Addictive behaviour in experimental animals: prospects for translation

Abstract

Since the introduction of intravenous drug self-administration methodology over 50 years ago, experimental investigation of addictive behaviour has delivered an enormous body of data on the neural, psychological and molecular mechanisms of drug reward and reinforcement and the neuroadaptations to chronic use. Whether or not these behavioural and molecular studies are viewed as modelling the underpinnings of addiction in humans, the discussion presented here highlights two areas-the impact of drug-associated conditioned stimuli-or drug cues-on drug seeking and relapse, and compulsive cocaine seeking. The degree to which these findings translate to the clinical state of addiction is considered in terms of the underlying neural circuitry and also the ways in which this understanding has helped develop new treatments for addiction. The psychological and neural mechanisms underlying drug memory reconsolidation and extinction established in animal experiments show particular promise in delivering new treatments for relapse prevention to the clinic.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Keywords: addiction; compulsion; extinction; habits; memory; reconsolidation.

Figure 1.

The effects of drug CSs acting as conditioned reinforcers on cocaine, heroin and alcohol seeking. (a–c) Drug-seeking instrumental responses during a fixed interval of 15 min (open columns on the left of each panel) and the impact of presenting drug-associated CSs response-contingently, i.e. as conditioned reinforcers (shaded bars) over several sessions of daily testing. Introduction of the CS (in the second-order schedule of reinforcement) results in a marked increase in the vigour of seeking responses for cocaine (a), heroin (b) and alcohol (c). These effects are prior to the first drug infusion and, therefore, measure the seeking of the drug and not the effects of drug on instrumental behaviour or conditioned reinforcement. Omitting presentations of the CS results in a marked decrease in responding (open columns on the right). Data are mean + s.e.m. of responses/fixed interval 15 min in the presence (coloured bars) or absence (white bars) of drug CS presentation. (Online version in colour.)

Figure 2.

The µ-opioid receptor antagonist, GSK1521498, decreased cocaine, heroin and alcohol seeking under second-order schedules of reinforcement and on voluntary alcohol consumption. The highly selective µ-opioid receptor antagonist, GSK1521498, was effective in reducing cocaine (in a), heroin (b) or alcohol (c(i)) seeking in rats responding for these drugs under second-order schedules. GSK1521498 also reduced alcohol intake (c(ii)) during the 20 min drinking period earned by prior alcohol-seeking responses reinforced by the alcohol-associated CS during the prior 15 min fixed interval. Data are mean + s.e.m. seeking responses/fixed interval 15 min; alcohol intake is expressed as grams per kilogram body weight. GSK1521498 was given at three different doses (0.1, 1, 3 mg kg⁻¹) and injected intraperitoneally (IP) 20 min before session. (Online version in colour.)

Figure 3.

Persistent compulsive alcohol-seeking phenotype in rats with a preference for alcohol (P rats) and its reduction by µ-opioid antagonism. (a) Rats were trained on a seeking–taking chained task to respond for alcohol, and when a stable baseline was established, seeking responses were punished probabilistically by mild electric foot-shocks of increasing intensity, from 0.25 to 0.30, 0.35, 0.40 mA, before stabilizing at 0.45 mA for six consecutive daily sessions. The arrow indicates the first session with a 0.45 mA foot-shock. Based on the persistence of alcohol seeking during the last three punishment sessions, measured as the number of completed seeking–taking cycles, a cluster analysis enabled the segregation of subgroups of rats: compulsive (C, in black), in which behaviour persisted despite unpredictable adverse outcomes (i.e. foot-shock punishment), and non-compulsive (NC, in grey), which ceased seeking under punishment and ‘abstained’. (b) Compulsive (in black, on the left) and non-compulsive (in grey, on the right) rats were tested under extinction (no reward was available) on the seeking lever only. Alcohol-seeking responses were greatly decreased, especially in compulsive rats, by systemic administration of the selective µ-opioid receptor antagonist GSK1521498. Data are mean seeking lever responses + s.e.m.); GSK1521498 was administered at the dose of 1 mg kg⁻¹, intraperitoneally 20 min before session. White bars, black and grey bordered bars represent the seeking responses in vehicle-injected, compulsive and non-compulsive rats, respectively. Black and grey bars represent the seeking responses in GSK1521498-treated compulsive and non-compulsive rats, respectively.