Véronique Deroche

Stress-induced sensitization to amphetamine and morphine psychomotor effects depend on stress-induced corticosterone secretion.

Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.

Individual differences in stress-induced dopamine release in the nucleus accumbens are influenced by corticosterone.

Stressful experiences, glucocorticoids hormones and dopaminergic neurons seems to interact in determining a higher propensity to develop drug abuse. In this report, we studied the acute interaction between these three factors. For this purpose, we compared stress‐induced dopamine release in intact rats and in rats in which stress‐induced corticosterone secretion was experimentally blocked. Ten‐minute tail‐pinch was used as a stressor and dopamine release estimated in the nucleus accumbens by using the microdialysis technique. Individual differences were also taken into account by comparing rats identified as either predisposed (HRs) or resistant (LRs) to develop self‐administration of drugs of abuse, on the basis of their locomotor response to novelty. It was found that suppression of stress‐induced corticosterone secretion significantly decreased stress‐induced dopamine release. However, such an effect greatly differed between HR and LR rats. When corticosterone secretion was intact HR animals had a higher and longer dopamine release in response to stress than LRs. The blockade of stress‐induced corticosterone secretion selectively reduced the dopaminergic response of HRs that did not differ from LRs anymore. These findings strength the idea that glucocorticoids could be involved in determining propensity to develop drug self‐administration. In particular, these hormones could play a role in determining the higher dopaminergic activity that characterizes drug proned individuals.

Cocaine self‐administration increases the incentive motivational properties of the drug in rats

A progressive increase in the frequency and intensity of drug use is one of the major behavioural phenomena characterizing the development of addiction. The nature of the drug‐induced adaptations involved in this escalating drug intake remains unknown. Some theories propose that this escalation is due to a progressive decrease (tolerance) in the reinforcing or incentive effects of the drug. Alternative views posit that with chronic use the reinforcing or incentive effects of drugs increase, by a sensitization or a learning mechanism. In this report, we address the question of whether escalating cocaine intake is paralleled by an increase or a decrease in the reinforcing and incentive effects of the drug. Using the experimental model of intravenous drug self‐administration with a within‐session dose–response paradigm, we first studied the course of cocaine intake over 14 sessions in rats. After acquisition of cocaine self‐administration, cocaine intake progressively increased at each dose tested. Then rats, previously allowed to self‐administer cocaine during either six or 29 sessions, were compared in three different tests of the incentive and reinforcing effects of cocaine: cocaine‐induced reinstatement of self‐administration, cocaine‐induced runway and cocaine‐induced place conditioning. As compared with rats briefly exposed to cocaine self‐administration (six sessions), rats with the longer experience (29 sessions) exhibited a higher intake of cocaine paralleled by a higher responsiveness in the cocaine‐induced reinstatement and runway tests. Both groups of rats were similarly sensitive to the rewarding effects of the drug as evaluated by the threshold dose of cocaine inducing place conditioning. Our results demonstrate that escalating cocaine intake is paralleled by an increase in the motivational properties of the drug in the absence of apparent signs of tolerance to the reinforcing or incentive effects of cocaine.

Individual differences in the psychomotor effects of morphine are predicted by reactivity to novelty and influenced by corticosterone secretion.

Clinical observations show that individual vulnerability to the reinforcing properties of drugs plays an important part in the subsequent development of addition. In animals, individual vulnerability to psychostimulants has been found to be predicted by their locomotor response to novelty as well as their corticosterone response. Rats with a high locomotor response to novelty (High Responders or HR) relative to Low Responders (LR), show a higher sensitivity to both the psychomotor and reinforcing effects of psychostimulants and a longer lasting corticosterone secretion in response to stress. In this study, we addressed two main questions. First, does the locomotor response to novelty also predict the psychomotor effects of morphine? Second, do differences in corticosterone secretion underlie individual differences in the stimulant effects of morphine? We compared the locomotor response to morphine (2 mg/kg s.c.) in: (i) HR and LR rats with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) HR and LR rats in which stress-induced corticosterone secretion was suppressed by adrenalectomy but basal levels of corticosterone were maintained by implantation of subcutaneous corticosterone pellets. In animals with an intact HPA axis, HR rats showed a higher locomotor response than did LRs to morphine. In animals in which corticosterone secretion was suppressed, the enhanced locomotor response of the HRs to morphine fell to that observed in the LRs. In conclusion our data show that, (1) individual reactivity to novelty can predict individual vulnerability to the psychomotor effects of opioids, and (2) stress-induced corticosterone secretion may play a role in determining individual differences in sensitivity to these drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

What juxtaposition, tradition and parsimony can do to vertical shifts in drug self-administration dose–response functions

In their Letter to the Editor, Zernig et al. (2003) analyzed the possible origins of the escalation of drug use observed in drug addicts. Two alternative interpretations of this phenomenon are confronted: tolerance and sensitization of drug reinforcing effects. The major message of Zernig et al. is that a “parsimonious interpretation” of the experimental literature “in accordance with the traditional clinical description” indicates “tolerance as a major factor in drug dependence.” The letter of Zernig et al. is affected by three major problems: (1) a series of sequential logic flaws that makes their demonstration not convincing, (2) a love for tradition so strong that brings the authors to support outdated ideas, (3) a so parsimonious vision of the literature that it appears unbalanced and self-serving. In our reply, we will first analyze each of these three affections from the letter of Zernig et al.. Then, we will provide an alternative interpretation of the role played by tolerance and sensitization in determining escalation of drug use.