Sunday, May 18, 2025
5/18/2025
Xylazine effects on methamphetamine-induced behavioral alterations in rats - The `tranq dope' threat involving combination of xylazine and fentanyl has been highly publicized, but emerging evidence indicates that methamphetamine (METH) is increasingly being adulterated with xylazine. A recent toxicology study reported that greater than one-third of all human METH samples were co-positive for xylazine. These emerging trends of METH and xylazine misuse necessitate pharmacological studies to determine if, and how, xylazine worsens METH effects. Evaluating effects of xylazine on METH-induced behavioral alterations in preclinical studies is a first step in better defining METH-xylazine interactions and guiding public health responses to xylazine-METH co- exposure. To our knowledge, there is not a single preclinical study that has investigated effects of xylazine on METH-induced effects. For amphetamine, there is only a 1994 rat study, which showed that convulsions elicited by amphetamine are reduced by a high dose of xylazine. In our studies, we observed xylazine-mediated regulation of METH locomotor and self-administration (SA) behaviors in adult rats. Our data demonstrate that xylazine (1) dose-dependently reduces locomotor activation evoked by acute METH and (2) increases METH infusions under fixed-ratio ((FR-1) SA conditions. These results provide a foundation to begin defining the unique behavioral and molecular consequences of dual METH and xylazine exposure. We will now expand upon these exciting findings to test the central hypothesis that xylazine (1) enhances acquisition of METH SA under FR-1 conditions, (2) enhances METH reinforcing efficacy, and the motivation to work for METH, under progressive-ratio (PR) conditions, (3) exacerbates anxiety- and depression-like effects that are associated with abstinence from chronic METH exposure, and (4) enhances METH seeking behaviors reinstated by different factors (METH prime, cue, or xylazine itself). We will also determine impacts of XYL-METH co-exposure on biomarkers of METH addiction in the nucleus accumbens transcriptome using unbiased RNA sequencing. We hypothesize that targets such as VMAT, TAAR1, DAT, D1, D2, and tyrosine hydroxylase, which are known to contribute to behavioral effects of METH, may be further exacerbated by METH-XYL co-exposure. To best match human preparations and human intake of XYL and METH, the two drugs will be mixed (in the syringe), and rats will be allowed to self-administer the drug-drug combination. Follow-up studies will probe receptor mechanisms underlying xylazine-METH interactions, including α2-adrenoceptor activation or kappa opioid receptor activation by xylazine. This comprehensive analysis of polydrug exposure of METH in combination with XYL will provide the first preclinical information about how XYL affects METH intake, reinforcing efficacy, seeking behaviors, and the nucleus accumbens transcriptome.
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