Enhanced motivation to self-administer cocaine is predicted by self-grooming behaviour and relates to dopamine release in the rat medial prefrontal cortex and amygdala Judith R. Homberg, Margot van den Akker, Halfdan S. Raasù, George Wardeh, Rob Binnekade, Anton N. M. Schoffelmeer and Taco J. de Vries Graduate School Neuroscience Amsterdam, Research Institute Neurosciences Vrije Universiteit, Drug Abuse Program, Department of Medical Pharmacology, VU Medical Center, Van Der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands Keywords: anxiety, individual differences, progressive ratio, stress Abstract Rats, like humans, show strong individual differences in their response to anxiogenic and stressful stimuli. In the present study we evaluated whether differences in stress-induced self-grooming behaviour may predict an individual's vulnerability to engage in drug self-administration behaviour. From a population of Wistar rats, the lower and upper quartile with respect to time spent self- grooming on an elevated plus maze (EPM) were selected and trained to intravenously self-administer cocaine under ®xed and progressive ratio schedules of reinforcement. High grooming (HG) rats reached considerably higher breakpoints than low grooming (LG) rats but showed no differences in acquisition rate and dose±response relationships. Further, EPM exposure elicited higher anxiety levels and enhanced plasma corticosterone secretion in HG rats. In addition, HG rats did not display enhanced novelty-seeking and still spent more time self-grooming during an EPM re-test following the cocaine self-administration procedure, indicating that stress-induced self-grooming is a stable behavioural trait marker. Neurochemically, electrically evoked [ 3 H]dopamine release in vitro was profoundly lower in brain slices from the substantia nigra, medial prefrontal cortex and amygdala of naive HG rats as compared to LG rats, whereas no differences were found in the nucleus accumbens shell and core, the ventral tegmental area and caudate putamen. In conclusion, stress-induced self-grooming speci®cally predicts enhanced motivation to self-administer cocaine rather than sensitivity to its reinforcing effects. Responsiveness of dopaminergic nerve terminals in the medial prefrontal cortex and amygdala may represent pre-existing underlying factors. Introduction One of the most intriguing issues in drug addiction research is the high individual variability in vulnerability to drug abuse (O'Brien et al., 1986). The neurobiological basis of this individual vulnerabil- ity is crucial for our understanding of the pathogenesis of this psychiatric disorder. It has been suggested that individual differences in vulnerability to drug addiction may be predicted by an enhanced response to `novelty', which could be related to the human personality trait of `sensation seeking' (Zuckerman, 1996). Accordingly, it has been shown that high responders to novelty self-administer more amphetamine (Piazza et al., 1989, 1991a; Pierre & Vezina, 1997) or cocaine (Piazza et al. 2000) than low responders to novelty. Epidemiological studies indicated that besides the sensation-seeking trait, anxiety- and stress-related dis- orders often precede substance abuse (Merikangas et al., 1998). It has been proposed that anxiety-related disorders may represent some form of pre-existing psychopathology and that drugs are used as a coping strategy or to self-medicate (Altman et al., 1996). Relationships between anxiety and psychostimulant self-administration have been demonstrated in laboratory animals. For instance, electric footshock stress (Goeders & Guerin, 1994) and tail-pinch (Piazza et al., 1990) facilitated, while an anxiolytic agent (Goeders et al., 1989) and a corticotrophin-releasing hormone antagonist (Goeders & Guerin, 2000) decreased psychostimulant self-administration. However, to what extent individual differences in anxiety and/or stress respon- siveness can be considered as predisposing factors in psychostimulant abuse has received little attention so far. Rats show increased self-grooming behaviour in response to environmental changes. This behaviour is part of a dearousal process that may serve to restore the homeostatic status disturbed by anxiogenic and/or stressful stimuli (Jolles et al., 1979; Gispen & Isaacson, 1981; Kametani, 1988; Spruijt et al., 1992). Studies reporting that self-grooming is mediated by nigrostriatal and tegmento-accumbens dopaminergic systems (Spruijt et al., 1986) provide a link between stress-induced grooming and reward-related behaviour. To study the relationship between self-grooming and the motiv- ation to self-administer cocaine, the lower and upper quartiles of a population of Wistar rats displaying self-grooming behaviour during a 5-min elevated plus maze (EPM) exposure were selected and cocaine self-administration behaviour was analysed under a progres- sive ratio schedule of reinforcement. This operant measure is tailored Correspondence: Dr T. J. de Vries, as above. E-mail: tj.de_vries.pharm@med.vu.nl Received 21 December 2001, accepted 11 March 2002 doi:10.1046/j.1460-9568.2002.01976.x European Journal of Neuroscience, Vol. 15, pp. 1542±1550, 2002 ã Federation of European Neuroscience Societies