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Abstract: Rats emit ultrasonic vocalizations (USVs) in a variety of contexts, and it is increasingly clear that USVs reflect more complex information than mere positive and negative affect states. We sought to examine USVs in a common model of addiction and relapse, the self-administration/reinstatement paradigm, in order to gain insight into subjective states experienced by rats during various types of methamphetamine seeking. We measured three subtypes of “50kHz” USVs [flats, trills, and non-trill frequency modulated (FM) USVs], as well as long and short duration “22kHz” USVs, during self-administration and extinction training, and during reinstatement elicited by cues, a methamphetamine prime, cues+prime, or the pharmacological stressor yohimbine. During self-administration and extinction, rats emitted many flats and FMs, (and short duration “22kHz” USVs on day 1 of self-administration), but few trills. In contrast, methamphetamine priming injections potently enhanced FMs and trills, and trill production was correlated with the degree of methamphetamine+cue-elicited reinstatement. Cues alone yielded increases only in flat USVs during reinstatement, though a subset of rats displaying strong cue-induced reinstatement also emitted long duration, aversion-related “22kHz” USVs. Although yohimbine administration caused reinstatement, it did not induce “22kHz” USVs in methamphetamine-experienced or methamphetamine-naïve rats (unlike footshock stress, which did induce long duration “22kHz” USVs). These findings demonstrate heterogeneity of rat USVs emitted during different types of methamphetamine seeking, and highlight their potential usefulness for gaining insight into the subjective states of rats in rodent models of drug addiction and relapse. [Copyright &y& Elsevier]

Addiction is a chronic relapsing disorder, in that most addicted individuals who choose to quit taking drugs fail to maintain abstinence in the long-term. Relapse is especially likely when recovering addicts encounter risk factors like small “priming” doses of drug, stress, or drug-associated cues and locations. In rodents, these same factors reinstate cocaine seeking after a period of abstinence, and extensive preclinical work has used priming, stress, or cue reinstatement models to uncover brain circuits underlying cocaine reinstatement. Here, we review common rat models of cocaine relapse, and discuss how specific features of each model influence the neural circuits recruited during reinstated drug seeking. To illustrate this point, we highlight the surprisingly specific roles played by ventral pallidum subcircuits in cocaine seeking reinstated by either cocaine-associated cues, or cocaine itself. One goal of such studies is to identify, and eventually to reverse the specific circuit activity that underlies the inability of some humans to control their drug use. Based on preclinical findings, we posit that circuit activity in humans also differs based on the triggers that precipitate craving and relapse, and that associated neural responses could help predict the triggers most likely to elicit relapse in a given person. If so, examining circuit activity could facilitate diagnosis of subgroups of addicted people, allowing individualized treatment based on the most problematic risk factors. [ABSTRACT FROM AUTHOR]