The missing variable: ultrasonic vocalizations reveal hidden sensitization and tolerance-like effects during long-term cocaine administration

Abstract

Rationale Subtypes of 50-kHz ultrasonic vocalizations (USVs) in rats are thought to reflect positive affect and occur with cocaine or amphetamine delivery. In contexts predicting forthcoming cocaine, pre-drug anticipatory USVs are initially minimal during daily sessions but gradually escalate over several weeks, presumably as the animal learns to expect and look forward to impending drug access. To gain more insight into motivational aspects of cocaine intake in animal models of drug dependence studies, it is important to compare experience-dependent changes in lever response rate, USVs and locomotion during cocaine conditioning and extinction trials. Objective To address whether cocaine-induced increases in lever responding and locomotor activity correspond with USV production. The study also determined whether short-term cocaine and context deprivation effects could be detected during conditioning or extinction. Methods Rats underwent 20 days of 60-min sessions of self- or yoked administration of cocaine (0.75 mg/kg/infusion, i.v.), followed by 19 days of extinction training (8 weeks total, weekends off). Results Lever responding for cocaine and cocaine-induced locomotor activity increased across conditioning sessions. In contrast, the number of frequency modulated (FM) 50-kHz USVs evoked in response to cocaine infusion decreased with cocaine experience, suggesting perhaps tolerance to the rewarding properties of the drug. In addition, USVs but not lever pressing or locomotion are affected after brief periods of drug and/or drug context abstinence. Conclusions Except for initial drug exposure, increased cocaine seeking during cocaine delivery could reflect either enhanced drug motivation or the development of drug tolerance, but not enhanced positive affect.

Individual differences in food cue responsivity are associated with acute and repeated cocaine-induced vocalizations, but not cue-induced vocalizations

“…In line with this idea, additional studies have shown that individuals exhibiting USV sensitization to psychostimulant drugs will also display a conditioned escalation in USVs in response to the drug-associated context alone (Ahrens et al 2009; Meyer et al 2012b; Simola and Morelli 2015). Although our study did not specifically test context-induced USVs, it can be noted that some sign-trackers immediately began producing USVs upon entering the chamber on all days following the first cocaine treatment, even though peak levels of cocaine in the brain are not achieved until 10 minutes after the injection (Javaid and Davis 1993; Maier et al 2012). These USVs could be a result of the conditioned effects of the context itself, possibly in anticipation of cocaine's effects (Ma et al 2010).…”

“…However, drugs including cocaine have other unconditioned effects, including the ability to elicit 50 kHz ultrasonic vocalizations (USVs; Browning et al 2011; Ma et al 2010; Maier et al 2012; Meyer et al 2012b). These USVs have been proposed to have a communicative purpose, and also to serve as an expression of motivational and affective states in rodents (Knutson et al 2002; Portfors and Perkel 2014; Radziwon and Dent 2014; Brudzynski 2013; Wohr and Schwarting 2013).…”

Alcohol enhances unprovoked 22–28kHz USVs and suppresses USV mean frequency in High Alcohol Drinking (HAD-1) male rats

“…Rodents emit USVs in the 50–55 kHz and 22–28 kHz ranges, which are reliably associated with positive and negative emotional states, respectively [15–17]. USVs have received increased attention in drug abuse studies because administration of cocaine [18], amphetamine [19] and drug-associated cues [20, 21] increase 50–55 kHz frequency-modulated (FM) USV emissions. In addition, escalated levels of alcohol consumed by alcohol-dependent rats are significantly correlated with alcohol anticipatory 50–55 kHz FM USVs [22] and alcohol-dependent rats in a state of withdrawal are more easily provoked to emit negative affect-associated 22–28 kHz USVs by mild aversive stimuli [23, 24].…”

Effects of the phencyclidine model of schizophrenia and nicotine on total and categorized ultrasonic vocalizations in rats

“…Ultrasonic vocalizations have recently come to attention as potential measures of the emotional and motivational states of rats, including reward (Panksepp & Burgdorf, 2000; Browning et al, 2011; Maier et al, 2012; Mu et al, 2009). Specifically, 50 kHz vocalizations are typically emitted in reinforcer-associated contexts (Brunelli et al, 2006; Knutson et al, 1998; Panksepp & Burgdorf, 2000; Sales, 1972; Schwarting et al, 2007; White et al, 1990) while 22 kHz vocalizations are generally associated with aversive situations (Francis, 1977; Jelen et al, 2003; Tonoue et al, 1986; Wohr et al, 2005; Mead et al, 2008; Sun et al, 2010).…”