Increased successive negative contrast in rats withdrawn from an escalating-dose schedule of d-amphetamine

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Abstract

The exposure of humans and animals to high doses of psychostimulant drugs, followed by their withdrawal, leads to a number of aversive psychological symptoms. These symptoms include increased anxiety and anhedonia, and may be manifested behaviorally as a decreased interest in normally rewarding stimuli. In the present study, we determine the effects of withdrawal from an escalating-dose schedule of d-amphetamine on the consumption of a 4% sucrose solution under normal conditions, and after an incentive downshift. The downshift was induced by subjecting animals to a consumatory negative contrast paradigm, by switching them from a familiar 32% sucrose solution to a novel 4% solution. In unshifted animals, there was no effect of d-amphetamine withdrawal on consumption of the 4% solution. In contrast, drug-withdrawn animals displayed an exaggerated negative contrast effect, primarily reflected as a delayed recovery from the downshift lasting for at least 60 h. This effect is interpreted as a consequence of the increased emotionality of withdrawn animals, and may be related to disruption of normal search behaviors.

Introduction

Both animals and humans are subject to the aversive affective states that arise from the discontinuation of high doses of psychostimulant drugs such as cocaine and d-amphetamine (Koob et al., 1997). Human drug abusers report dysphoric symptoms that include depression, psychomotor retardation and anxiety after excessive intake of drug American Psychiatric Association, 1995, Coffey et al., 2000, Gawin and Kleber, 1986, Gawin and Kleber, 1988, Gillin et al., 1994, Pathiraja et al., 1995. Animal paradigms have been developed that allow the objective measurement of these dysphoric states. For example, rodents that have self-administered binge-like doses of cocaine exhibit high levels of postdrug anxiety, as measured by increased acoustic startle and distressful ultrasonic vocalizations Barros and Miczek, 1996, Mutschler and Miczek, 1998. Similarly, animals given high doses of psychostimulants passively display increased anxiety during the postdrug withdrawal, when tested in tasks such as the elevated-plus maze and defensive burying Basso et al., 1999, Sarnyai et al., 1995.

Evidence for a state of anhedonia in drug-withdrawn animals has been determined with the refined use of rodent models of reinforcement. The decreased hedonic capacity of rodents that are in postdrug withdrawal has been well characterized by reductions in their responding for rewarding electrical brain stimulation Cassens et al., 1981, Kokkinidis et al., 1980, Leith and Barrett, 1976, Leith and Barrett, 1980, Lin et al., 1999, Markou and Koob, 1991, Wise and Munn, 1995. In our laboratory, we have recently shown that rats will exhibit reduced motivation to obtain natural reinforcers, including a sucrose solution and access to a sexually receptive conspecific, for up to 5 days after the termination of an escalating-dose schedule of d-amphetamine administration Barr and Phillips, 1999, Barr et al., 1999. These results indicate that postdrug withdrawal may be typified by a reduction in the motivation to respond for normally rewarding stimuli. What remains unknown, however, is how animals that are in a state of anhedonia will respond for a rewarding stimulus when its incentive properties are devalued unexpectedly.

In the successive negative contrast paradigm, animals are trained to receive reliably a reward of a consistent value. If this reward is unexpectedly substituted with one of lesser value, animals normally consume lower levels of the reward than subjects that continue to receive the lesser reward. This phenomenon, referred to as a “successive negative contrast,” has been widely demonstrated across different species, including rodents, primates and humans Flaherty, 1982, Flaherty, 1996, Grigson et al., 1994, Schnorr and Myers, 1967, Specht and Twining, 1999. Numerous explanations have been provided to account for the expression of successive negative contrast, many of which are based on the induction of negative affective states. Prominent among these affect-based theories are the development of emotional constructs such as disappointment and frustration Amsel, 1958, Crespi, 1942, Flaherty, 1982, Flaherty, 1996, as the animal fails to find the same reward expected on the basis of previous experience and instead finds one of a lesser value. These data are also consistent with the shift causing a decrease in the incentive salience of the lesser reward compared to its salience in unshifted animals (Berridge and Robinson, 1998), as “downshifted” animals not only consume less of the reward, but also decrease their running speed as they approach it Crespi, 1942, Flaherty, 1982.

Given that rodents exhibit a state of anxiety and anhedonia after withdrawal from psychostimulant drugs, we were interested in determining the effect of a further downshift in the incentive value of a stimulus by subjecting d-amphetamine-withdrawn rats to a successive negative contrast effect. Hypothetically, the adverse affective state that accompanies psychostimulant withdrawal should render animals especially sensitive to the emotionally disruptive effects of successive negative contrast, as two stressful situations would be experienced coincidentally. The purpose of the present experiment was therefore to determine the effects of withdrawal from a binge-like regimen of d-amphetamine on the consumption of a 4% sucrose solution in rats that had been downshifted from prior experience with a 32% sucrose solution.

Section snippets

Subjects

Thirty-two male Long–Evans rats (Charles River, Quebec), weighing 250–275 g at the beginning of the experiment, were housed individually in a temperature-regulated colony (21±1 °C) under a 12-h light–dark cycle (lights on at 0700 h); training and testing occurred during the light phase. All procedures were conducted in accordance with the Canadian Council on Animal Care guidelines for work with laboratory animals. Water was always available ad libitum in the home cage.

Apparatus

Subjects were trained and

Results

Prior to drug administration, all animals exhibited high rates of licking for either the 32% or the 4% sucrose solution. Analysis of the data during the 84-h period following drug termination with the repeated-measures ANOVA indicated a significant main effect of drug treatment, F(1,28)=7.31, P<.05, as animals that were shifted from the 32% to 4% solution after exposure to the escalating-dose regimen of d-amphetamine exhibited reduced consumption of the 4% sucrose solution, compared to

Discussion

In the present experiment, we have demonstrated that rats exhibit a greater consumatory negative contrast compared to control subjects when they are tested after withdrawal from an escalating-dose regimen of d-amphetamine. This effect was manifested initially as a marginally significant increase in the size of the contrast effect on the first day of exposure to the devalued sucrose solution. By the second day of exposure to the devalued stimulus, the magnitude of the contrast effect was

Acknowledgements

This research was made possible by a grant from CIHR to AGP.

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