Dennis L. Hjeresen

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.

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.

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.