Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission

Abstract

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats. It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%): (i) basal dopaminergic release and the release of dopamine induced by a depolarizing stimulus such as morphine (2 mg͞kg, s.c.), as measured in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine. The effects of adrenalectomy were glucocorticoid specific given that they were reversed by the administration of glucocorticoids at doses within the physiological range. Despite its profound diminution of dopaminergic neurotransmission, adrenalectomy neither modified the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or in the nucleus accumbens, as shown by tyrosine hydroxylase and glial fibrillary acidic protein immunostaining. In conclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral disturbances.The discovery of treatments reducing the activity of the central dopaminergic (DA) transmission is one of the main goals of neuroscience and pharmacological researches. Interest in dopamine has been sustained by the discovery that antipsychotic drugs (APD) were potent antagonists of the DA receptors (1). Decades of intensive research has considerably enlarged our knowledge about the functional role of DA neurons (2), suggesting that their hyperactivity may be involved in various behavioral pathologies, such as psychosis and addiction (3, 4). Nevertheless, antagonists of DA receptors are still the only class of drugs used in clinical practice to antagonize DA activity.There is evidence indicating that glucocorticoid hormones may be one of the factors determining a pathological hyperactivity of DA neurons. First, an increase in glucocorticoids can induce behavioral changes that are among those attributed to the enhancement of DA activity. For example, high levels of glucocorticoids can generate mood changes ranging from euphoria to psychosis in humans (5, 6), and increase the propensity to develop self-administration of drugs of abuse in animals (7). Second, administration of glucocorticoids increases extracellular concentrations of dopamine in vivo (8) and in vitro (9) and faci...

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

“…Thus it is unlikely that these contrasting effects on the HPA axis can be causative for the qualitatively similar effects of both our treatment regimens on the adult midbrain DA populations. Moreover, evidence suggests that although TH activity may be influenced by GCs, TH-IR cell counts in the SNc and VTA are not affected by adult adrenalectomy or GC treatment (Piazza et al, 1996b;Mizoguchi et al, 2004). The balance of evidence would thus favor a primary effect of dexamethasone on the developing neurons.…”

Chronic Stress Induces Impairment of Spatial Working Memory Because of Prefrontal Dopaminergic Dysfunction

“…Mesencephalic dopaminergic neurons have glucocorticoid receptors (Härfstrand et al, 1986), and the administration of glucocorticoids can modify DA metabolism (Versteeg et al, 1983;Rothschild et al, 1985) and increases the DA release in the PFC (Imperato et al, 1989). Conversely, suppression of endogenous glucocorticoids by adrenalectomy reduces the DA transmission in the nucleus accumbens under both basal and morphine-, a depolarizational agent, stimulative conditions with no change in the number of DA neurons in the VTA (Piazza et al, 1996). Adrenalectomy also reduces the DA transmission in the PFC (Mizoguchi, unpublished observations).…”

“…Immunohistochemistr y. On day 10 of recovery after a 4 week stress session, immunostaining for tyrosine hydroxylase (TH; tyrosine 3-monooxygenase; EC 1.14.16.2), the rate-limiting enzyme in catecholamine biosynthesis, was performed according to the method of Piazza et al (1996). Briefly, the animals were anesthetized with pentobarbital Na (45 mg / kg, i.p.)…”

Role of Endogenous Neurotensin in the Behavioral and Neuroendocrine Effects of Cocaine

“…Suppression of corticosterone secretion by adrenalectomy reduces the locomotor ) and reinforcing ) effects of cocaine, through a dopamine-dependent mechanism (Marinelli et al 1994;Piazza et al 1996). An interaction between glucocorticoids and NT in modulating the behavioral response to cocaine is suggested by the effects of this peptide on the HPA axis.…”