Michelle Doyle: MDPV Self-administration in Female Rats – Influence of Reinforcement History By Rachel Altshuler Ph.D., Animals in Research Committee Member Sex differences in addiction research studies are well-noted at the behavioral level, both in humans and animal models of substance use disorders. For example, women progress more rapidly from casual drug use to a substance use disorder. Likewise, cocaine acquisition in rodents tends to be faster in female rats than in male rats. These findings strengthen the argument for including male and female subjects in addiction research studies. While sex differences have been well characterized in some stimulants, sex differences in 3,4-methylenedioxypyrovalerone (MDPV) are not as well characterized. MDPV, a monoamine uptake inhibitor, is part of a family of synthetic cathinones also known as “bath salts.” MDPV and other bath salts are a public health concern due to their high abuse liability and marketing as the cheaper option to stimulants such as cocaine. Interestingly, a “high-responder” phenotype has been observed in subset of male rats that self-administration MDPV, and this phenotype carries over to other stimulants. However, some evidence suggested a history of cocaine self-administration may prevent the development of the phenotype. Understanding whether sex plays into the high-responder phenotype is of particular interest to Michelle Doyle, a Ph.D. student in laboratory of Dr. Greg Collins in the Department of Pharmacology at the University of Texas Health Science Center at San Antonio. In a recent study (Doyle et al. 2021 Psychopharmacology) Michelle Doyle and her colleagues examined whether the high-responder phenotype also developed in female rats self-administering MDPV, as well as, further characterized whether a history of cocaine self-administration protected against the development of this phenotype. Female rats were trained to self-administer MDPV, cocaine, or food pellets. The rats that initially responded for cocaine or food pellets were later switched to MDPV. Rats were classified as high-responders if more than 20% of their responses were made during time-out periods. Dose-response curves for MDPV were generated under a fixed ratio schedule of reinforcement to measure reinforcing potency, then the rats were switched to a progressive ratio (PR) schedule of reinforcement to measure the reinforcing effectiveness of MDPV. Half of the rats self-administering MDPV were characterized as high-responders, whereas only a single rat self-administering cocaine and no rats self-administering food pellets were characterized as high-responders. When all rats were switched to self-administering MDPV, more than half of the rats with a history of responding for food pellets developed the high-responder phenotype. However, no rats with a history of cocaine self-administration developed the high-responder phenotype during MDPV self-administration. There were no differences in the reinforcing potency or effectiveness of MDPV between the rats with different drug histories. This study demonstrated that a subset of female rats develops a high-responder phenotype following MDPV self-administration. Furthermore, protection against the development of the high-responder phenotype cannot be afforded simply to a history of operant behaviors, rather a history of cocaine responding is important for the protective effects. Michelle and colleagues noted that the outcomes of these studies were similar to earlier studies using male rats under the same conditions, suggesting that there may not be sex differences in MDPV self-administration or the development of the high-responder phenotype. Michelle Doyle’s introduction to psychopharmacology began as an undergraduate student at Tufts University, working in the laboratory of Dr. Klaus Miczek. With Dr. Miczek, Michelle first became involved with addiction research when she studied the intersection between stress and cocaine self-administration. She followed her interest in this line of research to the McLean Hospital and the Harvard Medical School where she worked as a technician in the laboratory of Dr. Jack Bergman, under the direction of Dr. Rajeev Desai. Michelle Doyle is entering her final year of her Ph.D. program and will soon be looking for postdoctoral research opportunities. She is particularly interested in studying treatments for substance-use disorders as well as identifying the processes that factor into substance-use disorders. Michelle has been a member-in-training of CPDD since 2018. In addition to many awards won over her time as a graduate student, Michelle was awarded the NIDA Director’s Travel Award and the NIDA Women and Sex/Gender Junior Investigator Travel Award to attend the annual CPDD meetings in 2021 and 2020, respectively. She also won the Excellence in Preclinical Work by a Pre-Doctoral Researcher Award at the Early Career Research Presentation Competition at the 2021 meeting.
