seminars in THE NEUROSCIENCES, Vol 5, 1993 : pp 329-336 Amphetamine conditioned cue neurobiology of drug-seeking Norman M. White* and Noboru Hiroit preference and the This brief review draws a parallel between the drug-seeking behavior of humans addicted to amphetamine and the preference exhibited by animals for a place in which they have previously experienced the pharmacological effects of the same drug. Anatomical and pharmacological analyses suggest that nucleus accumbens dopamine receptor activation is necessary for the development of this preference. Through connections that synapse in ventral pallidum, a neural representation of accumbens dopamine receptor activation may reach the lateral nucleus of the amygdala where it could become associated with representations of existing environmental cues that also reach the lateral nucleus from cerebral cortex. When these conditioned cues are encountered on future occasions, activation of the amygdala-based association may reach either nucleus accumbens or ventral tegmental area. This neural activation either produces an excess of accumbens dopamine release or acts in synergy with a tonic level of dopamine release to cause the animal to approach and maintain contact with the conditioned cues. Key words: nucleus accumbens/amygdala/ventral pallidum/amphetamine/dopamine/reward/drug addiction THE INFLUENCE OF drugs on human behavior has been characterized using terms such as 'addiction', 'dependence' and 'craving', among others. 1,2 These terms represent variously useful attempts to character- ize the influence of drugs on human behavior and the human experience of this phenomenon. Although there are undoubtedly many factors that influence human drug taking, including those in the social and cognitive realms, there is also clearly a biological component to the influence that certain drugs have on behavior. This influence manifests itself after the first contact with a drug and results from its pharmacological action on neural substrates that From the *Department of Psychology, McGiU University, 1205 Dr Penfield Avenue, Montreal, PQ H3A 1B1, Canada and the ~Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA @1993 Academic Press Ltd 1044-5 765/93/050329 + 0858. 00/0 control changes in behavior. An analysis using animals of how drugs alter behavior by acting on these substrates may provide insights into the actions that these drugs have on human behavior. Amphetamine is representative of a class of drugs (psychomotor stimulants) that are self-administered by both humans and animals. 3'4 Several experimental paradigms have been used to study the neuro- biological basis of the behavioral change produced by amphetamine. One that may model an important aspect of the behavior-altering action of amphetamine is the so-called, conditioned place preference, 5 perhaps more accurately labelled the conditioned cue p@rence (CCP). 6 In this paper we review some recent data on the neurobiology of the CCP produced by amphetamine and examine its implications for understanding how amphetamine alters behavior. The conditioned cue preference The CCP paradigm generally makes use of an apparatus consisting of three distinguishable environ- ments that are connected to each other in a way that permits rats to move freely among them. Usually two of the environments are large boxes or areas connected by a third smaller box or area. Different sets of explicit cues are provided in the large boxes (e.g. color, floor texture, smell) to ensure that they are discriminable. The apparatus is tested by placing naive animals in the smaller box, allowing them free access to the entire environment, and recording the amounts of time they choose to spend in each of the large boxes. Although individual animals may exhibit a preference for one or the other of the large boxes, on a group basis there should be no difference in the animals' preferences for either of them. To examine the effect of drugs in this paradigm animals are confined for short periods (usually 30 min) in each of the large boxes on alternate days. Each animal receives the drug of interest before being placed into one of the boxes and a control treatment, usually the vehicle used to administer the drug, before being placed into the other box. Half of the animals in each experimental group receive the drug 329