Locomotor Response to Psychostimulants

3.1.1. Acute Injection of Psychostimulants

Locomotor response to drugs is an interesting parameter, as it constitutes an unconditioned response to drugs that correlates well with drug self-administration (7). Studies on the role of corticosterone in drug-induced locomotor activity are consistent, showing a facilitatory effect of this hormone. This has been shown over a wide range of drug doses and with different methods of manipulating HPA activity.

Suppression of glucocorticoids by adrenalectomy reduces the psychomotor stimulant effects of cocaine (8) and amphetamine (9-11) These effects are corticosterone-depen-dent, as they are reversed by administration of corticosterone. Detailed dose-response studies have shown that adrenalectomy does not modify the locomotor response to low doses of cocaine, but decreases the response to higher doses; that is, adrenalectomy produces a vertical downward shift in the effects of psychostimulants, and decreases the maximal locomotor response to these drugs by approximately 50% (Fig. 1A). The decrease in drug effects caused by adrenalectomy is reversed by corticosterone replacement (a subcutaneous corticosterone pellet delivering constant basal levels of the hormone) in a dose-dependent manner (10,12), and the response to cocaine is fully restored when basal concentrations of corticosterone are reached (Fig. 1B).

The decrease in drug effects following adrenalectomy has been confirmed using pharmacological manipulations that reduce corticosterone levels. Thus, acute or repeated treatment with metyrapone, a corticosterone synthesis inhibitor, has been shown to decrease the locomotor response to cocaine (13,14, although see ref. 15).

Further confirmation that decreased drug responding after adrenalectomy or pharmacological blockade of corticosterone synthesis is truly due to suppression of circulating glucocorticoids comes from studies using corticosteroid receptor antagonists. These studies show that blockade of central corticosteroid receptors (both MRs and

Fig. 1. Glucocorticoids modulate the locomotor response to cocaine. (A) Suppression of corticosterone by adrenalectomy (ADX) decreases the maximal locomotor response to cocaine over a wide range of cocaine doses. (B) The effects of ADX are reversed dose-dependently by corticosterone replacement (subcutaneous implantation of corticosterone pellet; ADX + Cort). The response to cocaine (20 mg/kg, ip) is fully restored when animals receive a replacement treatment reproducing basal levels of corticosterone. (Modified from Marinelli et al. [12]).

Fig. 1. Glucocorticoids modulate the locomotor response to cocaine. (A) Suppression of corticosterone by adrenalectomy (ADX) decreases the maximal locomotor response to cocaine over a wide range of cocaine doses. (B) The effects of ADX are reversed dose-dependently by corticosterone replacement (subcutaneous implantation of corticosterone pellet; ADX + Cort). The response to cocaine (20 mg/kg, ip) is fully restored when animals receive a replacement treatment reproducing basal levels of corticosterone. (Modified from Marinelli et al. [12]).

GRs), by central administration of the MR antagonist spironolactone and of the GR antagonist RU 38486, also decreases the locomotor response to an injection of cocaine (12). This decrease is similar to that observed after adrenalectomy.

3.1.2. Repeated Injections of Psychostimulants

Repeated injections of psychostimulants produce an increase in their psychomotor effects, which is referred to as behavioral sensitization (for review, see ref. 16). Although suppression of glucocorticoids reduces the acute locomotor response to psychostimulants, its effect on repeated drug treatment is more controversial. For example, regarding amphetamine sensitization, Badiani and colleagues (9) have shown that although adrenalectomy attenuates the psychomotor effects of an acute injection of amphetamine, it does not prevent the development of sensitization to this drug. Rivet et al. (17), however, concluded that adrenalectomy does inhibit development of amphetamine sensitization. Regarding cocaine sensitization, Prasad et al. (18) reported that, similarly to amphetamine sensitization, adrenalectomy does not prevent behavioral sensitization tested at late withdrawal times. At early withdrawal times, however, different groups have shown that adrenalectomy does prevent the development of cocaine-induced sensitization (18,19). In these studies, adrenalectomy decreased sensitization only if it was performed before, but not after, the sensitizing paradigm. However, blockade of GRs by selective antagonists after sensitization has been shown to prevent the expression of amphetamine sensitization (20). These results illustrate the controversial role of glucocorticoids on drug-induced sensitization. One factor that could explain some of the discrepancies among different studies is the parameter used to measure sensitization. For example, the studies by both Badiani et al. and Rivet et al. (9,17) show a similar phenomenon: adrenalectomized rats, compared to controls, have a lower locomotor response to amphetamine during the first and last injections of the drug. However, both groups of rats show an increase in the psychomotor effects of the drug between the first and the last injections. Consequently, when a within-group comparison is performed, as in the case of Badiani et al., one concludes that sensitization is still present after adrenalectomy. Instead, if one compares, as in the case of Rivet et al., the response between groups, it could be concluded that sensitization is reduced.

Drugs of abuse, and in particular psychostimulants, induce an important increase in corticosterone secretion (for review, see ref. 21). However, this response does not seem to be involved in mediating the effects of glucocorticoids on the locomotor response to psychostimulants. Thus, animals with basal levels of corticosterone and that cannot secrete corticosterone in response to the drug challenge (i.e., adrenalectomized animals with corticosterone replacement treatments reproducing basal levels of the hormone) show a locomotor response to the drug that is similar to the one seen in control animals (8,12). This finding is consistent with the observation that there is no correlation between drug-induced locomotion and drug-induced corticosterone increase (22,23).

Finally, it is also noteworthy to specify that the reduction in drug effects induced by a decrease in glucocorticoids is not due to possible differences in the bioavailability of cocaine; thus cerebral concentrations of cocaine are not decreased in adrenalectomized animals, or in animals treated with metyrapone (12,14).

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