Psychopharmacology (1991) 103:455-461 003331589t 0005t K Psychopharmacology © Springer-Verlag 1991 Animal model for investigating the anxiogenic effects of self-administered cocaine Aaron Ettenberg and Timothy D. Geist Behavioral PharmacologyLaboratory, Department of Psychology, Universityof California, Santa Barbara, CA 93106, USA Received April 30, 1990 / Final version July 30, 1990 Abstract, Male albino rats were trained to traverse a straight alley for a reward of five intravenous injections of cocaine (0.75 mg/kg/injection in a volume of 0.1 ml/ injection delivered over 4 s). Animals were tested one trial per day with the following dependent measures assessed on each trial: start latency, running time, the number of retreats, and the location within the alley where each retreat occurred. While start latencies remained short and stable, running times tended to increase over days. This effect was apparently related to a concomitant in- crease in the number of retreats occurring in the alley (r= 0.896). Retreats tended to occur in very close prox- imity to the goal box, suggesting that animals working for IV cocaine come to exhibit a form of conflict behavior (i.e., retreats) putatively stemming from the drug's well documented rewarding and anxiogenic properties. Con- sistent with this hypothesis was the demonstration that diazepam (0.5, 1.0, 2.0 mg/kg IP) pretreatment dose- dependently reduced the incidence of retreat behaviors in the alley. In addition, the rewarding efficacy of the co- caine dosing parameters was subsequently confirmed in the runway subjects by conditioned place preference. The present paradigm, therefore, provides a useful method for investigating the anxiogenic effects of self-adminis- tered cocaine in laboratory animals. Key words: Cocaine - Stimulant-induced anxiety - Con- flict behavior - Drug reward - Diazepam - Self- administration Human users of cocaine report euphoria to be the domi- nant initial experience of drug self-administration (e.g., Gawin and Ellinwood 1989), typically followed by a negative affective state characterized by anxiety depress- ion, fatigue and cravings for more cocaine (e.g., Nikolic et al. 1984; Resnick and Resnick 1984; Spotts and Shontz 1984; Washton and Gold 1984; Smith 1986). Offprint requests to: A. Ettenberg While the euphoric effects reportedly remain stable over time, the aversive actions of cocaine appear to increase with repeated drug exposure such that chronic use of cocaine is now thought to precipitate the development of a variety ofanxiogenic states (e.g., see review by Anthony et al. 1989). The relationship between cocaine and anxi- ety is further suggested by recent animal work that has demonstrated cocaine-induced changes in brain ben- zodiazepine receptors (Goeders et al. 1987) and increased secretion of adrenocorticotropin (ACTH) and cortico- tropin-releasing factor (CRF) (Moldow and Fischman 1987; Rivier and Vale 1987). In behavioral studies with rodents, cocaine has been observed to decrease punished responding in a conflict test (Fontana and Commissaris 1989) and to potentiate animals' avoidance of an in- herently aversive environment (Costall et al. 1989). Together, these studies provide clinical, behavioral and neurochemical evidence consistent with the view that cocaine administration can have profound anxiogenic consequences in addition to its well reported euphoric properties. The present study describes an animal self- administration model that is particularly sensitive to the putative anxiogenic properties of cocaine. Animals were trained to traverse a straight-arm runway once each day for a reward of intravenous cocaine delivered automati- cally upon the animal's entry into the goal box. We have previously been successful employing this type of runway methodology in psychopharmacological studies of food and water reinforcement (Ettenberg and Camp 1986a, b; Horvitz and Ettenberg 1988). With natural reinforcers, animals typically run with increasing speed over the course of a couple of weeks of daily testing. However, in our preliminary work with cocaine reward, we unexpect- edly observed a progressive increase in the time it took subjects to enter the goal box across days. This occurred despite the fact that the subjects continued to leave the start box with normal response latencies. Upon closer observation of the animals within the runway, it ap- peared that the elevated goal-entry times were a result of a "stop and retreat" behavior rather than a simple slow-