Adolescent stress differentially modulates the affective, psychomotor, and neural responses to a first amphetamine exposure in male Wistar rats

Sequeira-Cordero, A.; Brenes, J. C.

Abstract:

The initial neurobehavioral adaptations following the first drug exposure may underlie the transition from recreational to compulsive use in vulnerable individuals. Compelling evidence indicates that early life adversity (ELA) is a significant risk factor for drug dependence. To better understand the relationship between ELA and initial drug experiences, we investigated whether chronic unpredictable stress (CUS) during adolescence modifies the affective (ultrasonic vocalizations, USVs), psychomotor (rearing and locomotion), and neural responses to a single dose of amphetamine in rats. CUS alone led to open-field hyperactivity and reduced flat USVs. CUS significantly blunted amphetamine-induced hyperactivity –suggesting a cross-tolerance effect– while it augmented amphetamine-induced appetitive 50-kHz calls, indicating a cross-sensitization effect. These results might suggest that CUS increases the rewarding and reduces the anxiogenic properties of initial amphetamine experience. At the neural level, amphetamine increased the expression of corticotropin-releasing factor (Crf)-related genes and the 2B subunit of the N-methyl-d-aspartate glutamate receptor (Nr2b) in a region-dependent manner. CUS upregulated the expression of brain-derived neurotrophic factor (Bdnf) in the medial prefrontal cortex (mPFC) and actin-related protein 2 (Arp2) in the nucleus accumbens (NAc). A cross-tolerance effect was observed for Bdnf, tropomyosin receptor kinase B (TrkB), and Cofilin-1 in the mPFC. Conversely, the expression of Rho GTPase-activating protein 32 (P250gap), cAMP-response element binding protein (Creb), and DNA methyltransferase 3A (Dnmt3a) was cross-sensitized in the NAc. The coexistence of cross-sensitization and cross-tolerance neurobehavioral effects between CUS and amphetamine supports the idea that ELA can simultaneously blunt and heighten different brain substrates, collectively increasing the risk of drug dependence.

Año:

2025

Tipo de publicación:

Artículo

Journal:

Pharmacology Biochemistry and Behavior

Volumen:

258

DOI:

https://doi.org/10.1016/j.pbb.2025.174126