ROLE OF GLUCOCORTICOIDS IN THE REGULATION OF DOPAMINERGIC NEUROTRANSMISSION

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REVIEW

ROLE OF GLUCOCORTICOIDS IN THE REGULATION OF DOPAMINERGIC NEUROTRANSMISSION

Anna Czyrak , Marzena Maækowiak, Agnieszka Chocyk, Katarzyna Fija³, Krzysztof Wêdzony

Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Role of glucocorticoids in the regulation of dopaminergic neurotrans- mission. A. CZYRAK , M. MAÆKOWIAK, A. CHOCYK, K. FIJA£, K. WÊDZONY. Pol. J. Pharmacol., 2003, 55, 667–674.

Several lines of evidence indicate that exposure to various types of stres- sors, or stress hormones may increase or induce sensitization to psycho- stimulants or enhance susceptibility of experimental animals to the effects of abusing substances. In order to find out what is a biological substrate of the above phenomenon, we investigate the impact of stress hormones on the dopaminergic neurotransmission. It is postulated, first, that corticosterone, an important stress hormone, regulates the dopaminergic neurotransmission at the level of dopamine D-1 receptors. Secondly, corticosterone may enhance the dopaminergic tone by the alterations in the synthesis of tyrosine hydroxylase, however, it is also conceivable that, alternatively, corticosterone may evoke translocation of that enzyme from the cell bodies of dopaminergic neurons to their terminals. Finally, arguments that dopamine D-1 receptors might regulate the release of corticosterone by activation of neurons in the paraventricular nucleus of hypothalamus are discussed.

Key words: dopamine, stress, tyrosine hydroxylase, corticosterone, do- paminergic receptors, addiction

ISSN 1230-6002

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Introduction

The main driving force of the experiments in- vestigating impact of glucocorticosteroids on the dopaminergic neurotransmission is search for the mechanism of action of abused substances and elu- cidation, how stressful life events influence the dopamine-mediated activity of the reward system [25, 30]. In the literature, there are several reports showing that exposure to various types of stress may increase or induce sensitization to psychosti- mulants as well as may increase self-administration of abused substances [23, 29]. The above pheno- menological observations have risen an important question what is the biological substrate of the above adaptive changes within the parameters con- trolling the intensity of the dopaminergic neurotransmission. Several arguments indicate that corticosterone or more precisely glucocorticoid receptors (GRs) are critically involved in the phenomenon of stress-induced increased vulnerability to sensitizing properties of abused substances [31, 32, 35]. It was shown that adrenalectomy, similarly like corticosterone synthesis inhibitors (metyrapone) and GR antagonists (RU 38486), all block sensitization, suggesting that corticosterone is critically involved in the processes discussed above [14, 31, 32].

These results prompted us to raise the question what type of effects at various levels of dopaminergic neurotransmission would be induced by prolonged administration of high dose of corticosterone. There are some evidences that at the level of neurotransmission, corticosterone may increase the release of dopamine and influence the activity of tyrosine hydroxylase, while relatively little is known about impact of corticosterone on the dopaminergic receptors. Thus, we thought that it would be of importance to find further arguments for the impact of corticosterone on dopaminergic neurotransmission at the receptor level.

Although the mechanisms of stress perception and addiction seem to be principal target of the currently conducted research, as it was stressed above, the results of these studies can be simply extended to other aspects of the pathology of dopaminergic neurotransmission, since, for example, we know now that the sensitization is not only related to the addictive properties, but is also associated with the pathology of the schizophrenia or, at least, drug-induced psychoses [4, 8, 9, 22, 43]. On the other hand, the further alterations in the dopaminergic

neurotransmission and alternations in the reward process might be linked with the pathology of de- pression [24]. Thus, using the sensitization as the major motive of the present study, we were looking for the changes in the dopaminergic neurotransmission after prolonged treatment with corticosterone. We have chosen dopaminergic receptors and tyrosine hydroxylase as the two determinants of corticosterone action on the dopaminergic neurotransmission. This selection was based on two observations, first, that D-1 receptors seem to be critically involved in the phenomena of the sensitization and second, that various types of stress induce changes in the activity or synthesis of tyrosine hydroxylase [6, 29, 33, 37–39, 42].

In the second part, we have been looking for anatomical basis of the above outlined interaction between glucocorticoids and dopaminergic system.

The existence of two types of receptors for corticosterone in the rat brain has been well documen- ted. As mentioned above, GRs are widely distributed throughout the brain while mineralocorticoid receptors (MRs) are located mainly in the hippo- campus [1, 13, 21]. Since corticosterone receptors act as transcription factors, their co-localization with dopamine D-1 receptors or tyrosine hydroxylase in the single neuron, may be taken into consideration as an additional argument for possibility of their direct interaction [38, 45].

Impact of chronic corticosterone on dopamine D-1 receptors

In the initial experiments, we investigated the impact of repeated administration of high dose of corticosterone on dopamine D-1 receptors at the level of receptor binding as well as at the level of mRNA encoding them. We applied quantitative receptor autoradiography using the selective D-1 receptor antagonist [³H]SCH 23390 as a ligand label- ing D-1 receptor binding sites and in situ hybridiza- tion method using synthetic oligodeoxynucleotide probes complementary to the specific fragments of mRNA encoding D-1 receptors [10, 11, 36]. These procedures were used not only to find out whether corticosterone is capable of altering these two fea- tures of D-1 receptors but also to establish the procedure with appropriate anatomical resolution, which will enable us to recognize the discrete changes in the above receptors. We found that prolonged treatment with corticosterone increased by

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15–30% the level of mRNA encoding D-1 receptors in the striatum and nucleus accumbens. In general administration of corticosterone did not influence the binding to D-1 receptors in the striatum and nucleus accumbens, however, in the latter brain structure some small down-regulation in the shell region has been noticed. On the other hand, we observed a clear increase in the D-1 receptor binding in the substantia nigra and ventral tegmental area (VTA). Thus, the general conclusion can be put for- ward that corticosterone evokes consistent up- regulation of D-1 receptors in the brain regions where the cell bodies of dopaminergic systems are located, but not in the brain structures containing terminals of the dopaminergic neurons.

It is tempting to link the above changes in the D-1 receptors in the substantia nigra and VTA with the available data indicating that D-1 receptors localized there may be involved in the process of the initiation of sensitization. The first suggestion shedding some light on these processes comes from the laboratory of Stewart and Vezina, [5, 37, 39, 40, 42], who have shown that direct administration of amphetamine to the VTA initiated the sensitization and its apparent effect was antagonized by SCH 23390, the D-1 receptor antagonist [5, 37, 39, 40].

Thus, it might be speculated that the observed up- regulation of D-1 receptors in the VTA after repeated administration of corticosterone will make animals more vulnerable to the effects of psy- chostimulants. It is also worth mentioning that stimulation of D-1 receptors in the VTA increases glutamate release. Similar effects were also observed after administration of cocaine. Glutamater- gic projections to the VTA originate from the fron- tal cortex. Thus, it is conceivable that up-regulation of D-1 receptors found by us after corticosterone administration may indicate that chronic corticosterone treatment is capable also indirectly of influencing the release of glutamate. Hypothesis about glutamate, cocaine and sensitization is also in line with the current concepts about the role of excitatory amino acids in addiction, since several reports indicate that sensitization may be antagonized by the blockade of NMDA receptors [41, 44]. It is conceivable that blockade of NMDA receptors may attenuate the increased outflow of glutamate in the VTA, which have reached the excessive level due to increased number of D-1 receptors on the gluta- matergic terminals [22].

Impact of metyrapone on the dopamine D-1 receptors

As it was mentioned in the introduction, the behavioral studies revealed that adrenalectomy, or pharmacological inhibition of the corticosterone synthesis by administration of metyrapone are capable of antagonizing or attenuating the expression of the sensitization [10, 31, 32]. Thus, we thought that in the next experiments it might be important to investigate the impact of such pharmacological adrenalectomy by metyrapone on dopamine D-1 receptors. We found that metyrapone was capable of decreasing the D-1 receptor binding as well as the amount of mRNA encoding it [10]. Consistent decreases have been observed in the striatum and nucleus accumbens, i.e. brain structures engaged in the expression of the sensitization. At the moment, binding studies in the substantia nigra and VTA are in progress. Thus, in general one may suggest that metyrapone by decreasing the synthesis of D-1 receptors may decrease the vulnerability of the animals to the effects of addictive drugs. It would be of great importance to develop highly selective procedure of D-1 receptor visualization and quanti- fication, procedure which will allow for examina- tion of D-1 receptors [12] in the brain cortex, since firstly, cortical pyramidal cell bodies express D-1 receptors, and secondly, there is a growing number of evidences suggesting that the prefrontal cortex, in addition to the VTA, may play a critical role in the phenomenon of sensitization and a role of cortical D-1 receptors in this phenomenon is still an open question [42].

Impact of chronic corticosterone treatment on dopamine D-2 receptors

We were also interested in elucidating the influence of corticosterone on the dopamine D-2 receptors [4]. Using brain autoradiography as well as in situ hybridization method, the binding to these receptors and their mRNA synthesis were investigated in the striatum, nucleus accumbens, substantia nigra and VTA. We found that prolonged treatment with corticosterone did not influence dopamine D-2 receptor binding as well as expression of its mRNA. Thus, our present data indicate that D-2 receptors are not influenced by the repeated administration of corticosterone.

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Impact of corticosterone on tyrosine hydroxylase

Tyrosine hydroxylase (TH) is the rate limiting enzyme in dopamine synthesis [38]. There are reports indicating that various types of stress may increase the level of TH protein, rate of its synthesis or finally its activity. There are also data showing that TH mRNA transcription (at least in adrenal glands) is under glucocorticoid control [13, 33].

Therefore, it seemed to us that it might be important to have the complementary studies evaluating possible changes in the TH after prolonged administration of corticosterone. In these studies, on the one hand, our attention was focused on the substantia nigra and VTA, where TH-positive neuronal cell bodies which form major dopaminergic pathways (mesolimbic, mesocortical and mesostriatal systems) are present, and on the other, we also looked for the possible changes in the striatum and nucleus accumbens, the brain structures where dopaminergic pathways terminate [15]. We used two major experimental procedures, one measuring the amount of TH protein (by Western blot assay), and the se- cond, measuring the amount of enzyme mRNA (in situ hybridization).

We found that chronic corticosterone administration decreased the amount of TH protein in the VTA while no changes in substantia nigra were observed. Interestingly, in the nucleus accumbens, the increase in the level of TH protein was observed, whereas no effect of corticosterone on TH protein level was detected in the striatum. It was also found that repeated treatment of corticosterone increased the level of the specific mRNA encoding TH in VTA only (manuscript in preparation). In additional consecutive experiments, we measured the level of dopamine and its metabolites in the VTA and substantia nigra. It was found that chronic administration of corticosterone decreased the metabolism of dopamine mainly in the VTA, what seems to be positively correlated with the observed decrease in the amount of TH in this brain structure.

Thus, chronic corticosterone treatment induces fairly complex effect on TH, influencing both enzyme protein as well as its mRNA. Opposite effects of corticosterone on the enzyme level and its mRNA in the VTA may indicate that initial decrease in the amount of TH protein is possibly compen- sated by an increase in its mRNA. Although it is

not possible to prove or rule out such hypothesis now, it is clear that such mechanism does not explain the observed parallel increase in the amount of TH in the nucleus accumbens or the selectivity of the corticosterone toward mesolimbic dopaminergic system. The above data incline us to speculate that corticosterone might influence the transport of TH protein from the cell bodies to the terminal regions. This hypothesis has been adopted from studies of Nestler, [3, 28], who found that addiction, or animal vulnerability to the effects of abused substances might depend on the level, or rate of phosphorylation of neurofilaments which transport proteins within the neurons. Taking into consideration the above hypothesis, it is conceivable that corticosterone may enhance the transport of TH to the terminal region by, for example, increasing the amount of the neurofilaments or their phosphorylation [3]. Thus, the net effect will be the increase in the amount of TH in the nucleus accumbens with the subsequent decrease in the VTA. Such a lower- ing of the level of TH, the rate limiting enzyme in dopamine synthesis will immediately decrease synthesis of dopamine in the VTA and, consequently, will induce further decrease in the presynaptic inhibition, what, as it has been speculated, may increase the excitability of dopaminergic neurons [3, 19, 28]. On the other hand, the increased amount of TH in the terminal regions may increase the synthesis of dopamine and its “releasability” in response to the environmental stimulation. Our ef- forts to prove that hypothesis have not yet been fin- ished but we hope that experiments evaluating effect of corticosterone on neurofilament proteins will prove or rule out such hypothesis. Neverthe- less, this hypothesis may, at least partly, explain how dopaminergic system is adapted to the prolonged corticosterone exposure and offers some mechanisms underlying increases in dopaminergic tone due to long-term exposure to glucocorticoids.

Co-localization of dopamine D-1 receptors and tyrosine hydroxylase with glucocorti- coid receptors

The data mentioned above indicate that GRs might modulate the activity of the dopaminergic systems, both at the level of biosynthesis of dopamine as well as at the level of D-1 receptors. The above findings encouraged us to investigate the anatomical background of this interaction. Using

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the immunohistochemical techniques and selective antibodies against GR and D-1 receptors, we investigated whether the above receptors are co- localized in the same neurons, and whether neurons of the substantia nigra and VTA, positive for TH immunoreactivity are also positive for presence of GRs. We found that in the rat prefrontal cortex all D-1 immunoreactive neurons were also positive for GRs. Co-localization has been observed in the pyramidal neurons and possibly GABA-ergic inter- neurons [12], where GRs were located in neuronal nucleus, and cytoplasm of the neuron was immunoreactive for D-1 receptors (Fig. 1). The presence of GRs in the nucleus indicates that apparent receptors are in the activated form [20]. The same pattern of co-localization was seen in the striatum, substantia nigra and VTA, again all D-1 positive neurons showed immunoreactivity for GRs [6].

Certain exception from that rule has been observed in the striatum, where large striatal neurons showing D-1 receptors were not always immunopositive for GRs. Thus, in general, all D-1 immunopositive neurons have GRs as well.

Interestingly, in experiments looking for the co-localization of GRs and TH, only very small number of neurons in the rat substantia nigra and VTA showed clear co-localization [6]. This obser- vation is in the sharp contrast to the results from the locus coeruleus, where the co-localization of GRs with TH was a general rule [6].

The results obtained with a double labeling technique indicate that there is anatomical basis for the direct regulation of D-1 receptors by GRs in all tested regions of the brain. On the other hand, our present results do not fully support suggestions that GRs may directly influence TH. It is apparent that direct interaction within the same neuron may depend on the type of neurotransmitter and brain structure. Another conclusion is that the appear- ance of GRE (glucocorticoid response element) se- quences in the promoter of gene encoding TH does not determine presence of the GRs.

Dopaminergic receptors in the paraven- tricular nucleus of the hypothalamus

So far we presented arguments for the role of the glucocorticoids in the regulation of the dopaminergic activity at the level of TH and dopaminergic receptors. This research direction supports hy- pothesis that glucocorticoids acting via GRs may somehow influence the dopaminergic neurotransmission. However, the question arises whether do- paminergic neurons or dopamine via its receptors may regulate the level of the circulating corticosterone, thereby affecting vulnerability of the brain to stress. In order to find some arguments for a po- tential role of dopamine in the regulation of corticosterone secretion, we analyzed whether the paraventricular nucleus of the hypothalamus is an anatomical basis for this interaction [7, 16, 17], since the paraventricular nucleus of the hypothalamus comprises a population of corticotropin-releasing hormone (CRH) neurons which play an important role during stress [2]. CRH neurons in the paraventricular nucleus project to the median eminence and CRH released from these neurons stimulates secretion of adrenocorticotropic hormone (ACTH) from anterior pituitary, and ACTH regulates release of corticosterone from the adrenal cortex. This path- way is also indicated by some well known facts that most of abused substances, acting at the level of the hypothalamus, induce a robust increase in the level of circulating corticosterone. Thus, using

Fig. 1. Photomicrographs illustrating co-localization of glucocorticoid receptors (GRs) with dopamine D-1 receptor protein in the rat medial prefrontal cortex. Black deposits correspond to the GRs immunorectivity arrowhead, while light brown deposits visualize the presence of dopamine D-1 receptor proteins

arrow (objective 100x)

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the monoclonal antibody against dopaminergic D-1 receptors, we examined their distribution in the paraventricular nucleus of the hypothalamus [7, 34]. It was found that a large number of dopamine D-1 positive neurons is present in the paraventricular nucleus of the hypothalamus, and they are located in both magnocellular and parvocellular parts of this nucleus, however, magnocellular part seems to contain more D-1 immmunopositive neurons [7].

Receptor protein was found to be co-localized with pCREB (phosphorylated cyclic AMP response element-binding protein), measured in the same brain slices with the anti-pCREB monoclonal antibody [7, 26, 27]. Such co-localization allowed us to speculate that D-1 receptors are apparently in the active form since there is a certain level of sponta- neous phosphorylation of CREB possibly due to the stimulation of the D-1 receptors, as revealed by the pCREB expression. Our very preliminary results suggest also that amphetamine might increase the amount of pCREB in the D-1 positive neurons in this region of the hypothalamus, which may lead to the increase in the synthesis and release of CRH and, consequently, to the increased amount of the circulating corticosterone [16]. Currently, there are also certain evidences indicating, on the one hand, that corticosterone may regulate dopamine D-1 re- ceptors, and on the other, that dopamine via D-1 re- ceptors may regulate the amount of circulating corticosterone [7, 16], however, the precise link between the VTA and paraventricular nucleus of the hypothalamus is not clear and further experiments are required to elucidate all aspects of the connec- tions between the paraventricular nucleus and the brain structures which are engaged in the reward and the locomotor stimulant effects.

The observations reported here incline us to speculate that not only glucocorticoids acting through GRs widely distributed throughout the brain may regulate the function of the dopaminergic systems, but also dopamine, especially via its receptors of D-1 subtype [18], may regulate the level of the circulating hormones, thereby influencing the perception of stress factors by the organism.

Conclusions

In general, our present study indicates that corticosterone is an important factor which may regulate the dopaminergic neurotransmission at the level of dopamine D-1 receptors. This conclusion is

supported by the observations that its chronically elevated level increased the D-1 receptor binding and expression of its mRNA while the lowered level decreased them. Although the above effects were seen only in some but not all brain regions where D-1 receptors are present, apparent direction of changes is in line with the current concepts of the mechanism of sensitization phenomenon that emphasize the critical role of D-1 receptors in this phenomenon. Thus, it is conceivable that corticosterone-evoked changes in D-1 receptors may explain the mechanism of acquisition of the sensitization on the one hand, and, on the other, they suggest that drugs which decrease the level of the circulating corticosterone may have some thera- peutic potentials in treatment of addiction associated with overactivity of the dopaminergic tone.

We also observed that corticosterone might enhance the dopaminergic tone by the alterations in the synthesis of TH, however, this interaction is fairly complex, and may not only involve the regulation of TH synthesis but possibly also translocation of the enzyme from the cell bodies of dopaminergic neurons to their terminals.

At the anatomical level, there is a clear co- localization of D-1 dopamine receptors with GRs, but not TH and GRs. Thus, in the anatomical terms, there is a high probability of direct interaction between D-1 and GRs within the same neurons.

Finally, we have found some arguments that not only dopamine D-1 receptors can be regulated by GRs but also oppositely D-1 receptors might regulate the release of corticosterone by activation of neurons in the paraventricular nucleus of the hypothalamus.

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Received: July 7, 2003; in revised form: August 26, 2003.