Although most acute stress studies focus on the response to each stimulus given separately, the possible interaction between stressors of different or similar nature has a critical theoretical relevance as in nature organisms can face more than one stimulus simultaneously (or almost simultaneously). Regardless of its nature (physical or emotional), stressors have in common the capability to activate the hypothalamus-pituitary-adrenal axis (HPA). Although depending on their characteristics stressors are differentially processed by the SNC, signals eventually converge at the paraventricular nucleus of the hypothalamus (PVN), the key area in the regulation of the HPA axis. Many drugs of abuse such as cocaine and amphetamine are able to activate a wide range of brain areas and also the HPA axis and, as such, are considered as pharmacological stressors. Previous research from our laboratory has demonstrated in rats some interactions between psychostimulants (amphetamine) and emotional stressors (forced swim) when both stimuli were administered simultaneously, resulting in reduced activation of the HPA axis and stress-induced hyperglycemia. The aforementioned interaction was also observed with the exposure to forced swim and the administration of another psychostimulant, methylphenidate, at doses that are used for the treatment of the attention deficit and hyperactivity disorder (ADHD). The first aim of the present work objective has been the study of how simultaneous exposure to psychostimulants (amphetamine or methylphenidate) and emotional stressors (forced swim) alter the activation of specific neuronal populations in brain areas related to the processing of both stimuli. In order to extend the possibility of interaction to simultaneous exposure to two emotional stressors, we have also preliminary studied the consequences of simultaneous exposure to predator odor and immobilization. The characterization of activated neuronal populations has been carried out mainly by double in situ hybridization (FISH) of the immediately early gene c-fos in combination with specific neuronal phenotype markers. Our interest has focused on glutamatergic and GABAergic neurons of the medial prefrontal cortex, D1R+ and D2R+ neurons of the striatum, CRH+ neurons of the PVN, and tyrosine hydroxylase (TH+) neurons of the ventral tegmental area and the locus coeruleus. Our results indicate that simultaneous exposure to two stimuli leads to different types of interactions with respect to activated neuronal populations. The effects are more evident with amphetamine, which by itself, causes wide-spread activation of the brain, than with methylphenidate, which by itself has null or modest effect. The following response patterns were observed: i) lack of additive effect, when activation of one stimulus dominate over the other; ii) additive effect, which seems to reflect an independent contribution of each stimulus; iii) negative synergy, when one stimulus reduces the activation caused by the other stimulus; and iv) positive synergy, when simultaneous exposure causes more activation than the sum of each stimulus. Negative synergies have also been observed after simultaneous exposure to predator odor and immobilization. Taken together, the present data contribute to a better understanding of the interaction between emotional stressors and two types of psychostimulants that are important for addiction and the treatment of ADHD. In addition, we add some evidence on the interaction between two emotional stressors when processed simultaneously, what may be of interest in pathologies such as the post-traumatic stress disorder.
- Emotional stress
- Immediate early genes