Repeated intravenous cocaine experience: development and escalation of pre-drug anticipatory 50-kHz ultrasonic vocalizations in rats

Abstract

Ultrasonic vocalization (USV) in the 50-kHz range occurs in rats immediately upon first-time exposure to cocaine or amphetamine, and rapidly increases with repetitive drug exposure at the same dose. This sensitized positive-affect response to these drugs of abuse is persistent in that the peak level of USVs again appears when the drug is reintroduced after several weeks of drug discontinuation. The present study explored whether with enough experience USVs might be elicited, and gradually escalate, in anticipation of impending drug delivery. Rats were trained to self-administer (SA) cocaine intravenously by lever pressing 5 days per week for 4 weeks. Yoked rats received experimenter-delivered cocaine matching that of SA rats. USVs and locomotor activity were recorded during each 10-min period prior to 60-min drug access sessions. Extinction trials in which drug access was denied were then carried out over an additional 4-week period. After about a week of cocaine experience, both the SA and yoked groups began to progressively increase USVs when placed in an environment that predicted forthcoming drug exposure. Extinction of anticipatory calls and locomotion occurred over days after drug access ended. USVs may be a useful model for specifically investigating the neural basis of drug anticipation and aid in developing and assessing new addiction treatment strategies for reducing craving and relapse.

Figure 1. Anticipatory USV Acquisition

50-kHz USVs (mean ± SEM) of SA (self-administering) and Yoked rats recorded during daily (Days 1–20) 10-min intervals prior to Conditioning sessions for SA Cocaine (filled circle, n = 7), Yoked Cocaine (filled trident, n = 6), SA Saline (open circle, n = 6) and Yoked Saline (open trident, n = 5) groups. Mean USVs across all Conditioning sessions were significantly greater in both Cocaine groups compared to either Saline group. Posthoc comparisons (LSD) revealed differences between groups on specific days. *, ** = significantly more USVs elicited than either or both Saline conditions; p < 0.05 or p < 0.01, respectively. No long-duration 22-kHz calls were detected in any animals during this interval.

Figure 2. Conditioned Locomotor Activity During Acquisition

Locomotor activity (photobeam interruptions) recorded during 10-min intervals prior to Conditioning sessions. Data presented as the mean (± SEM) daily intervals for SA Cocaine (filled circle) Yoked Cocaine (filled trident), SA Saline (open circle) and Yoked Saline (open trident) groups (same animals as in Fig 1). Mean locomotor activity across all pre-Conditioning intervals was significantly greater in the SA Cocaine group than either Saline group, and in the Yoked Cocaine group compared to the Yoked Saline group (p < 0.01). Posthoc comparisons (LSD) revealed group differences on specific days. *, ** = significantly greater daily mean than either or both Saline conditions; p < 0.05 or p < 0.01, respectively. ^ = significantly greater than Yoked Cocaine group; p <0.05.

Figure 3. Anticipatory USVs During Extinction

50-kHz USVs (mean ± SEM) of SA (self-administering) and Yoked rats recorded during daily (Days 21–39) 10-min intervals prior to Extinction sessions for SA Cocaine (filled circle, n = 6) Yoked Cocaine (filled trident, n = 6), SA Saline (open circle, n = 6) and Yoked Saline (open trident, n = 5) groups. Mean USVs across Extinction sessions were significantly greater in the Yoked Cocaine (but not SA Cocaine) group than either Saline group. Posthoc tests (LSD) revealed that USVs in the Yoked Cocaine group (but not the SA Cocaine group) remained significantly higher than controls over several days. *, ** = significantly greater daily mean than either or both Saline conditions; p < 0.05 or p < 0.01, respectively. No long-duration 22-kHz calls were detected in any animals prior to Extinction sessions.

Figure 4. Conditioned Locomotor Activity During Extinction

Locomotor activity (photobeam interruptions) recorded during 10-min intervals prior to Extinction sessions. Locomotor activity data presented as the mean (± SEM) daily intervals for SA Cocaine (filled circle) Yoked Cocaine (filled trident), SA Saline (open circle) and Yoked Saline (open trident) groups (same animals as in Fig 3). Over the course of Extinction sessions, locomotor activity in the SA Cocaine group decreased, but was significantly greater overall compared to the Yoked Saline group (p < 0.01).