Abstract
Twelve male Sprague-Dawley rats, following training on one of two food-motivated operant schedules (Fixed-Ratio 30 or Variable Interval 30 s), were exposed to an escalating regimen of daily ethanol (1.125–3.0 g/kg, IP) administration. This increasing dose regimen continued until the maximally tolerable dose for each subject was reached. Tolerance was then monitored for approximately 6 months by periodic ethanol challenge doses (1.5 g/kg). Dose-effect curves (DECs) were obtained prior to chronic ethanol (DEC1), immediately after ethanol tolerance development (DEC2), and 6 months (DEC3) following termination of ethanol exposure. At DEC1, ethanol produced dose-dependent decreases in rate on both schedules with no significant schedule differences in ED50 (the dose effective at reducing the maximal response rate by one-half) values. Maximal tolerance was achieved in means of 46 and 55 days on the VI and FR schedules, respectively. Differences in rate of tolerance acquisition on the initial dose of the chronic regimen (1.125 g/kg) account for most of the difference in the overall rate of acquisition. Comparison of the ED50 data from DECs 1 and 2 indicated that daily ethanol exposure resulted in a 2-fold decrease in ethanol sensitivity (i.e., tolerance) on both operant schedules. The ED50 data from DECs 1 and 3 demonstrated a 1.7-fold decrease in ethanol potency on DEC3. This duration of tolerance was considerably longer than that generally reported, and possibly related to the extended ethanol exposure and the sensitivity of operant schedules to drug effects.
Similar content being viewed by others
References
Andry DK, Luttges MW (1972) Memory traces: Experimental separation by cycloheximide and electroconvulsive shock. Science 178:518–520
Bass MB, Lester D (1980) Tolerance to ethanol-induced impairment of water escape in rats bred for ethanol sensitivity. Psychopharmacology 71:153–158
Breen T, Thompson R (1966) Cortical and subcortical structures mediating a visual conditioned response motivated by thirst. J Comp Physiol Psychol 61:146–150
Cappell H, LeBlanc AE (1979) Tolerance to, and physical dependence on, ethanol: Why do we study them? Drug Alcohol Depend 4:15–31
Chen CS (1972) A further note on studies of acquired behavioral tolerance to alcohol. Psychopharmacologia 27:265–274
Cicero TJ (1978) Tolerance to and physical dependence on alcohol: Behavioral and neurobiological mechanisms. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: A generation of progress. Raven press, New York, pp 1603–1617
Cicero TJ (1980) Alcohol self-administration, tolerance and with-drawal in humans and animals: Theoretical and methodological issues. In: Rigter H, Crabbe JC (eds) Alcohol tolerance and dependence. Elsevier/North Holland Biomedical Press, Amsterdam, pp 1–51
Crow LT, Higbee MW (1977) Behavioral augmentation of tolerance to alcohol and the response measure. Bull Psychonom Soc 10:5–8
de Souza Moreira LF, Capriglione MJ, Masur J (1981) Development and reacquisition of tolerance to ethanol administered pre- and post-trial to rats. Psychopharmacology 73:165–167
Dews PB (1978) Behavioral tolerance. In: Krasnegor N (ed) Behavioral tolerance: Research and treatment implications (NIDA Research Monograph 18, US Department of Health and Human Services). US Government Printing Office, Washington DC, pp 18–26
Finnegan KT, Ricaurte G, Seiden LS, Schuster CR (1982) Altered sensitivity to d-methyl-amphetamine, apomorphine, and haloperidol in Rhesus monkeys depleated of caudate dopamine by repeated administration of d-methyl-amphetamine. Psychopharmacology 77:43–52
Flood JF, Bennett EL, Orme AE, Rosenzweig MR (1975) Effects of protein synthesis inhibition on memory for active avoidance training. Physiol Behav 14:177–184
Gibbins RJ, Kalant H, LeBlanc AE, Clark JW (1971) The effects of chronic administration of ethanol on startle thresholds in rats. Psychopharmacologia 19:95–104
Gitlow SE, Dziedzic SW, Dziedzic LM (1977) Tolerance to ethanol after prolonged abstinence. In: Gross M (ed) Alcohol intoxication and withdrawal, Vol. IIIa, Biological aspects of ethanol. Plenum Press, New York, pp 571–592
Gold PE, Macri J, McGaugh JL (1973) Retrograde amnesia gradients: Effects of direct cortical stimulation. Science 179:1343–1345
Hendry JS, Rosecrans JA (1982) The development of pharmacological tolerance to the effect of nicotine on schedule-controlled responding in mice. Psychopharmacology 77:339–343
Hinson RE, Siegel S (1980) The contribution of Pavlovian conditioning to ethanol tolerance and dependence. In: Rigter H, Crabbe JC (eds) Alcohol tolerance and dependence. Elsevier/North Holland Biomedical Press, Amsterdam, pp 181–199
Holloway FA, Bird DC, Holloway JA (1983) Long-term tolerance to ethanol's effect on operant performance in the rat. Neurosci Abstr 9:1241
Kalant H, LeBlanc AE, Gibbins RJ (1971) Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev 23:135–191
Kalant H, LeBlanc AE, Gibbins RJ, Wilson A (1978) Accelerated development of tolerance during repeated cycles of ethanol exposure. Psychopharmacology 60:59–65
Kesner RP, Priano DJ, DeWitt JR (1976) Time-dependent disruption of morphine tolerance by electroconvulsive shock and frontal cortical stimulation. Science 194:1079–1981
Lê AD, Poulos CX, Cappell H (1979) Conditioned tolerance to the hypothermic effect of ethyl alcohol. Science 206:1109–1110
LeBlanc AE, Kalant H, Gibbins RJ (1975) Acute tolerance to ethanol in the rat. Psychopharmacologia 41:43–46
LeBlanc AE, Kalant H, Gibbins RJ (1976a) Acquisition and loss of behaviorally augmented tolerance to ethanol in the rat. Psychopharmacology 48:153–158
LeBlanc AE, Kalant H, Gibbins RJ, Berman ND (1969) Acquisition and loss of tolerance to ethanol by the rat. J Pharmacol Exp Ther 168:244–250
LeBlanc AE, Matsunaga M, Kalant H (1976b) Effects of frontal polar cortical ablation and cycloheximide on ethanol tolerance in rats. Pharmacol Biochem Behav 4(2):175–179
Meltzer LT, Rosecrans JA (1982) Tolerance to the disruptive effects of arecoline on schedule-controlled behavior. Psychopharmacology 77:85–93
Morse WH, Kelleher RT (1977) Determinants of reinforcement and punishment. In: Honig WK, Staddon JER (eds) Handbook of operant behavior. Prentice-Hall, New Jersey, pp 174–200
Pieper WA, Skeen MJ (1975) Retention of functional tolerance to ethanol in rhesus monkeys (Macaca mulatta). Pharmacol Biochem Behav 3:909–913
Schuster CR (1978) Theoretical basis of behavioral tolerance: Implications of the phenomenon for problems of abuse. In: Krasnegor N (ed) Behavioral tolerance: Research and treatment implications (NIDA Research Monograph 18, US Department of Health and Human Services). US Government Printing Office, Washington DC, pp 4–17
Schuster CR, Dockens WS, Woods JH (1966) Behavioral variables affecting the development of amphetamine tolerance. Psychopharmacologia 9:170–182
Siegel S (1978) A Pavlovian conditioning analysis of morphine. In: Krasnegor N (ed) Behavioral tolerance: Research and treatment implications. (NIDA Monograph 18) US Department of Health and Human Services, US Government Printing Office, pp 27–53
Siegel S, Hinson RE, Krank MD (1978) The role of predrug signals in morphine analgesic tolerance: Support for a Pavlovian conditioning model of tolerance. J Exp Psychol: Anim Behav 4(2):188–196
Tabakoff B, Rothstein JD (1983) Biology of tolerance and dependence. In: Tabakoff B, Sutker PB, Randall CL (eds) Medical and social aspects of alcohol abuse. Plenum Press, New York, pp 187–220
Wenger JR, Berlin V, Woods SC (1980) Learned tolerance to the behaviorally disruptive effects of ethanol. Behav Neural Biol 28:418–430
Wenger JR, Tiffany TM, Bombardier C, Nicholls K, Woods SC (1981) Ethanol tolerance in the rat is learned. Science 213:575–577
Wood JM, Laverty R (1979) Metabolic and pharmacodynamic tolerance to ethanol in rats. Pharmacol Biochem Behav 10:871–874
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bird, D.C., Holloway, F.A. & Carney, J.M. Schedule-controlled behavior as an index of the development and loss of ethanol tolerance in the rat. Psychopharmacology 87, 414–420 (1985). https://doi.org/10.1007/BF00432505
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00432505