Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission.

Abstract

An increase in the activity of mesencephalic dopaminergic neurons has been implicated in the appearance of pathological behaviors such as psychosis and drug abuse. Several observations suggest that glucocorticoids might contribute to such an increase in dopaminergic activity. The present experiments therefore analyzed the effects of corticosterone, the major glucocorticoid in the rat, both on dopamine release in the nucleus accumbens of freely moving animals by means of microdialysis, and on locomotor activity, a behavior dependent on accumbens dopamine. Given that glucocorticoids have certain state-dependent neuronal effects, their action on dopamine was studied in situations differing in dopaminergic tonus, including during the light and dark phases of the circadian cycle, during eating, and in groups of animals differing in their locomotor reactivity to novelty. Dopaminergic activity is increased in the dark period, further increased during food-intake, and is higher in rats defined as high responders to novelty than in low responders. Corticosterone, peripherally administered in a dose that approximates stress-induced plasma concentrations, increased extracellular concentrations of dopamine, and this increase was augmented in the dark phase, during eating, and in high responder rats. Corticosterone had little or no effects in the light phase and in low responder rats. Corticosterone also stimulated locomotor activity, an effect that paralleled the release of dopamine and was abolished by neurochemical (6-hydroxydopamine) depletion of accumbens dopamine. In conclusion, glucocorticoids have state-dependent stimulant effects on mesencephalic dopaminergic transmission, and an interaction between these two factors might be involved in the appearance of behavioral disturbances.It is generally admitted that an increase in the activity of the mesencephalic dopaminergic (DA) neurons is related to the appearance of pathological behaviors. The major antipsychotic drugs are antagonists of DA receptors (1) and prolonged use of psychotropic compounds known to increase DA activity can induce psychotic symptoms (2). Furthermore, an enhanced DA activity in the nucleus accumbens is associated with an increased vulnerability to develop drug self-administration in laboratory rats (3).Indirect observations suggest that glucocorticoids, the final product of the activation of the hypothalamus-pituitaryadrenal axis by stress, might be one factor capable of increasing the activity of mesencephalic DA neurons. DA neurons express corticosteroid receptors (4) and dopamine-mediated behaviors are profoundly facilitated by glucocorticoids (5). Furthermore, increased glucocorticoid levels can induce behavioral changes similar to those attributed to enhanced DA activity. In humans, high levels of glucocorticoids can induce mood changes ranging from euphoria to psychosis (6, 7). In animals, glucocorticoids, within the range of stressor-induced plasma concentrations, increase the propensity to develop self-administration of drugs of a...

Drug Addiction, Dysregulation of Reward, and Allostasis

“…Dopaminergic hyperresponsiveness in forebrain structures involved in regulation of motivation, such as the accumbens shell/ extended amygdala, is glucocorticoid-dependent (Barrot et al 2000), but this effect is state dependent in that it varies with nutritional status and arousal status (Piazza et al 1996b). In addition, high circulating levels of glucocorticoids can feedback to shut off the hypothalamic pituitary adrenal axis and can "sensitize" the CRF systems in the central nucleus of the amygdala known to be involved in behavioral responses to stressors (Lee et al 1994;Schulkin et al 1994;Shepard et al 2000).…”

The Size and Distribution of Midbrain Dopaminergic Populations are Permanently Altered by Perinatal Glucocorticoid Exposure in a Sex- Region- and Time-Specific Manner

“…It is known that physiological levels of GCs augment DA activity in the striatum (Piazza et al, 1996a) and evidence suggests that perinatal exposure to synthetic GCs alters the responsiveness of the adult HPA axis (Weinstock, 2001;Owen et al, 2005). It should therefore be considered whether the effects of perinatal GC exposure could be secondary to changes in the prevailing adult levels of the adrenal steroid.…”

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

“…The decrease in GR levels in brain structures involved in a feedback inhibition mechanism, that is, inhibition of CRH synthesis and secretion from the hypothalamus, may cause HPA hyperactivity. Furthermore, it has been shown that high levels of glucocorticoids can induce psychosis in humans (Bloch et al, 1994;Ling et al, 1981), and enhance extracellular concentrations of dopamine and dopaminedependent behaviors in animals (Marinelli et al, 1994(Marinelli et al, , 1997Piazza et al, 1996). Besides exacerbation of dopaminergic system activity, glucocorticoids are known to enhance neurodegenerative processes, which along with changes in monoamine systems are likely responsible for the development of schizophrenia (McEwen and Magarinos, 2001).…”