Relations between metabolic and nervous tolerance toward ethanol in naive and chronically intoxicated rats

Interindividual differences in blood alcohol elimination rates indicating metabolic tolerance (MT) were determined in adult male Wistar rats following the injection of ethanol via chronically implanted intra-jugular catheters. Nervous tolerance (NT) was measured using a behavioral test based on the latency of drinking in 20-hr water-deprived rats following the IV injection of a challenge dose of ethanol. Individual elimination rates varied between 0.312 and 0.570 mg/ml/hr (mean ± SE: 0.427 ± 0.006) and drinking latencies (1/NT) between 45 and 255 min (mean=125 ± 12). MT and NT determinations performed on the same animals indicated no correlation between the initial degrees of tolerance. In one experiment, MT and NT measurements were obtained prior to and following chronic IV pulsed-administration (4 days) of either ethanol or physiological saline. In comparison to controls, the ethanol-treated rats showed both a significant increase (22.7%) in MT (p<0.01) and a reduction (66.8%) in the latency (1/NT) of drinking (p<0.05). The extrapolation of BALs present at the onset of drinking indicated the concomitant increase in MT of ethanol-treated animals to be negligible in accounting for the observed increase in NT and that the latter was more likely attributable to adaptive changes in CNS sensitivity. Another experiment attempted to investigate the time course of development of MT in rats during continuous IV ethanol infusion (5–9 days). Mean daily MT values were calculated on the basis of 24-hr BAL samplings and known quantities of ethanol administered. The results indicated an initial adaptive increase in MT occurring within 48 hr and attaining rates about as high as 35% above initial values. This phase was usually followed by a rapid decrease in MT below that of initial levels and associated with elevated BALs and loss of body weight due to reduced food intake. The possible role played by the MT and NT factors in the defense mechanisms involved in preference and aversion conditioning and regulating the voluntary consumption of ethanol in the naive and chronically intoxicated animal are discussed.