Drug effects on multiple and concurrent schedules of ethanol- and food-maintained behaviour: context-dependent selectivity

Abstract

Background and purpose: Drugs that more potently or effectively reduce ethanol-maintained behaviour versus an alternative are considered selective and are considered promising pharmacotherapies for alcoholism. Such results are often obtained using separate groups or multiple schedules where ethanol and the alternative are available alone or sequentially. Recently, we observed that when ethanol and food were available sequentially under a multiple schedule, fluvoxamine and varenicline were selective; yet this selectivity disappeared when ethanol and food were concurrently available.

Experimental approach: We examined the generality of these findings by comparing doses of several drugs required to decrease ethanol- and food-maintained responding under a multiple schedule and under a concurrent schedule. Effects were determined for chlordiazepoxide, 2,5-dimethoxy-4-iodoamphetamine (DOI), meta-chlorophenylpiperazine (mCPP), morphine, naltrexone and d-amphetamine.

Key results: Under the multiple schedule, ED50 values for decreases in ethanol-maintained responding were significantly different and lower than ED50 s for decreases in food-maintained responding (demonstrating selectivity) for each drug except for chlordiazepoxide (which was equipotent) and naltrexone (which did not affect responding). However, this selectivity vanished or even inverted under the concurrent schedule, such that ED50 values for decreasing ethanol- and food-maintained responding were not different (or, following DOI, the ED50 for food-maintained responding was lower than for ethanol-maintained responding).

Conclusions and implications: Results are consistent with those seen following fluvoxamine and varenicline administration, and suggest that selectivity is assay-dependent. These results indicate the need for careful interpretation of selective drug effects, especially when obtained in situations where ethanol or the alternative is the only programmed reinforcement available.

Keywords: 5-HT; alcohol; benzodiazepine; choice; operant; opioid; pharmacotherapy; rat.

Figure 1

Effects of chlordiazepoxide on responding maintained by food or ethanol under the multiple schedule (A) and concurrent schedule (B). Points represent the mean ± SEM for n = 6 rats for each schedule, expressed as a % of responding following vehicle for each rat. Plots illustrate the number of fixed ratios completed as a function of the dose of chlordizaepoxide administered before the session. Filled symbols represent ethanol-maintained responding and open symbols represent food-maintained responding. Doses are plotted on a log scale.

Figure 2

Effects of mCPP (A and B) and DOI (C and D) on responding maintained by food or ethanol under the multiple (A and C) and concurrent (B and D) schedules. Points represent the mean ± SEM for n = 6 rats for each schedule (except for mCPP effects under the concurrent schedule, which had n = 5 rats) expressed as a % of responding following vehicle for each rat. Plots illustrate the number of fixed ratios completed as a function of the dose of mCPP or DOI administered before the session. Filled symbols represent ethanol-maintained responding and open symbols represent food-maintained responding. Doses are plotted on a log scale.

Figure 3

Effects of morphine (A and B) and naltrexone (C and D) on responding maintained by food or ethanol under the multiple (A and C) and concurrent (B and D) schedules. Grey points in the left panels represent effects following naltrexone pretreatment followed 5 min later by morphine treatment see text for details. Points represent the mean ± SEM for n = 8 rats in the multiple schedule and n = 6 rats in the concurrent schedule, expressed as a % of responding following vehicle for each rat. Plots illustrate the number of fixed ratios completed as a function of the dose of morphine, naltrexone or the combination of both administered before the session. Filled symbols represent ethanol-maintained responding and open symbols represent food-maintained responding. Doses are plotted on a log scale.

Figure 4

Effects of amphetamine on responding maintained by food or ethanol under the multiple (A) and concurrent (B) schedules. Points represent the mean ± SEM for n = 3 rats in the multiple schedule and n = 4 rats in the concurrent schedule, expressed as a % of responding following vehicle for each rat. Plots illustrate the number of fixed ratios completed as a function of the dose of amphetamine administered before the session. Filled symbols represent ethanol-maintained responding and open symbols represent food-maintained responding. Doses are plotted on a log scale.