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Involvement of dopaminergic mechanisms in conditioned and unconditioned fear: modulation by hormonal factors

Abstract

Since the social and economic impact of stress-associated disorders is increasing, the investigation of the biological changes underlying such disorders is of fundamental importance. Studies suggest that dopaminergic activity, when associated with the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, could determine aversive states. We showed that manipulations that interfere with the activation of the HPA axis led to alterations in dopaminergic neurotransmission and, as a consequence, in the expression of conditioned fear responses. Less is known, however, about the involvement of these mechanisms in the expression of unconditioned defensive responses. In general, an opposite role of dopaminergic mediation in fear/anxiety states seems to exist depending on the nature of the threat, whether conditioned or unconditioned. In conditioned fear, there seems to be an increase in dopaminergic neurotransmission to more rostral structures, such as the amygdala; in unconditioned fear, the increase in dopamine in more caudal structures such as those of the brainstem would act as a modulator of the expression of defensive responses. With the present project, we aim to advance the understanding of the role of dopaminergic neurotransmission via D2-like receptors, and the relationship with the activation of the HPA axis and mineralocorticoid (MR) and glucocorticoid (GR) receptors, in the expression of conditioned and unconditioned fear. At the same time, a point worth mentioning is that, although women have a higher prevalence of stress-related disorders, most of the basic research does not use females as experimental subjects. Female characteristics potentially linked to mental disorders remain poorly studied. More efforts are needed for a better understanding of the neural bases recruited during the expression of conditioned and unconditioned fear, in parallel in males and females. Thus, in order to assess the extent to which interactions between dopaminergic neurotransmission and HPA axis activity are important for the expression of conditioned and unconditioned fear, we will pharmacologically manipulate these systems and monitor defensive responses in male and female rodents. Male and female Wistar rats, approximately 10 weeks old, will be used. The estrous cycle of females will be monitored during all experiments. Dopaminergic drugs and/or corticosteroids will be administered intraperitoneally or locally to brain structures of interest. Defensive responses will be evaluated through aversive conditioning protocols and elevated plus maze tests. Potential motor effects will be evaluated with open-field and catalepsy tests. Different groups of animals will be used for plasma corticosterone dosage and analysis of dopamine concentration in structures of interest. We expect that the results of the present study support the hypothesis that a differential involvement of dopaminergic neurotransmission via D2-like receptors, and consequently of the interaction of dopamine with corticosteroids, occurs in conditioned and unconditioned fear responses. We also expect that exploring the influence of biological sex on the data will contribute to closing the gap in understanding the etiology, symptomatology, and treatment of mental disorders in women - largely associated with the neglect of the use of females in preclinical research in neuroscience. (AU)

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