Corticosterone levels determine individual vulnerability to amphetamine self-administration.

Abstract

Individual vulnerability to the reinforcing properties of drugs appears to be an essential characteristic predisposing humans to addiction. In animals, a greater behavioral reactivity to a mild stress, such as exposure to a novel environment, is an index of the vulnerability to acquire amphetamine self-administration. Biological responses to stress as well as behavioral reactivity may predict such a vulnerability. In the present study, rats with a longer duration of corticosterone secretion after exposure to novelty showed facilitation of acquisition of amphetamine self-administration. Furthermore, corticosterone administration in nonpredisposed individuals increased the reinforcing value of the drug and facilitated the acquisition of amphetamine self-administration. These results indicate that the stress-related activity of the hypothalamicpituitary-adrenal axis may play a role in the pathogenesis of psychostimulant addiction.Individual differences to the reinforcing effects of the drugs (1) are considered by clinicians to be central to the etiology ofaddiction (2, 3). However, this aspect ofaddiction has been largely neglected in experimental studies using intravenous self-administration (SA) as a model ofdrug-taking behavior in animals. Nevertheless, when SA is studied during the period of acquisition and low doses of drug are used, individual differences to the drug's reinforcing effects are readily observed (4, 5). The ability to predict individual vulnerability and select populations of rats with different risks for developing drug SA may represent a valuable methodology for investigation of the biological basis of predisposition to drug-seeking behavior.Recently, it has been reported (6) that a predisposition to develop amphetamine SA in animals may be predicted by the behavioral reactivity of the individual animal to exposure to a novel environment. Thus, rats with an higher noveltyinduced locomotor activity readily acquired amphetamine SA, whereas rats with the lower response did not. These results prompted a search for the biological substrate of SA vulnerability in the activity of the hypothalamic-pituitaryadrenal (HPA) axis, such as the secretion of corticosterone during stress. This choice was based on three main observations. First, corticosteroids are central to the control ofthe homeostatic disturbances induced by environmental stimulations and stress (7-9). Second, this hormone modifies the activity of the central nervous system (10-13). Third, dopaminergic (DA) neurons, whose activity influences SA behavior (14-15), have corticosterone receptors on the cell bodies (16).This study addressed two specific questions. (i) Could corticosterone secretion during stress predict amphetamine SA vulnerability? (ii) Could corticosterone levels modify individual sensitivity to amphetamine? To explore these questions, the secretion of corticosterone after exposure to novelty was measured in rats tested for sensitivity to amphetamine SA, and the effects of an experimentally induced increase of corticos...

Prenatal stress does not alter innate novelty-seeking behavioral traits, but differentially affects individual differences in neuroendocrine stress responsivity

“…Other studies suggest that an optimal level of glucocorticoids may promote certain behaviors, including locomotor activity (Galina et al, 1983) and psychostimulant self-administration (Goeders and Guerin, 1996). Work by Piazza , Piazza et al, 1991a as well as our group (Kabbaj et al, 2000) clearly demonstrates that HR-LR animals exhibit distinct neuroendocrine reactivity, and such differences may set the stage for these animals to react differently when confronted with chronic stress. While non-stressed HRs may exhibit optimal glucocorticoid levels that favor exploration in a novel environment, chronic stress elevates basal corticosterone levels, potentially exceeding this optimal range and thereby inhibiting HRs' behavior.…”

“…When exposed to a novelty, some rats (High Responders, HR) vigorously explore the new environment, while others (Low Responders, LR), are inhibited and exhibit very little activity. HR-LR rats exhibit a variety of other interesting behavioral differences, including differences in anxiety-like behavior (Kabbaj et al, 2000, aggression (Abraham et al, 2006), stress responsiveness , Piazza et al, 1991a, Piazza et al, 1993, Kabbaj et al, 2000, and willingness to self-administer psychostimulants , Kabbaj et al, 2001. For example, HR animals show reduced anxiety-like behavior across multiple tests, including the elevated plus maze, light dark box, and open field test, compared to LRs (Kabbaj et al, 2000, Mallo et al, 2007, White et al, 2007, although prior benzodiazepine treatment eliminates these differences .…”

Drug Addiction, Dysregulation of Reward, and Allostasis

“…In addition, the hormone secretion lasts longer in HRs. Finally, the levels of the stress hormone before drug administration are correlated positively with the extent of self-administration (Goeders and Guerin 1994;Piazza et al 1991a). In summary, a vulnerable phenotype, whatever the origin, inherent and/or acquired through life experience, implies intersystemic and interrelated changes at central and peripheral levels with new drug reward set points.…”

“…A now classic operational design to identify individual differences is to differentiate animals on the basis of their reactivity to a stressful event (for instance their locomotor reactivity to novelty) and divide them into high reactive (HR) and low reactive (LR). The propensity of HRs to develop drug intake, compared to LRs, has been correlated with other drug-dependent responses, administered either peripherally or centrally within the mesolimbic region (Exner and Clark 1993; Hooks et al 1991Hooks et al , 1992aPiazza et al 1989Piazza et al , 1991a. HR rats, independent of drug administration, show an increase of dopamine utilization in the nucleus accumbens and a decrease in the prefrontal cortex (Piazza et al 1991b), a lower number of dopamine D2 receptors and an opposite change in D1 receptor binding (Hooks et al 1994b).…”

Increased impulsive behavior and risk proneness following lentivirus-mediated dopamine transporter over-expression in rats' nucleus accumbens

“…Interestingly, elevated inter-individual variability appeared in all groups, with huge standard errors, suggesting that distinct sub-populations may exist (Piazza et al, 1991), thus increasing the risk of missing to detect group differences. This variability is also shown by slope values (Fig.…”