Nijmegen high and low responders to novelty: a new tool in the search after the neurobiology of drug abuse liability.

Knowledge about the differences in structure, function, and reactivity of the brain and body between Nijmegen high responders to novelty and Nijmegen low responders to novelty may help us to understand which factors give rise to the vulnerability and/or susceptibility to drugs of abuse. For that purpose, this contribution provides a short overview of the outcome of the available studies on Nijmegen high responders to novelty and Nijmegen low responders to novelty. These animals can be selected using three major behavioral paradigms: (a) the open-field test (which allows the separation of high and low responders to novelty); (n) the intruder test (which allows the separation of fleeing and nonfleeing rats); (c) the apomorphine test (which allows the separation of apomorphine-susceptible and apomorphine-unsusceptible rats). Data to date suggest that the same traits have been selected by all three paradigms, and point to the hypothesis that the neurochemical state of the nucleus accumbens directs the sensitivity to drugs of abuse. In addition, recent evidence suggests that the sensitivity to the psychostimulant and/or reinforcing effects of dexamphetamine and ethanol is smaller in HR than in LR under certain experimental conditions, whereas the reverse is found when different experimental conditions are chosen. The data all together lay the foundation for the overall hypothesis that there are three factors ultimately determining the individual-specific sensitivity to drug of abuse: (a) the genetic background that predisposes an individual to become a HR or a LR, (b) early postnatal factors that direct the phenotypic expression of a particular genotype at adult age, and (c) the degree of stress during exposure to the drug of abuse. Further testing of this hypothesis may provide important information about the factors that contribute to individual differences in vulnerability to drugs of abuse.