waking state by 44%, but had virtually no effects on the durations of different types of non-REM sleep (i.e., drowsiness that which involved quiet sleep or slow-wave sleep containing delta and spindle state components) or on the times of active waking behavior that corresponded to the body movements. Quantitative decomposition analyses revealed marked variations in the frontal cortex and hippocampal activity as well as REM during the course of the extracted sleep-wake stages described and there were also some group differences. Of those individual features that were used to determine different sleep-wake stages, the overall hippocampal theta time (41% decrease) and single REM frequency (71% reduction during the REM sleep) were most affected. In contrast, the various properties of desynchronization/synchronization patterns of frontal cortex EEGs were consistently hardly influenced by the FR lesioning. Therefore, the present data suggest the involvement of the FR in the REM sleep processes by establishing prominent associations with the limbic and REM control mechanisms that involve the hippocampus and plausibly pontine ocular activity networks.

The effect of metoprine, an inhibitor of histamine (HA) catabolism, on fluid balance was studied in Wistar (W) and Long-Evans (LE) rats. AVP deficient Brattleboro (BB) rats were used to evaluate which phenomena were AVP-related. W and LE rats were quite different: LE rats were "dry" rats, they drank less, had higher plasma AVP, smaller urine volume and excreted more AVP, and responded less to salt loading and water deprivation. Furthermore, LE and W rats responded differently to metoprine. When water was provided as drinking fluid, metoprine increased water intake and urine flow in W rats, but these changes were not significant in LE rats. In contrast, when the rats drank saline, urine output and saline consumption were similarly decreased in LE and W rats. Although no metoprine-induced changes in plasma AVP were observed, urinary excretion of AVP per 24 h was reduced in metoprine treated rats. Inhibition of HA catabolism by metoprine caused only minor changes in fluid balance of AVP deficient BB rats. The results show that significant differences in fluid balance can exist between rat strains and that increased availability of HA after IP given metoprine strongly affects body fluids in normal rats, especially those of the W strain. The results provide further support to the involvement of HA in the regulation of fluid balance, but to obtain a more complete picture, other factors, such as atrial natriuretic peptide, should be studied.

In vivo microdialysis was used to study the effects of a potent and selective alpha 2-adrenoceptor antagonist, atipamezole, on histamine and noradrenaline release from the medial hypothalamus in anesthetized rats. Local perfusion with atipamezole via the microdialysis probe increased histamine release significantly and dose-dependently. However, the effect of systemic administration of atipamezole (1 mg/kg) was opposite: it significantly decreased histamine release. Local and systemic administration of atipamezole produced an approx. 2-fold increase in noradrenaline release. To study the modulatory effect of noradrenergic neurons on histamine release, noradrenaline synthesis was inhibited with alpha-methyl-p-tyrosine. In the microdialysis experiment, rats that received alpha-methyl-p-tyrosine exhibited no decrease, but rather a slight increase in histamine release in response to systemic atipamezole administration. These results show clearly that atipamezole enhances noradrenaline release in vivo from rat hypothalamus and its effects on histamine release are dependent on the route of drug administration.

In vivo microdialysis was used to study the effects of serotonergic drugs on histamine release from the suprachiasmatic nuclei region of the anterior hypothalamus in anesthetized rats. Local perfusion with serotonin (5-hydroxytryptamine, 5-HT) increased histamine release significantly and dose dependently. Methysergide (10 mg/kg i.p.), a 5-HT2C/2A receptor antagonist, given 30 min before 5-HT perfusion, blocked the 5-HT-evoked histamine release. Methysergide (10 mg/kg i.p.), given alone, also suppressed basal histamine release by 33%. Dexfenfluramine (10 microM), a 5-HT releaser and uptake blocker, administered via the microdialysis probe, significantly enhanced hypothalamic histamine release. With the same dose of dexfenfluramine, 5-HT release increased 10-fold in the same brain area. These results show for the first time that endogenous 5-HT modulates histamine release in vivo and it has a tonic stimulatory effect on the histaminergic nerve terminals of the rat anterior hypothalamus.

Portocaval anastomosis and vagotomy operations were performed in Long-Evans (L-E) and Han/Wistar (H/W) rats to elucidate the mechanism of anorexia induced by TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). TCDD-sensitive L-E rats were given a sublethal (5 micrograms/kg) or a lethal dose (20 micrograms/kg) by gavage 5-8 weeks after portocaval anastomosis. TCDD-resistant H/W rats were given a nonlethal dose (500 or 7200 micrograms/kg). The shunt operation did not reduce lethality from TCDD. The effect on wasting of the marginally toxic dose of 5 micrograms/kg in L-E rats was potentiated by the portocaval operation, and the lethal dose was effective in both shunted and sham-operated L-E rats. TCDD failed to decrease food intake and body weight in shunted rats of H/W strain at either dose level though it did so in sham-operated controls. The lack of effect may be due to the already reduced weight of shunted rats at the time of TCDD dosing. TCDD anorexia was not explained by changes in histamine or serotonin (5-HT) turnover in the brain. Vagotomy did not influence lethality after TCDD, although reduction in food intake was somewhat blunted in H/W rats. The results seem to indicate that the anorectic effect of TCDD is modified when portal blood bypasses the liver. The mechanisms remain to be elucidated in detail, but the results do not favor the role of liver as the only or the major initiator of TCDD anorexia. Little evidence was found to support a crucial role of vagal afferent input.

Histamine was infused into the third or lateral ventricle of conscious hydrated goats, and urine samples were analyzed for volume, osmolality and electrolytes. Doses of 10--1000 microgram of histamine induced dose-dependent antidiuretic responses both as to the maximum osmolality and the duration of the osmolality increase. Urine osmolality began to rise within a few minutes, reached its maximum within 0.5--2 h and was elevated for 1.5--4 h, depending on the dose. Thereafter a second increase in osmolality often occurred, which lengthened the effect of histamine dose-dependently up to about 10 h with the largest dose of histamine. Histamine (50--300 microgram) and the control solution given into the lateral ventricle increased the excretion of Na+ into the urine. After the largest dose of histamine (1000 microgram), however, the excretion of Na+ was significantly lower than in the control experiments. After the larger doses of histamine, effects on motor or autonomic functions were seen. These included decreased spontaneous motor activity, increased respiratory rate, defecation and miosis. It is suggested that the site of action of histamine is central, and that the release of vasopressin through the activation of the neurosecretory system is probably involved. In addition the changes in electrolytes may suggest an involvement of the release of other factors such as prolactin.

Our previous experiments have shown that several metal cations affect dopaminergic uptake and release processes in synaptosomes in vitro. It is thus possible that other membrane-related steps of neurotransmission, such as receptor binding, are affected as well. We studied the effect of Mn2+, Cu2+, Cd2+, Zn2+, Hg2+, Pb2+ and of two organometals, methyl mercury and triethyl lead, on [3H]haloperidol binding in the striatal P2 fraction assuming that such a study would reveal direct effects of the ions on dopaminergic D2 receptor binding. According to non-linear curve fitting and Scatchard analysis, [3H]haloperidol bound to two sites in striatal tissue. The Kd of the higher affinity site was 0.14 +/- 0.05 nM and the Bmax 226.3 +/- 50.3 fmol/mg protein. The respective values for the lower affinity site were 2.49 +/- 0.56 nM and 678.3 +/- 111.4 fmol/mg protein. Among the divalent cations, Hg2+ (IC50 0.7 microM) and Cu2+ (IC50 2.9 microM) inhibited the high affinity [3H]haloperidol binding most potently. The inhibition by Cu2+ was due to a decrease in the binding affinity (increase in the Kd) while the number of binding sites remained unchanged. Zn2+ inhibited the binding by 41.8% and Cd2+ by 38.7% at 10 microM concentration while Pb2+ and Mn2+ did not affect binding significantly at this or lower concentrations. Methyl mercury (IC50 0.9 microM) and triethyl lead (IC50 2.6 microM) inhibited binding as well. Both these organometallic cations decreased the binding affinity but did not change significantly the number of binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

The vasopressin releasing activity of histamine was studied in conscious goats. Histamine was infused into the brain ventricles or intravenously and serial blood samples were taken from the jugular vein. Plasma vasopressin was assayed by a radioimmunoassay for arginine vasopressin (AVP). After i.v. infusions of 300 micrograms and 1 mg of histamine, a pronounced increase in plasma AVP up to greater than 100 pg/ml occurred. This was considered secondary to hypotension, since it only occurred with doses that markedly decreased arterial blood pressure. When given i.c.v. even smaller doses of histamine increased plasma AVP without any concomitant decrease in blood pressure. There was a simultaneous decrease in renal free water clearance in hydrated animals. Up to the dose of 300 microgramshistamine, the increase in AVP was modest. Histamine 1 mg i.c.v., given to either hydrated or non-hydrated animals, increased plasma AVP about tenfold, up to 38.3 +/- 23.3 pg/ml and 56.7 +/- 19.0 pg/ml, respectively. In individual experiments the correlation between the AVP level and the degree of antidiuresis was less apparent, since the kidney seemed to be very sensitive even to small changes in plasma AVP. It is concluded that histamine releases vasopressin through a central mechanism and it is reasonable to suppose that histamine may act as a neurotransmitter in the vasopressin releasing system.