Chronic Fentanyl Self-Administration Generates a Shift toward Negative Affect in Rats during Drug Use.

Drug addiction is thought to be driven by negative reinforcement, and it is thought that a shift from positive affect upon initial exposure to negative affect after chronic exposure to a drug is responsible for maintaining self-administration (SA) in addicted individuals. This can be modeled in rats by analyzing ultrasonic vocalizations (USVs), a type of intraspecies communication indicative of affective state based on the frequency of the emission: calls in the 22 kHz range indicate negative affect, whereas calls in the 50 kHz range indicate positive affect. We employed a voluntary chronic, long-access model of fentanyl SA to analyze affective changes in the response to chronic fentanyl exposure. Male Sprague-Dawley rats self-administered either fentanyl (N = 7) or saline (N = 6) for 30 consecutive days and USVs were recorded at four different time points: the day before the first SA session (PRE), the first day of SA (T01), the last day of SA (T30), and the first day of abstinence (ABS). At T01, the ratio of 50 to 22 kHz calls was similar between the fentanyl and saline groups, but at T30, the ratio differed between groups, with the fentanyl group showing significantly fewer 50 kHz calls and more 22 kHz calls relative to saline animals. These results indicate a shift toward a negative affect during drug use after chronic exposure to fentanyl and support negative reinforcement as a main driving factor of opioid addiction.