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P Lomax

Publications and source records attributed to P Lomax.

At least 19 recordsLinked to original sources
PubMed1990

Cocaine and body temperature in the rat: effect of exercise.

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.

Animals↗
PubMed1990

Cocaine and body temperature in the rat: effects of ambient temperature.

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.

Animals↗
PubMed1990

Cocaine and body temperature in the rat: effects of exercise and age.

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.

Aging↗
PubMed1989

Anticonvulsant effect of muscimol injected into the thalamus of spontaneously epileptic Mongolian gerbils.

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.

Animals↗
PubMed1987

Increased enkephalin and dynorphin immunoreactivity in the hippocampus of seizure sensitive Mongolian gerbils.

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.

Animals↗
PubMed1987

Relationship between the temperature and endocrine changes induced by cholinesterase inhibitors.

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.

Animals↗
PubMed1986

Opioid receptor alterations in a genetic model of generalized epilepsy.

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.

Animals↗
PubMed1986

Neuropeptides: anticonvulsant and convulsant mechanisms in epileptic model systems and in humans.

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)

Adrenocorticotropic Hormone↗
PubMed1986

Benzodiazepine/barbiturate/GABA receptor-chloride ionophore complex in a genetic model for generalized epilepsy.

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.

Animals↗
PubMed1985

Benzodiazepine/gamma-aminobutyric acid receptor deficit in the midbrain of the seizure-susceptible gerbil.

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.

Animals↗
PubMed1984

The effect of spontaneous seizures on pentylenetetrazole and maximum electroshock induced seizures in the Mongolian gerbil.

The seizure sensitive Mongolian gerbil, a genetic model of epilepsy, has been used to investigate the effects of prior spontaneous seizures on the threshold for pentylenetetrazole (PTZ) and maximum electroshock (MES) induced convulsions. In animals which had spontaneous epileptic seizures prior to testing the threshold for PTZ induced convulsions was raised compared to non-seized animals. This inhibitory effect of a spontaneous seizure was not observed for MES convulsions. Pretreatment with naltrexone, an opioid antagonist, attenuated the post-ictal inhibitory effect on PTZ induced convulsions. It is concluded that a spontaneous seizure in the epileptic gerbil leads to non-specific post-ictal inhibition of seizure sensitivity. Endogenous opioids may exert a modulatory action in mediating this phenomenon.

Animals↗
PubMed1984

Neuropeptides: a role as endogenous mediators or modulators of epileptic phenomena.

As more small peptidergic components of the central nervous system are isolated, their role in disease states is being investigated. Several of these neuropeptides, especially the opioidlike peptides, adrenocorticotropic hormone, and some hypothalamic releasing factors, have been found to alter neuronal excitability. This finding has led to the proposal that these peptides may play a role in the pathogenesis of the epilepsies. We tested this hypothesis in a genetic model of epilepsy. At nontoxic doses, several exogenously administered peptides had anticonvulsant properties, while others were proconvulsant. The most potent anticonvulsant was the opioidlike peptide beta-endorphin. Its effect was similar to that of the opioid alkaloids. Using the potent antagonist naloxone hydrochloride to block possible endogenous opioid-like peptides, we found no effects on seizures in naive animals. Naloxone did alter postictal events, however, by partially blocking the postictal refractoriness to further seizures. We speculate that one possible role for the endogenous opioid peptides may be to limit the spread of seizures or to modulate postictal susceptibility to further seizures. Naloxone was effective in this model only after stressful situations occurred that modified the seizures and presumably induced a release of endogenous opioidlike peptides. Support for this hypothesis from other epilepsy models is discussed. Other peptidergic systems may also be active in various epileptic models, and the current understanding of their roles is reviewed.

Adrenocorticotropic Hormone↗
PubMed1984

Role of the gamma-aminobutyric acid receptor-ionophore complex in seizure disorders.

The possibility of a role for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in seizure disorders has been strengthened by biochemical studies showing that various nervous system depressant drugs can modulate GABA receptor binding in vitro. In particular, two classes of anticonvulsant agents, the benzodiazepines and the barbiturates, have modulatory receptor sites on the GABA receptor-ionophore protein complex of the postsynaptic membrane. Furthermore, it is well established that direct block of GABA function causes seizures and that augmentation of GABA function can protect against seizure activity. Direct evidence for altered GABA synaptic markers has been obtained in some animal models of epilepsy, as well as in human focal epilepsy. We present preliminary evidence for a deficit in benzodiazepine receptor binding in the midbrain of seizure-susceptible Mongolian gerbils. These data would be consistent with an impairment of GABA-mediated inhibitory synaptic transmission that contributes to susceptibility to the genesis or spread of seizures in some kinds of epilepsy.

Animals↗