Glucocorticoids and the Dopamine System

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Here we will review several observations suggesting that glucocorticoid hormones could facilitate drug-related behaviors by acting on the dopamine system.

5.2.1. Glucocorticoids and Dopamine-Dependent Responses to Drugs

The first evidence of dopamine involvement in the interaction between glucocorti-coids and psychostimulants probably comes from studies investigating changes in behavioral effects of centrally injected psychostimulants. Thus, the locomotor response induced by the injection of psychostimulants in the NAc is dopamine-dependent (126,127). It was shown that the locomotor response to intra-NAc cocaine is decreased by suppressing glucocorticoid hormones (8) and reestablished by restoring basal levels of the hormone. In addition, this response is also modulated by glucocorticoids in stress conditions. In food-restricted animals, blockade of stress-induced increase in corticos-terone (by adrenalectomy and replacement of basal levels of corticosterone) prevents the stress-induced increase in locomotor activity following intra-NAc amphetamine. These effects are reversed by reproducing stress levels of the hormone (128).

5.2.2. Glucocorticoids and Dopamine Transmission in the NAc

As noted above, glucocorticoids facilitate dopamine-dependent behaviors. Several studies tried to determine whether these hormones act by modulating dopamine transmission in the NAc. The effects of both suppression and enhancement of corticosterone have been examined using in vivo microdialysis and expression of Fos-related proteins.

Suppression of glucocorticoids by adrenalectomy reduces extracellular concentrations of dopamine in the NAc, both in basal conditions and in response to psychostimulants (129,130). These effects are corticosterone-dependent, as they are reversed by corticosterone replacement. Interestingly, glucocorticoids have a specificity of action in the NAc. Thus, as Fig. 5 shows, adrenalectomy selectively and dramatically (over 50%) decreases dopamine in the shell of the NAc, without modifying dopamine concentrations in the core (129). The reduction in NAc shell dopamine following adrenalectomy has been observed for basal levels of dopamine, as well as for dopamine increases following cocaine or stress (129). Detailed studies of the role of MRs and GRs in these effects have proposed a role for GRs. Thus, the administration of the MR antagonist spironolactone does not modify extracellular levels of dopamine, whereas the administration of GR receptor antagonist RU 38486 or RU 39305 dose-dependently decreases basal levels of dopamine in the shell of the NAc (131). These effects are very similar to those produced by adrenalectomy, as these antagonists reduce the basal levels of dopamine by more than 50%.

The decrease in dopamine levels in the NAc shell following glucocorticoid suppression is also translated postsynaptically. Thus, in adrenalectomized animals, Fos expression, an index of cellular activation that depends mainly on dopamine D1 receptor

Fig. 5. Glucocorticoids selectively modulate dopamine concentrations in the shell of the NAc. (A) Suppression of corticosterone by adrenalectomy (ADX) decreases dopamine concentrations in the shell of the NAc, both in basal conditions and in response to cocaine (15 mg/kg). These effects are reversed by administration of corticosterone (ADX + Cort). (B) Adrenalectomy does not modify dopamine concentrations in the core of the NAc. (Modified from Barrot et al. [129]).

Fig. 5. Glucocorticoids selectively modulate dopamine concentrations in the shell of the NAc. (A) Suppression of corticosterone by adrenalectomy (ADX) decreases dopamine concentrations in the shell of the NAc, both in basal conditions and in response to cocaine (15 mg/kg). These effects are reversed by administration of corticosterone (ADX + Cort). (B) Adrenalectomy does not modify dopamine concentrations in the core of the NAc. (Modified from Barrot et al. [129]).

activation (132,133), is also decreased in the shell of the NAc after administration of cocaine, whereas no changes are observed in the core (129). In other words, decreased levels of dopamine in the NAc shell following adrenalectomy produce decreased postsynaptic activation. On the other hand, adrenalectomized and sham controls show similar Fos activation in the shell in response to the D1 receptor agonist SKF 82958, suggesting that postsynaptic D1 receptors are functionally unaltered in this structure. Changes in NAc D1 receptors have, however, been reported following corticosterone manipulations. Thus, adrenalectomy decreases D1 receptors in the NAc (134), and this effect is reversed by administration of the GR agonist dexamethasone, suggesting, once again, a role for GRs. Furthermore, decrease in circulating corticosterone by administration of metyrapone, the corticosterone synthesis inhibitor, also decreases D1 receptor binding and mRNA in the NAc (135). Overall, these results indicate that glucocorticoids, through GRs, have a facilitatory action on dopamine transmission presynapti-cally, probably by modulating dopamine release, and that this effect results in reduced postsynaptic activity.

Studies on the effects of stress levels of corticosterone on NAc dopamine are more controversial. Thus, using in vivo microdialysis, Imperato and co-workers (109,110) found that adrenalectomy does not prevent stress-induced increase in NAc dopamine, and Reid et al. (15) reported that blockade of stress levels of corticosterone by treatment with metyrapone enhances amphetamine-induced dopamine release. Instead, we found that blockade of stress-induced corticosterone secretion by either adrenalectomy or metyrapone treatment prevents the increase in NAc dopamine induced by stress (71,136) (Fig. 3B). It is possible that the location of the microdialysis probe (core vs shell), which was not clearly determined in these studies, could explain these discrepancies.

Studies on dopamine levels following administration of corticosterone are also controversial. Using in vivo microdialysis, Imperato and co-workers (109,110) reported that corticosterone administration produces a modest increase in NAc dopamine, but these effects are only obtained with concentrations of corticosterone that are well above the physiological range observed during stress. Instead, voltammetry studies by Mittleman et al. (137) have found that dopamine release is increased following administration of stresslike levels of corticosterone.

The variability in the effects of glucocorticoids on NAc dopamine may be explained by possible state-dependent effects of these hormones. Thus, it has been shown that corticosterone administration increases NAc dopamine when it is administered during the dark phase, but not during the light phase, and these effects are greater in the dark phase if the hormone is administered just before eating (138). In addition, after administration of corticosterone, there is a greater increase in NAc dopamine in rats that spontaneously show higher dopamine release than in those with lower dopaminergic activity (136). In other words, it appears that corticosterone can only increase NAc dopamine if the hormone is administered in conditions in which the dopamine system is activated, such as during the dark phase (139), during food intake (140,141), or in animals with a spontaneously increased dopaminergic tone (105).

In conclusion, glucocorticoids, via GRs, modulate extracellular concentrations of dopamine in the NAc. These hormones specifically modulate dopamine transmission in the shell of the NAc, without influencing dopamine transmission in the core. In addition, the effects of glucocorticoids are state-dependent, and are greater when the dopamine system is activated. These observations suggest that glucocorticoid hormones could enhance drug responding by selectively facilitating dopamine transmission in the shell of the NAc.

5.2.3. Possible Mechanims Underlying the Effects of Glucocorticoids on NAc Dopamine

The mechanisms by which glucocorticoids facilitate dopamine transmission and increase NAc dopamine are unknown, but various hypotheses can be made on possible effects of glucocorticoids on dopamine metabolism, dopamine reuptake, and dopamine cell activity. It is still unclear whether these effects of glucocorticoids are direct or indirect, but the presence of glucocorticoid receptors in a subset of dopamine neurons (142) in the VTA suggests a possible direct action of glucocorticoid hormones on these cells. A strict relationship between glucocorticoids and dopamine neurons is also comforted by the observation that mesencephalic dopamine cell cultures respond to blockade of corticosteroid receptors by decreasing dopamine release in basal and stimulated conditions (143).

One possible action of glucocorticoids is modulation of dopamine synthesis and degradation. Thus, it has been shown that suppression of corticosterone by adrenalectomy decreases the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis (144). Conversely, administration of glucocorticoids increases TH activity in mouse brain (145), in the locus coeruleus (146), and in the VTA (147). However, total TH protein content in the midbrain was not modified by adrenalectomy in other studies (148). Regarding dopamine catabolism, it has been shown that hydrocortisone or the GR receptor agonist dexamethasone decreases the activity of monoamine oxidases (MAO) in vivo and in vitro, but have no effects on catechol-O-methyltransferase (COMT) (149-152). This is in agreement with the effects of glucocorticoids on the degradation products of MAO and COMT. Thus, treatment with dexamethasone decreases

DOPAC (the deamination product of dopamine by MAO), and increases 3MT (the O-methylated product of dopamine by COMT) (152,153).

It is also possible that glucocorticoids increase dopamine levels by blocking dopamine transporter sites, or that these hormones modulate the sensitivity or the number of dopamine transporter sites in dopamine terminal regions. For example, Gilad et al.

(154) have shown that dopamine reuptake is decreased in striatal synaptosomes incubated with methylprednisolone, a glucocorticoid analog. More recently, Sarnyai et al.

(155) reported that removal of corticosterone by adrenalectomy decreases the number of dopamine-binding sites in the shell of the NAc, without modulating those in the core. These effects depend on corticosterone, as they are reversed by replacing basal levels of corticosterone. In addition, these findings are consistent with the selective role of glucocorticoids in the shell of the NAc.

Finally, glucocorticoids could modulate dopamine transmission by acting on the impulse activity of dopamine cells. An increase in the impulse activity of dopam-ine cells, and in particular the bursting mode, is associated with increased dopam-ine release in dopamine terminal regions (156,157). Although there are only a few electrophysiological studies about the influence of glucocorticoids on the activity of midbrain dopamine cells, in vivo extracellular recordings by Overton and co-workers (158) have shown that glucocorticoids facilitate glutamate-induced bursting of midbrain dopamine cells. Thus, adrenalectomy reduces the activity of VTA dopamine cells when these cells are stimulated by iontophoretically administered glutamate, and corticos-terone administration reverses this effect. In addition, in vitro extracellular recordings by Cho and Little (159) also showed that corticosterone potentiates the response of dopamine cells to excitatory amino acid activation. Thus, corticosterone enhances NMDA-induced increase in dopamine cell impulse activity, but has no effects on spontaneous firing. Once again, these studies confirm the state-dependent effect of glucocorticoids on dopamine transmission. It is probable that the effects of glucocorticoids on the activity of dopamine cells are mediated by GRs, as in the work by Cho and Little (159) the effects of corticosterone were reversed by the GR antagonist RU 38486. Overton and co-workers, however, suggested an involvement of MRs (159), but in this study plasma levels of corticosterone were not measured, so it is possible that the dose of corticosterone used to reverse the effects of adrenalectomy was high enough to induce GR activation.

Corticosterone's facilitation of cell activity could also depend on intrinsic components of dopamine cells that modulate bursting activity, such as impulse-regulating somatodendritic receptors (160-166). These autoreceptors, primarily of the D2 subtype (164,167,168), are activated by somatodendritically released dopamine (169-171) and reduce neuronal activity by hyperpolarizing the cell by activating K+ channels, possibly G-protein inwardly rectifying potassium channels (GIRKs) (172-177). Other ion-gated channels, such as L-type Ca2+ channels and Ca2+-activated K+ channels, are also important modulators of dopamine cell impulse activity (178) and could also be involved (179). Although no studies have yet examined the mechanisms by which glucocorticoids could modulate the impulse activity of midbrain dopamine cells, we could speculate that glucocorticoids alter cell excitability by modifying these ion-gated channels, or even the intracellular signaling cascades, such as pertussis toxin-sensitive G proteins coupled to potassium channels. For example, in the hippocampus, it has been shown that low levels of glucocorticoids increase cell excitability, possibly by modify ing Ca2+ conductances, Ca2-activated K+ channels, and the binding of the Ca2+-calmodulin complex to cell membranes (180-189). In addition, in the hippocampus, these hormones are able to modulate GIRK protein levels (190) and could thus participate in regulating cell excitability. It is also possible that glucocorticoids modulate dopamine activity by acting on the density or function of impulse-regulating dopamine autoreceptors in the VTA; however, to our knowledge, no data are available on this possible action of glucocorticoids in the midbrain.

Whatever the mechanism by which glucocorticoids influence dopamine transmission and facilitate dopamine release in the NAc, their effect does not seem to be derived from an action on the integrity of the dopamine system. In fact, although suppression of glucocorticoids reduces dopamine transmission, this manipulation does not induce changes in dopamine cell death or gliosis. Thus, the number of cells immunostained with TH or with glial fibrillary acidic protein in the midbrain is similar between adrena-lectomized and control rats (130).

The above studies suggest that glucocorticoids could modulate dopamine activity by acting directly on dopamine neurons, but we cannot exclude that these hormones could modify dopamine transmission via indirect mechanisms. Glucocorticoids could influence, for example, glutamatergic, opioid, and GABAergic systems (5), which, in turn, are susceptible of modulating the activity of midbrain dopamine cells (for review, see ref. 191). Although we cannot exclude this effect, the hypothesis is rather improbable, as most of theses excitatory and inhibitory afferences to dopamine cells seem to implicate MRs (192), whereas many effects on dopamine activity have been shown to depend on GRs (193,194).

In summary, the mechanisms by which glucocorticoid hormones facilitate dopam-ine transmission could be diverse and could vary from direct actions on dopamine neurons to indirect ones involving afferent regulation of dopamine transmission. Although a direct modulation of dopamine cell activity seems plausible, further electrophysi-ological, molecular, and biochemical investigations are definitely necessary to dissect the mechanisms underlying the interaction between glucocorticoids and dopamine that mediates the addictive properties of drugs of abuse.

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