Stating the problem:
Drug addiction is a debilitating neuropsychiatric disorder that affects a substantial number of individuals in the United States and worldwide. It is characterized by compulsive seeking and taking of drugs of abuse despite negative consequences. Repeated drug use can induce long-lasting molecular and cellular changes within the brain leading to behavioral adaptations that can have profound life-long negative consequences, especially if drug consumption commences during adolescence (Iniguez et al., 2009). Alprazolam (Xanax) is a potent short-acting benzodiazepine (BDZ) that is widely prescribed for the management of symptoms of anxiety and panic disorders. However, alprazolam possesses abuse liability with a risk for physical dependence, withdrawal, and addiction. Its use and abuse have increased in recent years and has been linked to fueling the opioid epidemic (Gladden et al., 2019). Reports show that concomitant use of alprazolam and opioids among adolescents is common, resulting in a heightened risk for developing a substance use disorder, overdose, and death (Schepis et al., 2016). Giving that drug use early in life can prime the organism for potential future drug abuse, it is surprising how little is known about the interaction(s) between alprazolam and opioid drugs, especially during adolescence. In our recent article published in Models of Addiction we investigated the short- and long-term behavioral and molecular consequences of alprazolam exposure during this critical developmental period.
What we did:
We were interested in how alprazolam exposure during adolescence influences behavior in adulthood given that early life exposure to drugs of abuse can aid in the development of substance use disorders later in life. Adolescent male (postnatal day [PD] 35) mice were pretreated with alprazolam daily from PD35-49 and assessed for behavioral and biochemical adaptations 24h or 1-month after the last alprazolam exposure. We tested the hypothesis that alprazolam exposure during adolescence influences sensitivity to opioids (i.e., morphine) later in life. First, we examined the effects of once daily (14-days) alprazolam exposure in adolescent mice using the conditioned place preference paradigm (CPP), a well-established behavioral assay that measures drug reward sensitivity and drug-seeking behavior in rodents. Previous work has suggested that the ventral tegmental area (VTA) might be a brain region where BDZ-opioids interact to enhance dopamine release into the nucleus accumbens (NAc), a brain area where the encoding of incentive and motivational value of drugs is believed to occur (Walker & Ettenberg, 2005). Therefore, we also investigated changes in molecular/second messenger signaling within the VTA-NAc using biochemical assays (i.e., RT-qPCR, western blot) to determine the effects of alprazolam on gene and protein expression of molecules that are crucial for drug-induced plasticity known to be associated with the state of addiction.
What did we find?
We found that alprazolam exposure (0.5, 1.0 mg/kg) enhanced the rewarding effects of low, non-rewarding doses of morphine (2.5 mg/kg), when compared to the controls. Interestingly, mice pretreated with alprazolam (1.0 mg/kg) avoided the compartments paired with a higher dose of morphine (5.0 mg/kg), suggesting a left-ward shift of the dose response curve for morphine. Surprisingly, some of these effects were long lasting, with mice pretreated with the lowest dose of alprazolam (0.5 mg/kg) showing a preference for the non-rewarding dose of morphine (2.5 mg/kg) one month after cessation of alprazolam treatment, a time when the mice had reached adulthood. We also found that exposure to alprazolam disrupted molecular/signaling activity within the VTA-NAc pathway, enhancing the expression of gene products that have been associated with increased vulnerability to drugs of abuse and stress, and this molecular/signaling activity dysregulation persisted into adulthood.
What do the results mean?
It is known that repeated exposure to drugs of abuse induce changes in brain pathways that aid in the development of substance use disorders. Within this framework, these results indicate that alprazolam exposure during adolescence can have long lasting deleterious consequences by enhancing the sensitivity to the rewarding effects of morphine and dysregulating the molecular integrity in brain reward pathways (VTA-NAc). Given evidence tying BDZ as exacerbating the effects of opioids, these findings have critical implications for the potential risk and perpetuation of substance use disorders, as alprazolam use and abuse during adolescence may be factors that can drive the continuation of drug use well into adulthood. In our view, this work starts laying the foundation to further our understanding of the neurobiological and neural circuitry changes underlying BDZ abuse liability and inform the development of better pharmacological interventions that could minimize the risk for developing substance use disorders.
Poster illustration credits: Owain Anderson
References
Gladden, R. M., O'Donnell, J., Mattson, C. L., & Seth, P. (2019). Changes in Opioid-Involved Overdose Deaths by Opioid Type and Presence of Benzodiazepines, Cocaine, and Methamphetamine - 25 States, July-December 2017 to January-June 2018. MMWR Morb Mortal Wkly Rep, 68(34), 737-744. https://doi.org/10.15585/mmwr.mm6834a2
Iniguez, S. D., Warren, B. L., Parise, E. M., Alcantara, L. F., Schuh, B., Maffeo, M. L., Manojlovic, Z., & Bolanos-Guzman, C. A. (2009). Nicotine exposure during adolescence induces a depression-like state in adulthood. Neuropsychopharmacology, 34(6), 1609-1624. https://doi.org/10.1038/npp.2008.220
Schepis, T. S., West, B. T., Teter, C. J., & McCabe, S. E. (2016). Prevalence and correlates of co-ingestion of prescription tranquilizers and other psychoactive substances by U.S. high school seniors: Results from a national survey. Addict Behav, 52, 8-12. https://doi.org/10.1016/j.addbeh.2015.08.002
Walker, B. M., & Ettenberg, A. (2005). Intra-ventral tegmental area heroin-induced place preferences in rats are potentiated by peripherally administered alprazolam. Pharmacol Biochem Behav, 82(3), 470-477. https://doi.org/10.1016/j.pbb.2005.10.002