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Cold acclimatization (4-5 degree C) is accompanied by 2-3 fold increase of brown adipose tissue (BAT). This rapid growth of interscapular BAT was studied after histamine depletion. In control rats maintained at room temperature (28 +/- 2 degree C) the BAT histamine content was 23.4 +/- 5.9 (mean +/- SD) microgram/g of tissue and cold acclimatization (5 +/- 1 degree C) produced a significant increase of BAT weight, but reduced the histamine content to 8.4 +/- 1.9 microgram/g. The total weight of BAT after 20 days of acclimatization was unaffected by depletion of histamine due to compound 48/80. The low level of histamine in BAT of cold acclimatized rats could be due to a fast rate of amine utilization; alternatively an altered synthesis or storage process may occur during acclimatization.

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Injection of large doses of ammonia (1.2g/kg, i.p.) was used to induce acute toxicity in mice which was characterized by hyperresponsiveness, taquipnea, clonic and tonic seizures and death. Pretreatment with 20, 40, or 80 mg/Kg, i.p., of ketamine increased 30 to 55% survival rate. This pretreatment significantly retarded the beginning of the first tonic convulsion attenuating its intensity and delayed the time of the animal death; but did not alter the onset of the first clonic seizures. These experiments may be an evidence that support the hypothesis that seizures due to hyperammonemia involve activation of excitatory amino acid receptors.

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The effects of sudden cooling of the spinal cord were studied in three species of amphibians--a cold-sensitive tropical toad (Bufo marinus), a cold-resistant, aquatic, hibernating frog (Rana pipiens, northern leopard frog) and a freeze-tolerant frog (Rana sylvatica, wood frog). Ventral root (motoneuron) potentials were recorded from isolated, hemisected spinal cords of each species mounted in a sucrose-gap recording apparatus and superfused with HCO3(-)-buffered Ringer's solution at room temperature (21 degrees C). In the toad, sudden cooling to 6-8 degrees C produced large, sustained motoneuron depolarizations that returned slowly to baseline levels and were accompanied by extensive paroxysmal activity. Larger, but shorter-lasting, motoneuron depolarizations associated with only a limited amount of paroxysmal activity were generated by rapid cooling of the leopard frog spinal cord. Small, brief motoneuron depolarizations followed by a hyperpolarization, or hyperpolarizations not preceded by depolarizations, were seen in cooled wood frog spinal cords. The wood frog displayed a large amount of spontaneous motoneuron activity, but little paroxysmal activity in response to sudden cooling. Following prolonged cooling, rewarming the spinal cords of all three species resulted in motoneuron hyperpolarizations that slowly decayed towards the baseline value. The amplitude of the rewarming-induced response was larger and longer in toad motoneurons than in leopard frog and wood frog motoneurons. At room temperature, a single supramaximal dorsal root stimulus evoked a depolarizing ventral root potential in toad and leopard frog motoneurons that was decreased in amplitude and prolonged when the spinal cords were cooled to 8 degrees C or below. In contrast, at room temperature, the ventral root reflex in the wood frog was followed by a distinct hyperpolarization. Cooling the wood frog spinal cord only slightly reduced the amplitude of the ventral root potential. In contrast, the evoked hyperpolarization was blocked by sudden cooling and also by the addition of dihydro-ouabain to the Ringer's solution. The motoneuron hyperpolarizations induced by sudden cooling in the wood frog were converted to depolarizations when Cl- in the superfusate was replaced with isethionate. The depolarizations elicited by sudden cooling were reduced by the addition of kynurenate in all three species. A dose-response curve generated by short applications of L-glutamate demonstrated that wood frog motoneurons were less sensitive than leopard frog motoneurons to L-glutamate. In summary, three species of amphibians, differing in their adaptations to the temperature of their environments, vary in their responses to sudden reductions in temperature. The relationship of these responses to their environmental adaptations remains to be determined.

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Spinal seizures evoked by sudden cooling (SSSC) were used to investigate the anticonvulsant activity of ketamine (KET) injected either intralymphatically (i.l., 5-40 mg/kg) or intrathecally (i.t., 0.5-1.0 mumol/20 microliters) using isolated spinal cord-hindleg preparation. KET inhibited the tonic phase and prolonged the clonic phase in a dose-dependent manner. The cionic phase was depressed or totally blocked at KET doses of 80-160 mg/kg, i.l. or 2 mumol/20 microliters, i.t. This depression was not prevented by i.t. administration of concanavalin A. The latency of onset of seizures was also increased by KET. KET abolishes the tonic-extensor phase of SSSC in which activation of N-methyl-D-aspartate-receptors may play a role.

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The effect of low doses of urethane on three phases of spinal seizures evoked by sudden cooling (SSSC) of toad isolated spinal cord was studied. In control toads, SSSC began with a latency of 91 +/- 3 sec (mean +/- S.E.M.) exhibiting brief tremors, followed by clonic muscle contractions and finally reaching a tonic contraction (tonic phase). The latency of onset of seizures was significantly enhanced. The tonic phase was markedly abolished in toads pretreated intralymphatically with 0.15 g/kg of urethane. Tremors were the only phase observed in 55% of toads that received doses of 0.2 g/kg, and a total blockade of seizures was seen after doses of 0.25 g/kg of urethane in 50% of the preparations. A possible depressant effect of urethane on transmission mediated by excitatory amino acids is suggested.

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Sudden cooling of the isolated spinal cord of frogs results in characteristic seizure-like activity in the hind legs. In the present investigation, these spinal seizures induced by sudden cooling (SSSC) were studied to determine whether excitatory amino acids (EAAs) are involved in the mediation of this activity. The nonspecific EAA antagonist, L-glutamic acid diethyl ester and cis-2,3-piperidine dicarboxylic acid inhibited the clonic and tonic phase of SSSC after intralymphatic or intrathecal administration. The antagonist gamma-D-glutamylaminomethylsulfonic acid and gamma-D-glutamyltaurine also suppressed both phases after intrathecal injections. The NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid, DL-2-amino-7-phosphonoheptanoic acid, and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid were effective inhibitors of the tonic phase and actually prolonged the duration of the clonic phase, an effect similar to that observed after low doses of gamma-D-glutamylglycine. SSSC were resistant to spinal perfusion to tetrodotoxin (1 microM). The concentrations of glutamate, aspartate, and glycine were increased in the Ringer's solution surrounding rapidly cooled spinal cord slices, but only in cords from species that elicited some magnitude of SSSC, not in cords from species resistant to induction of SSSC. Our data support the hypothesis that EAAs play a role in SSSC via activation of quisqualate receptors.

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Urethane and ketamine were tested for their ability to alter the caudally directed binding and scratching response elicited by the intrathecal (i.t.) injection of excitatory amino acids (EAAs) or substance P (SP). EAAs, such as N-methyl-D-aspartate (NMDA), kainate acid and quisqualic acid, but not SP, were inhibited by subanesthetic doses of urethane. In contrast, SP was more sensitive than NMDA to the inhibitory effect of (+)-ketamine. (-)-Ketamine produced much less inhibition of the SP-induced behaviors than the (+)isomer. These results have important implications regarding the use of urethane and ketamine as anesthetics for studies in which these excitatory compounds are potential mediators.

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Sudden cooling of the isolated spinal cord of toads results in characteristic seizure-like activity in the hindlegs. In the present investigation, kynurenate (KYN), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and 2-amino-5-phosphonovalerate (APV), a competitive NMDA receptor antagonist, were tested in the pattern, latency and duration of the spinal seizures. APV, 1.3-2.5 mmol/kg and KYN, 2.6 mmol/kg, inhibited the tonic phase of the spinal seizures and prolonged the duration of the clonic phase after intralymphatic (i.l.) administration. The same effect was observed after intrathecal injection of either 10 or 20 mumol/20 microliter of each drug. The clonic phase was markedly attenuated by KYN at high doses of 5.3 or 10.6 mmol/kg, i.l., suggesting that non-NMDA receptors may have some mediation in the generation of that phase. Both antagonists retarded the onset of seizures indicating that activation of NMDA receptors is likely involved in the beginning of this convulsive-like activity. This model may be a useful technique to assay other excitatory amino acid antagonists.

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RESUMEN

Sudden cooling of the isolated spinal cord of toads results in characteristic seizure-like activity in the hindlegs. In the present investigation, kynurenate (KYN), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and 2-amino-5-phosphonovalerate (APV), a competitive NMDA receptor antagonist, were tested in the pattern, latency and duration of the spinal seizures. APV, 1.3-2.5 mmol/kg and KYN, 2.6 mmol/kg, inhibited the tonic phase of the spinal seizures and prolonged the duration of the clonic phase after intralymphatic (i.l.) administration. The same effect was observed after intrathecal injection of either 10 or 20 mumol/20 microliter of each drug. The clonic phase was markedly attenuated by KYN at high doses of 5.3 or 10.6 mmol/kg, i.l., suggesting that non-NMDA receptors may have some mediation in the generation of that phase. Both antagonists retarded the onset of seizures indicating that activation of NMDA receptors is likely involved in the beginning of this convulsive-like activity. This model may be a useful technique to assay other excitatory amino acid antagonists.

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The concentration of endogenously formed tryptamine in central nervous system tissue was determined after extraction into ethyl acetate, purification on a weak cation-exchange resin and analysis using high-performance liquid chromatography with fluorometric detection. Final chromatographic separation of this indoleamine was achieved using a muBondapak C18 reversed-phase column under isocratic conditions. Using this method, the concentration of tryptamine in the whole brain of normal rats was found to be 0.60 +/- 0.06 ng/g of tissue, while pretreatment with dl-p-chlorophenylalanine, tranylcypromine and l-tryptophan increased the concentration to 96.7 +/- 21.9 ng/g.

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