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Hot flushes are frequently incapacitating to the patient and the severe vasomotor disturbances may seriously impair normal daily life. This review attempts to provide an understanding of the pathophysiology of the hot flush as a basis for rationale therapy for each individual patient. The physiological mechanisms controlling body temperature are discussed briefly, and the changes in the system which precipitate the menopausal hot flush are detailed. The neuroendocrine events leading to the onset of the flushing syndrome are then considered. Finally, the therapeutic strategies which may be used in the management of the affected patient are discussed.

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The laboratory rat has been used as an animal model to investigate the effects of cocaine on body temperature and to determine if abuse of the drug is a risk factor in the pathogenesis of exercise-induced heat stroke. Animals were trained to run on a treadmill which was enclosed so that the ambient temperature could be regulated. Exercise at ambient temperatures of 20 and 30 degrees C led to a similar rise in core temperature of approximately 1 degrees C, although the starting core temperature was higher in the rats at 30 degrees C (38.5 +/- 0.10 degrees C compared to 37.9 +/- 0.06 degrees C). Cocaine (20 mg/kg) led to a transient fall in core temperature in the 20 degrees C group; the temperature then rapidly recovered, so that after 60 min exercise there was no significant difference between these and the control animals. At the higher ambient temperature cocaine augmented the rise in core temperature during running, although the animals had regained thermal balance by 30 min and core temperature was maintained at 40.2 +/- 0.13 degrees C until the end of the exercise period. The dopamine D1 receptor antagonist SCH 23390 (0.1, 0.3 or 1.0 mg/kg) led to suppression of spontaneous motor activity so that the rats could be persuaded to exercise for only 30-45 min after treatment. Pretreatment with the antagonist did not affect the rise in core temperature induced by cocaine at 30 degrees C which again stabilized by 30 min at 40.0 +/- 0.12 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

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The laboratory rat is being studied as a model to determine if abuse of cocaine constitutes a risk factor in the pathogenesis of stress or exertion induced heatstroke. During running on a treadmill for 60 min under thermoneutral conditions (Ta 22 degrees C) a rise in core temperature of approximately 1 degree C was recorded. Injection of cocaine (10 or 20 mg/kg IP) or its vehicle (0.9% NaCl solution) did not modify the running behavior or the core temperature change. Cocaine (30 mg/kg IP) led to a significant increase in the core temperature (compared to animals treated with saline or the lower doses of cocaine) at 45 and 60 min. The rats recovered rapidly following cessation of exercise. Repeated (3) injections of cocaine (30 mg/kg) at 7-day intervals did not alter the magnitude of the final hyperthermia, i.e., neither tolerance nor potentiation were in evidence.

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The laboratory rat is being developed as a model to determine whether abuse of cocaine constitutes a risk factor in the pathogenesis of stress or exertion-induced heatstroke. Under thermoneutral conditions (Ta 20 degrees C) cocaine (10-40 mg/kg i.p.) caused a dose-dependent fall in core temperature ranging from 0.45 +/- 0.18 to 1.77 +/- 0.26 degrees C. When the ambient temperature (Ta) was increased to 35 degrees C, cocaine (10-40 mg/kg i.p.) led to a dose-dependent hyperthermia (0.3 +/- 0.08 to 1.43 +/- 0.43 degrees C). Repeated injection of cocaine (40 mg/kg at Ta 20 degrees C or 20 mg/kg at Ta 40 degrees C) on days 1, 3, 8, 15, and 23 did not alter the magnitude of the temperature change compared to that following the first injection, i.e., neither tolerance nor potentiation occurred.

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The laboratory rat is being used to determine if abuse of cocaine is a risk factor in the pathogenesis of exercise-induced heatstroke. The effect of running on a treadmill on the core temperature (Tc) has been studied in two groups of rats: animals approximately 20 weeks old ('young rats') and animals approximately 52 weeks old ('old rats'). During 60 min running the Tc increased to a steady level, within 15-30 min, which was higher in the old than in the young animals at environmental temperatures (Ta) of 25 and 30 degrees C. A significantly greater rise occurred in both groups of animals at Ta of 30 compared to 25 degrees C. Injection of cocaine (20 mg/kg) was without effect on the rise in Tc in young animals running at a Ta of 25 degrees C but significantly increased the hyperthermia in the old rats. It is suggested that the rise in the thermoregulatory set point induced by muscle exercise is greater with advancing age. Also in older animals, the effect of cocaine on the central nervous system may be enhanced.

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Injections of muscimol (12.5 or 25 ng bilaterally), a GABAA agonist, into the posterior nuclei of the thalamus suppressed generalized convulsive seizures in the spontaneously epileptic Mongolian gerbil. This anticonvulsant effect was dose-dependent and was reversed by picrotoxin (10 ng bilaterally), a GABAA antagonist. Bilateral intrathalamic injections of 1-baclofen (50 ng), an agonist of the GABAB receptor, were ineffective in suppressing seizures in this model. These results suggest that GABAergic transmission within the thalamus is involved in the control or the genesis of some generalized convulsive seizures.

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Human urine samples obtained before and after active and passive exposure to marijuana were analyzed by immune kits (Roche, Amersham, and Syva) and gas chromatography/mass spectrometry (GC/MS). Seven of eight subjects were positive for the entire five-day test period with one immune kit. The latter correlated with GC/MS in 98% of the samples. Passive inhalation experiments under conditions likely to reflect realistic exposure resulted consistently in less than 10 ng/mL of cannabinoids. The 10-100-ng/mL cannabinoid concentration range essential for detection of occasional and moderate marijuana users is thus unaffected by realistic passive inhalation.

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Cholinesterase inhibitors induce changes in plasma hormones in the rat. Since these compounds induce hypothermia the question has been raised as to whether the endocrine responses are secondary to the fall in core temperature. The time course of the changes in temperature and plasma levels of corticosterone, growth hormone and prolactin have been examined following injection of diisopropylphosphofluoridate (DFP), soman or physostigmine. All three cholinesterase inhibitors caused an initial rise in corticosterone; DFP decreased growth hormone; physostigmine reduced prolactin. The time course of the hypothermia after DFP and soman did not correlate with that of the rise in corticosterone. The data do not suggest that the hormone changes are secondary to the temperature change.

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Radioimmunochemistry (RIA) and immunocytochemistry (ICC) were used to measure proenkephalin and prodynorphin peptides in the brain of a genetic model of epilepsy, the seizure-sensitive (SS) Mongolian gerbil. Brain levels of both [Met5]- or [Leu5]-enkephalin (ME-LI) and dynorphin A1-8 and dynorphin A1-17 (DN-LI) like immunoreactivity were increased in the hippocampal region of the SS gerbil. However, ME-LI and DN-LI did not follow the same patterns. ME-LI was significantly increased in the SS gerbils (post-seizure) compared to SR gerbils while ME-LI in SS (preseizure) gerbils was not significantly different from SR gerbils. DN-LI was significantly increased in the hippocampal region of both SS (preseizure) and SS (postseizure) gerbils compared to SR gerbils. These results strongly imply differences in the regulation of proenkephalin and prodynorphin metabolism in the Mongolian gerbil. The differences in metabolic regulation may signal fundamentally different roles of these opioid peptides in the modulation of seizure activity in this animal.

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Autoradiography was used to examine opioid receptor binding in the Mongolian gerbil, a genetic model of the epilepsies. Coronal brain sections of seizure-resistant (SR) and seizure-sensitive (SS) (both pre- and post-seizure conditions) gerbils were labeled with [3H]dihydromorphine. SS (pre-seizure) gerbils demonstrated overall greater brain opioid binding when compared to SR animals. The periaqueductal gray, substantia nigra and medial geniculate body were specific areas in SS (pre-seizure) gerbils which demonstrated highly significant increases in opioid binding compared to SR animals (% increase vs SR were 98%, 91.3% and 42.9%, respectively). Scatchard analysis demonstrated that the increase in opioid binding was due to an increase in the total number of receptors without a significant change in receptor affinity (i.e. periaqueductal gray area: total number of binding sites was 12.7 (SR) and 18.0 fmol/mg tissue (SS pre-seizure), while Kd values were 4.0 (SR) and 4.0 mM (SS pre-seizure). Opioid binding was also increased in the SS (post-seizure) animals when compared to SR animals, especially in the substantia nigra. However, when compared to SS (pre-seizure) gerbils, there was a general but not significant, decrease in opioid binding in SS post-seizure gerbils. The increased opioid binding in the SS (pre-seizure) gerbil compared to SR gerbils could reflect an up-regulation due to a deficit in endogenous ligand (e.g. a deficit in synthesis or decreased release) which could underlie the seizure diathesis in the gerbil.

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The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) acts through postsynaptic receptor sites which regulate membrane chloride ion channels. The GABA receptor-ionophore complex also contains modulatory receptor sites for two classes of centrally acting drugs, one for the benzodiazepines, and a second for both barbiturates and related depressants and for picrotoxin and related convulsants. The presence of these drug modulatory sites, directly on the GABA receptor protein, is consistent with other experimental observations; blocking GABA function can cause seizures, and augmenting GABA function can afford protection against seizures. This, and other circumstantial evidence, has suggested the possibility that a functional GABA deficit may be involved in some kinds of human epilepsy. Some neurochemical markers for GABA synapses have been reported to be altered in certain animal models as well as in human temporal lobe epilepsy. We have examined the postsynaptic GABA receptor complex using receptor binding assays for GABA, benzodiazepine (BZ), and barbiturate receptor sites in the seizure-susceptible gerbil, a genetic model of generalized epilepsy. A 30% deficit in BZ receptor binding was observed in the midbrain of seizure-sensitive animals relative to normal controls. This was shown by quantitative brain-slice binding autoradiography to involve a decrease in the number of binding sites in the substantia nigra (SN) and periaqueductal gray regions. A deficit in membrane receptors for BZs (which are linked to a subtype of postsynaptic GABA receptors) in a crucial region of brain might therefore contribute to seizure susceptibility in some kinds of epilepsy.

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Neuropeptides represent a new class of compounds with important implications for the understanding of the mechanisms and treatment of epileptic disorders. Several systems of peptide modulators--in particular the opioid-like peptides, vasopressin, somatostatin, thyrotropin-releasing hormone (TRH) and ACTH--have partially demonstrated endogenous roles in some forms of epilepsy. Seizures and stressful situations may release endogenous opioid peptides and mediate postictal depression and postictal seizure refractoriness. Vasopressin is believed to increase susceptibility to convulsions and may be involved in the pathogenesis of febrile convulsions. Derangements in TRH regulation may lower thresholds for seizure expression by regulating arousal systems; however, some TRH analogs have proven to be effective anticonvulsants. Long-term alterations in somatostatin regulation could be components of focal epilepsies. ACTH is particularly useful in the treatment of infantile spasms. Pharmacological effects of these and other peptides have potentials for defining new classes of anticonvulsants. Cholecystokinin (CCK) and its analogs, the opioid peptides beta-endorphin and FK33824, TRH analogs, and several dipeptides exhibit potent anticonvulsant properties in chemical, electroshock, and genetic model screens. Convulsant actions of CRF, somatostatin, TRH, vasopressin, and high doses of endorphin or enkephalins may provide new tools to study regulatory mechanisms of cerebral excitability. The enkephalin epileptogenic effect is being developed as a predictive tool for new anti-petit mal anticonvulsants. Advances in molecular biology have identified the genes of particular peptide families. A concept has developed that the large propeptide precursors, coded by these genes, whose processing leads to functional peptide formation and release, regulate peptidergic humoral responses to external stimuli. This idea may have particular application in the understanding of the genetic basis of some seizure states. Techniques for amplification of mRNA expression have identified specific neuronal proteins and peptides. Knowledge of protein and propeptide structural cleavage sites has suggested previously unknown candidates for modular systems in epileptic states. Technological advances in automated peptide sequencing and synthesis have allowed the development of metabolically resistant analogs and antagonist peptides. The anticonvulsant potencies of CCK, TRH, and opioid peptides have been defined more clearly with these methods.(ABSTRACT TRUNCATED AT 400 WORDS)

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The density of benzodiazepine/gamma-aminobutyric acid receptor binding sites was lower in the midbrain of seizure-susceptible gerbils compared to control seizure-resistant gerbils. Binding of [3H]diazepam to high-affinity brain-specific sites in membrane homogenates of gerbil brain showed a 20-30% lower binding in midbrain (but not other regions) in adult seizure-susceptible gerbils than in controls. This binding deficit was localized by tissue slice autoradiography with [3H]flunitrazepam to the substantia nigra and mesencephalic periaqueductal gray regions, while higher binding was observed in the interpeduncular nucleus. These differences were also seen in animals sacrificed immediately after a seizure. A parallel deficit of [3H]bicuculline methochloride binding to low-affinity gamma-aminobutyric acid receptors also was seen in the same midbrain regions. Scatchard plot analysis showed that the benzodiazepine binding deficit in the nigra was due to a lower number of binding sites with not significant difference in affinity. Lower [3H]flunitrazepam binding was likewise seen in younger animals (29% lower at 30 days of age, 38% at 60 days, and 21% at 90 days), indicating that the midbrain receptor deficit is present in the seizure-susceptible gerbil prior to the age of onset of seizures at 50-100 days. Therefore, these changes are not likely to result from seizures but reflect genetically determined biochemical differences that could play a role in the expression of seizure susceptibility. The deficit in midbrain benzodiazepine/gamma-aminobutyric acid receptors in the seizure-susceptible gerbil would be consistent with the hypothesis that a deficit of gamma-aminobutyric acid-mediated inhibition might contribute to some kinds of epilepsy.

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A non-invasive saliva sample delta 9-THC radioimmunoassay has been applied to 352 samples from 25 male and 10 female marijuana users after administration of one-half to two standard cigarettes (27 mg delta 9-THC/cigarette) and 72 control negative subjects who ingested a large variety of foods, condiments, or medications in an attempt to demonstrate interferences. The shortest duration of a positive was 2 hrs and the longest was 5 hrs after administration of the cannabis. No positives occurred in control subjects.

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