Tolerance to hypothermia induced by ethanol depends on specific drug effects.

Two experiments were conducted to test the hypothesis that tolerance to the hypothermic effect of ethanol fails to develop if rats are denied the unconditional stimulus represented by hypothermia. In both experiments, rats were injected with either ethanol (1.9 or 2.5 g/kg) or saline and given microwave hyperthermia (MHT) to offset the hypothermic effect of the drug or sham-MHT. In one experiment, rats no longer demonstrated a hyperthermic response to a saline challenge after hypothermia was offset during 5 MHT treatment sessions. In a second experiment, rats prevented from becoming hypothermic did not develop tolerance to the hypothermic effect of ethanol due to MHT treatment, but did become tolerant to the ataxic effects of ethanol, which were unaffected by MHT. Results suggest that rats must experience the specific consequences of a drug to become tolerant to that effect.

The role of arginine vasopressin in the development of tolerance to ethanol in normal and Brattleboro rats.

Administration of AVP and related peptide fragments following ethanol (EtOH) administration has been shown to enhance retention of tolerance to ethanol. The present studies were designed specifically to: (1) examine the influence of AVP given concurrently with EtOH on the development of tolerance to the ataxic and hypothermic effects of EtOH in Long-Evans rats, and (2) to determine if tolerance to these effects develops in Brattleboro rats which are deficient in AVP. In Experiment 1, EtOH (2.5 g/kg, 15% v/v) was administered IP to 2 groups of rats in combination with a SC injection of either AVP (6 micrograms/kg) or an equal volume of saline. Two additional control groups received IP saline injections in combination with either saline or AVP. After 13 days, EtOH-treated rats were significantly more tolerant than saline-treated animals. AVP significantly increased the hypothermic and ataxic effects of EtOH and failed to enhance tolerance development. AVP delayed the extinction of tolerance to the hypothermic (but not the ataxic) effects of ethanol when administered during the extinction phase to rats previously treated with EtOH. In Experiment 2, Brattleboro rats were injected with EtOH or an equivalent volume of saline and tested for ataxia and hypothermia. Rats receiving EtOH failed to demonstrate significant tolerance to either effect of ethanol after 12 treatment days.

Nicotine interactions with ethanol tolerance.

Nicotine (N) administration (0.05 mg/kg SC) was paired with ethanol (E, 2.5 g/kg, 15% v/v, IP) to determine if N alters either the acquisition of extinction of tolerance to the hypothermic and sedative effects of E. During tolerance acquisition the following groups were tested: E + N (N = 16), E + NaCl vehicle (V) (N = 16), V + N (N = 4) and V + V (N = 4). For 11 days a colonic temperature was taken, both drugs were injected and the rats were tested for locomotor activity for 45 min, after which a final colonic temperature was taken. N significantly enhanced the rate of tolerance development to the hypothermic effects of E and blocked a degree of the sedative effects. On Days 12 to 17 rats in all groups received V injections to extinguish tolerance. On Days 18 to 24 rats in the E + N group were tested with either E + N or E + V and rats in the E + V group were similarly divided. Previous treatment with N significantly attenuated the extinction process which in turn enhanced the reacquisition of tolerance.

Microwave attenuation of ethanol-induced interactions with noradrenergic neurotransmitter systems.

Research suggests that microwave (MW) irradiation can attenuate ethanol (EtOH)-induced hypothermia in a manner that may depend, in part, on noradrenergic (NE) neurotransmitter systems. To investigate this possible interaction, neonatal rats were injected with the neurotoxin 6-hydroxydopamine (6-OHDA) to lesion central NE neurons. When tested as adults, lesioned, MW irradiated rats did not demonstrate the interaction between MW (2.45 GHz, 45 min, specific absorption rate = 0.3 W/kg) and EtOH-induced hypothermia that was seen among control animals. Additional experiments examined MW interactions with centrally and peripherally acting beta-adrenergic antagonists. Acute low-level MW irradiation attenuated EtOH-induced hypothermia in the rat. Pretreatment with 1.0 mg/kg of the centrally active beta-adrenergic antagonist propranolol significantly attenuated the ethanol-induced hypothermia of sham-irradiated (SH-irradiated) rats. There was no consistent effect of propranolol on MW irradiated animals, regardless of dose. Similarly, the degree of hypothermia demonstrated by SH-irradiated controls was significantly attenuated compared to MW irradiated animals by pretreatment with the peripheral beta-adrenergic antagonist CGP-12177 (doses of 0.1, 1.0 and 10.0 mg/kg). In vivo binding data indicates only the highest dose of CGP-12177 to be centrally active. Taken together, the results confirm NE mediation of EtOH-induced hypothermia and suggest that MW energy may in some way mimic the role of beta-adrenergic antagonists.

Ontogeny of susceptibility to experimental febrile seizures in rats.

Two experiments were conducted using microwave hyperthermia (MHT) to induce seizures among limited numbers of Long-Evans rat pups. The MHT model of febrile seizures eliminates several methodological complications inherent in previous animal models of the disorder. In Experiment 1, rat pups were rendered hyperthermic with MHT or were sham-irradiated on Days 11, 13, 15 or 17 postpartum. The results indicate a statistically significant decline in seizure susceptibility with age. In Experiment 2, rats were subjected to either single or multiple hyperthermic episodes on Days 11, 13, 15, or 17 postpartum. The results indicate an increase in susceptibility to seizures attributable to prior seizure history. In both experiments, seizures were induced with increases in rectal temperature of 1 to 3 degrees C. The results parallel many clinical features of febrile seizures and argue the efficacy of the MHT model.

Ontogeny of seizure incidence, latency, and severity in genetically epilepsy prone rats.

The Genetically Epilepsy-Prone Rat (GEPR) is a widely studied model of epileptiform disorders. While there is considerable evidence that neurotransmitter abnormalities contribute to the unusual sensitivity of these animals to seizures, the possibility that seizure susceptibility may reflect developmental changes in the central nervous system has not been fully addressed. In the present study, 91 GEPR-9 pups were tested for incidence, latency and severity of an audiogenically induced seizure at 6, 9, 12, 15, 18, 21, 24, 27, 28, 29, or 30 days postpartum (1 test per pup) and retested at 60 days. Seizure incidence, latency, and severity were significantly greater on Days 27, 28, 29, and 30 than on all previous days. The first observation of running fits occurred in Day 18 pups and the first evidence of seizures occurred in Day 21 pups. When retested at Day 60, seizure incidence and severity were significantly greater than on initial tests while latency declined. The results suggest that seizure susceptibility in the GEPR-9 occurs as the result of developmental events in the CNS occurring on or shortly after Day 18 postpartum.

Microwave attenuation of ethanol-induced hypothermia: ethanol tolerance, time course, exposure duration, and dose response studies.

Four experiments were conducted to quantify the reported attenuation by microwave (MW) irradiation of ethanol-induced hypothermia. In one experiment rats were irradiated (continuous wave 2.45 GHz, specific absorption rate = 0.3 W/kg) or sham irradiated for 45 min, injected with 3.6 g/kg, 20% (v/v) ethanol (EtOH) or saline (NaCl) i.p.. Colonic temperature was monitored at 20-min intervals for 2 h. This procedure was repeated for 8 days to determine the rate of tolerance development to the hypothermic effect of ethanol. While MW irradiation did significantly attenuate EtOH-induced hypothermia, it did not enhance or retard the rate of tolerance development. To determine the duration of irradiation necessary to attenuate EtOH-induced hypothermia, groups of rats were irradiated or sham irradiated for 5, 15, 30, or 60 min prior to EtOH injection and subsequent temperature measurements. The attenuation was apparent only after 60 min of irradiation. To determine the duration of the attenuation effect after irradiation, rats were injected with EtOH or NaCl at 0, 30, 60, 120, or 480 min after 45 min of irradiation or sham irradiation. The attenuation effect was apparent among rats injected 0 to 30 min after irradiation and for the first 40 min for groups injected at 120 min. Additional rats were injected with NaCl or 0.9, 1.8, or 2.7 g/kg of EtOH i.p. following 45 min of irradiation or sham irradiation to determine if the attenuation effect depends on the dose of EtOH administered. Attenuation of EtOH-induced hypothermia was more apparent at lower doses of EtOH than at higher doses. These results indicate that the effect is an acute response to irradiation, and rule out several other potential explanations.

Effects of 60-Hz electric fields on avoidance behavior and activity of rats.

In repeated short-term tests (four sessions, each of 45-minute duration), and one longer test (a 23.5-hour session), behavior of rats was evaluated in a long, narrow shuttlebox. One side of the box was exposed to an electric field at various strengths, while a visually identical opposite side was shielded from exposure. In the short-term tests, rats generally remained shielded from electric fields of 90 kV/m and greater during the first session, and maintained this response in subsequent sessions. In the longer test, this same preference response was demonstrated at field strengths of 75 kV/m and greater; however, at 25 and 50 kV/m, rats exhibited a statistically significant preference for the exposed region of the shuttlebox, but only during the light portion of a 12-hour light: 12-hour dark cycle. Exposed animals made more traverses than sham-exposed controls between the two ends of the shuttlebox during the first hour of the test. The experimental data support the hypothesis that the observed behavioral effects are the result of direct interaction of the electric field with the animal, and not the result of secondary factors such as electric shocks, corona discharge, audible noise, ozone, or vibration of the experimental apparatus.

A behavioral response of swine to a 60-Hz electric field.

It has been shown that rats, given the choice, will spend more time out of a 60-Hz electric field than in it at field strengths greater than or equal to 75 kV/m. This paper describes research to examine the relevance of these data to a different species, the pig. Miniature pigs that had been exposed to a 60-Hz electric field at 30 kV/m for 20 h/day, 7 days/week for as long as 6 months, were tested for their preference for the presence or absence of the field during a 23.5-h period. Similar to earlier results with rats, miniature pigs spent more time out of the electric field than in it during the sleeping period.

A microwave-hyperthermia model of febrile convulsions.

While convulsions associated with fever represent a serious problem in pediatric medicine, conventional animal models of febrile convulsions suffer numerous technical limitations. A microwave-hyperthermia model that eliminates these problems was tested. Microwave energy was used to increase the core temperature of 13- and 17-day-old rats, resulting in convulsions similar to febrile convulsions in human infants. Rats were irradiated for 10 min in circularly polarized waveguides at 918 MHz, CW (average SAR = 9.4 W/kg at 13 days and 18.0 W/kg at 17 days as determined by twin-well calorimetry). Day 17 irradiated rats were less susceptible to convulsions that were day 13 irradiated rats, indicating an age-dependent decline in susceptibility. Contrary to findings of earlier models using infrared or hot-oven heating, convulsions induced with microwave hyperthermia impaired neither brain growth nor subsequent performance during behavioral testing. Simultaneous measurement of brain and rectal temperatures during microwave irradiation revealed differential heating rates that favor thermal homeostasis in brain tissue.