Neurobiological Correlates of Individual Differences in Novelty-Seeking Behavior in the Rat: Differential Expression of Stress-Related Molecules

It is well established that individual rats exhibit marked differences in behavioral responses to a novel environment. Rats that exhibit high rates of locomotor activity and sustained exploration in such an environment also exhibit high concentrations of stress-induced plasma corticosterone, linking this behavior to the stress system. Furthermore, these high-responding (HR) rats, in contrast to their low-responding (LR) counterparts, have a greater propensity to self-administer drugs. Thus, HR rats have been described as “novelty” seeking in that they are more active and explore novel stimuli more vigorously, despite the fact that this elicits in them high stress responses. In this study, we have further characterized the behavior of HR and LR rats in tests of anxiety and characterized their stress responses to either experimenter- or self-imposed stressors. We then investigated the physiological basis of these individual differences, focusing on stress-related molecules, including the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) in the context of the limbic–hypothalamo–pituitary adrenal axis. We have found that HR rats did not differ from LR in their basal expression of POMC in the pituitary. However, HR rats exhibited higher levels of CRH mRNA in the hypothalamic paraventricular nucleus but lower basal levels in the central nucleus of the amygdala. The basal expression of hippocampal MR is not different between HR and LR rats. Interestingly, the basal expression of hippocampal GR mRNA is significantly lower in HR than in LR rats. This low level of hippocampal GR expression in HR rats appears to be responsible, at least in part, for their decreased anxiety in exploring novelty. Indeed, the anxiety level of LR rats becomes similar to HR rats after the administration into the hippocampus of a GR antagonist, RU38486. These data indicate that basal differences in gene expression of key stress-related molecules may play an important role in determining individual differences in responsiveness to stress and novelty. They point to a new role of hippocampal GR, strongly implicating this receptor in determining individual differences in anxiety and novelty-seeking behavior.

[1]  F. Rougé-Pont,et al.  Individual differences in stress‐induced dopamine release in the nucleus accumbens are influenced by corticosterone , 1998, The European journal of neuroscience.

[2]  F. Holsboer,et al.  Age‐ and stimulus‐dependent changes in anxiety‐related behaviour of transgenic mice with GR dysfunction , 1998, Neuroreport.

[3]  J. Stewart,et al.  Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period , 1996, Psychopharmacology.

[4]  K. Miczek,et al.  Activational effects of social stress on IV cocaine self-administration in rats , 1996, Psychopharmacology.

[5]  C. Frye,et al.  Effects of paced and non-paced mating stimulation on plasma progesterone, 3α-diol and corticosterone , 1996, Psychoneuroendocrinology.

[6]  Y. Shaham,et al.  Relapse to heroin-seeking in rats under opioid maintenance: the effects of stress, heroin priming, and withdrawal , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  M. Dallman,et al.  The Neural Network that Regulates Energy Balance Is Responsive to Glucocorticoids and Insulin and Also Regulates HPA Axis Responsivity at a Site Proximal to CRF Neurons a , 1995, Annals of the New York Academy of Sciences.

[8]  P. Piazza,et al.  Social stress increases the acquisition of cocaine self-administration in male and female rats , 1995, Brain Research.

[9]  F. Holsboer,et al.  Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders. , 1995, Neuroendocrinology.

[10]  P. Kalivas,et al.  Individual locomotor response to novelty predicts selective alterations in D1 and D2 receptors and mRNAs , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  M. Le Moal,et al.  Corticosterone in the range of stress-induced levels possesses reinforcing properties: implications for sensation-seeking behaviors. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[12]  G. Koob,et al.  Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal , 1993, Brain Research.

[13]  M. Davis,et al.  Lesions of the central nucleus of the amygdala, but not the paraventricular nucleus of the hypothalamus, block the excitatory effects of corticotropin-releasing factor on the acoustic startle reflex , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  H. Anisman,et al.  Depression as a Consequence of Inadequate Neurochemical Adaptation in Response to Stressors , 1992, British Journal of Psychiatry.

[15]  J. B. Justice,et al.  Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine , 1991, Synapse.

[16]  P. Piazza,et al.  Hippocampal type I and type II corticosteroid receptor affinities are reduced in rats predisposed to develop amphetamine self-administration , 1991, Brain Research.

[17]  P. Piazza,et al.  Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration , 1990, Brain Research.

[18]  R. Sapolsky,et al.  Glucocorticoid feedback inhibition of adrenocorticotropic hormone secretagogue release. Relationship to corticosteroid receptor occupancy in various limbic sites. , 1990, Neuroendocrinology.

[19]  M. Zuckerman,et al.  The psychophysiology of sensation seeking. , 1990, Journal of personality.

[20]  M. Le Moal,et al.  Factors that predict individual vulnerability to amphetamine self-administration. , 1989, Science.

[21]  H. Akil,et al.  Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[22]  R. W. Kuhn,et al.  Pharmacological evidence that the inhibition of diurnal adrenocorticotropin secretion by corticosteroids is mediated via type I corticosterone-preferring receptors. , 1989, Endocrinology.

[23]  F. Bloom,et al.  Cellular and molecular mechanisms of drug dependence. , 1988, Science.

[24]  R. Wise,et al.  A psychomotor stimulant theory of addiction. , 1987, Psychological review.

[25]  B. McEwen,et al.  Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[26]  H. Eysenck,et al.  The comparative approach in personality study , 1984, Behavioral and Brain Sciences.

[27]  M. Zuckerman,et al.  Sensation seeking and psychopathology , 1979, Psychiatry Research.

[28]  J. Glowinski,et al.  Selective activation of the mesocortical DA system by stress , 1976, Nature.

[29]  R. Spencer,et al.  Evidence for Mineralocorticoid Receptor Facilitation of Glucocorticoid Receptor-Dependent Regulation of Hypothalamic-Pituitary-Adrenal Axis Activity * , 1998 .

[30]  M. Le Moal,et al.  Novelty-seeking in rats--biobehavioral characteristics and possible relationship with the sensation-seeking trait in man. , 1996, Neuropsychobiology.

[31]  G F Koob,et al.  The role of corticotropin-releasing factor in behavioural responses to stress. , 1993, Ciba Foundation symposium.