Behavioral and Neurobiological Consequences of Benzodiazepine Exposure During Adolescence in Male and Female Mice

Alprazolam (Xanax; ALP) is a potent, short-acting benzodiazepine (BDZ) widely prescribed for the treatment of anxiety disorders despite its abuse liability. ALP is one of the most abused BDZ among adolescents, and approximately 73% of non-medical BDZ users engage in polydrug use, resulting in increased risk for developing substance use disorders (SUDs) later in life. In adults, prolonged use of BDZs often leads to negative mood and a rebound of anxiety during periods of abstinence. Importantly, patients seeking treatment for opioid use disorder and/or withdrawal are commonly BDZ co-dependent. Concomitant ALP and opioids use have also been reported in the adolescent population. Surprisingly, little is known about ALP-opioid interactions and the negative effects resulting from their coingestion during this critical period of development. In an early study, I found that ALP exposure during adolescence in mice potentiates the rewarding properties of morphine (MOR) and induces persistent changes in second messenger signaling within the ventral tegmental area -- nucleus accumbens (VTA-NAc) pathway, a neurocircuit implicated in the regulation of drug reward and mood-related behaviors. Building upon this, in Chapter 2 and 3 I assessed the effects of repeated ALP exposure on stress susceptibility and spontaneous MOR withdrawal. In Chapter 4, I assessed the role played by the VTA-NAc pathway underlying BDZ-induced modulation of opioid reward. Lastly in Chapter 5, I assessed sex specific changes induced by adolescent ALP exposure. I found that ALP exposure results in increased stress susceptibility, dysregulation of mood-related behavior, exacerbating and prolonging symptoms of spontaneous MOR withdrawal and these effects persist into adulthood. Moreover, chemogenetic inhibition of the VTA-NAc pathway blocked the enhancement of opioid reward induced by ALP pretreatment, suggesting that this pathway plays a critical role in the modulation of BDZ-opioid reward. Lastly in female mice, enhanced sensitivity to the negative behavioral effects of ALP when compared to males was observed. These findings indicate that adolescent ALP exposure can result in long-lasting negative consequences manifested in enhancement of sensitivity to stress and drugs of abuse such as morphine. Importantly, the results suggest that the VTA-NAc pathway plays a role in BDZ-induced enhancement of opioid reward.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Psychological Sciences

Grantor

Texas A&M University

Year dc:date.issued

2025

Author dc:creator

• Cardona-Acosta, Astrid Mariela 1996-

Advisor dc:contributor.advisor

• Bolanos, Carlos

Committee members dc:contributor.committeemember

• Stephen Maren
• Justin Moscarello
• Jennifer Dulin

• Psychology, Psychobiology
• Psychology, Behavioral

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/1969.1/1595270

OAI record oai:identifier

https://oaktrust.library.tamu.edu/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Aoaktrust.library.tamu.edu%3A1969.1%2F1595270