Memory Processes Governing Amphetamine-induced Psychomotor Sensitization

Memory Processes Governing Amphetamine-induced Psychomotor Sensitization Stephan G. Anagnostaras, Ph.D., Timothy Schallert, Ph.D., and Terry E. Robinson, Ph.D. We investigated how, under certain circumstances, the expression of psychomotor sensitization comes to be contextspecific. Rats that had previously sustained 6hydroxydopamine-induced unilateral dopamine depletion received repeated injections of d-amphetamine (AMPH) or saline in group-specific environments, and rotational behavior was measured as an index of psychomotor activation. Following these treatments some groups were given electroconvulsive shock (ECS), when memories of the drug experience were reactivated (and therefore vulnerable to disruption), in order to produce retrograde amnesia. Animals given an AMPH challenge in the environment in which they received drug treatments (Paired) expressed robust sensitization. Animals given an AMPH challenge in a context that was never paired with drug administration (Unpaired) did not express sensitization. A saline challenge in the AMPH paired context produced a conditioned rotational response (CR). ECS had no effect in Control animals, no effect on the expression of sensitization in Paired animals, and no effect on the expression of the CR in Paired animals. However, ECS did affect Unpaired groups: unlike Unpaired animals given sham ECS, Unpaired animals given ECS expressed robust sensitization. Thus, without ECS, the expression of sensitization must have been suppressed in the Unpaired animals (who had the same drug history as Paired animals), and ECS released this otherwise suppressed sensitization. Based on these and other findings, we propose that three memory mechanisms regulate context-specificity of AMPH sensitization: (1) Repeated drug administration induces sensitization of the neural substrate that mediates the unconditional response (UR) to the drug, a form of nonassociative learning; (2) An inhibitory process can block the expression of neural sensitization in contexts where the drug is not expected, a process we speculate may involve a form of inhibitory occasion-setting; (3) An excitatory conditioned response (CR) can amplify the sensitized response in a context where the drug is expected. It is suggested that the ability of drug-associated contexts to modulate the expression of neural sensitization via occasion-setting may combine with the ability of a drug-associated context to produce conditioned responses, together providing powerful associative control over not only behavioral sensitization, but in addicts, over craving and relapse. [Neuropsychopharmacology 26:703–715, 2002] © 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. From the Dept. of Psychology and Neuroscience Program, University of Michigan, Ann Arbor (SGA, TS, TER), and Dept. of Psychology and Center for Behavioral Neuroscience, Emory University, Atlanta, GA (SGA). Address correspondence to: Dr. Stephan Anagnostaras, Dept. of Psychology, Emory University, 532 N. Kilgo Circle, Atlanta, GA 30322, Tel.: (404) 727-4761, Fax: (404) 727-0372, E-mail: sanagno @emory.edu Received October 16, 2000; revised October 1, 2001; accepted October 9, 2001. Online publication: 10/30/01 at www.acnp.org/citations/ Npp103001197. KEY WORDS: Conditioning; Occasion-setting; Addiction; NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 6 © 2002 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Context Behavioral sensitization refers to a progressive and persistent increase in the psychomotor activating and rewarding effects of drugs, which is often seen when drugs of abuse are given repeatedly and intermittently (Segal et al. 1981; Robinson and Becker 1986). There is considerable interest in this phenomenon, both because it is a compelling example of experience-dependent 0893-133X/02/$–see front matter PII S0893-133X(01)00402-X 704 S.G Anagnostaras et al. plasticity (Robinson and Kolb 1997; Robinson and Becker 1986; Stewart and Badiani 1993; Pierce and Kalivas 1997), and because sensitization-related neuroplasticity in brain reward systems may contribute to addiction (Lett 1989; Piazza et al. 1989; Robinson and Berridge 1993, 2000). However, despite many studies on the neurobiology of sensitization the fundamental nature of the behavioral phenomenon is still poorly understood. By one view, behavioral sensitization is thought solely as the manifestation of cellular plasticity that occurs as a consequence of repeated exposure to drugs of abuse (Kuczenski et al. 1982; Robinson and Becker 1986). In behavioral terms, this neuroadaptationist model views sensitization as a progressive increase in the unconditional response (UR) to a drug, because of drug-induced changes in the neural substrates that mediate the UR. By this strict non-associative view, conditional stimuli (CS), such as contextual stimuli, should have little influence over the induction or expression of sensitization. There is, however, considerable evidence showing that under some circumstances behavioral sensitization can come under complete contextual control. For example, sensitization is often absent or reduced if animals are tested in an environment where they have not experienced the drug before, even following treatments that produce very robust sensitization (Anagnostaras and Robinson 1996; Stewart and Vezina 1991; Tilson and Rech 1973; Battisti et al. 2000; Carey and Gui 1998). This phenomenon has been called “context-specific sensitization”, and supports an associative view of sensitization, in which sensitization is considered an example of drug-context conditioning. By this view, when drug administration (the unconditional stimulus; US) is paired with placement into a distinct environmental context (the CS), contextual stimuli acquire the ability to elicit conditional responses (CR), including drug-like psychomotor effects (Pavlov 1927; Post et al. 1981; Stewart 1984; Carey 1986, 1988; Beninger and Hahn 1983; Drew and Glick 1987; Fontana et al. 1993; Tirelli and Terry 1998; Wolgin 2000). By this excitatory conditioning view, behavioral sensitization simply reflects the addition of an increasing CR to the unchanging UR produced by the drug (Tilson and Rech 1973; Hinson and Poulos 1981; Siegel et al. 1987). However, several findings are problematic for this conditioned excitation model of sensitization. First, the psychomotor CR observed (when saline is given in the context) is small, short-lasting, and does not account for the difference between the sensitized and naïve response to the drug (Anagnostaras and Robinson 1996; Badiani et al. 1995; Beninger and Hahn 1983; Carey 1986). Second, extinction of the CR by exposures to the context without the drug eliminates the CR, but only slightly reduces the sensitized response to an AMPH challenge (Anagnostaras and Robinson 1996; Battisti et NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. (...truncated)