Poor sensitization of 50-kHz vocalization response to amphetamine predicts rat susceptibility to self-administration of the drug

Abstract

RationaleOur previous studies showed promise for using sensitization of the frequency-modulated 50-kHz vocalization response to amphetamine (AMPH) as an index of rat vulnerability to AMPH addiction.ObjectiveThis study aimed to test the utility of sensitizing frequency-modulated (FM) 50-kHz vocalization in the AMPH self-administration paradigm as well as the ability of N-acetylcysteine to prevent self-administration relapse.MethodsRats were subjected to the so-called two-injection protocol of sensitization (TIPS) using AMPH and were categorized as low-sensitized callers (LCTIPS) or high-sensitized callers (HCTIPS) based on the individual outcomes. Then, they were given 44 sessions of AMPH self-administration followed by a 17-session N-acetylcysteine-aided extinction course and a single session of AMPH-primed self-administration reinstatement.ResultsLCTIPS compared to HCTIPS rats showed no considerable difference in the FM 50-kHz vocalization rate during the self-administration training or extinction course, but they were considerably more likely to acquire AMPH self-administration and experience drug-induced reinstatement of this trait. Moreover, the LCTIPS rats were more likely than HCTIPS rats to have a markedly higher FM 50-kHz vocalization rate after AMPH reinstatement. N-acetylcysteine did not affect the course of self-administration extinction or the instrumental or FM 50-kHz vocalization responses to AMPH reinstatement.ConclusionsThere is no link between the FM 50-kHz vocalization and key characteristics of AMPH self-administration. Additionally, N-acetylcysteine does not help prevent AMPH self-administration relapse. However, there is a high predictive value for poor sensitization of the FM 50-kHz vocalization response to AMPH with respect to the acquisition and maintenance of self-administration of this psychostimulant.

Amphetamine-induced prolonged disturbances in tissue levels of dopamine and serotonin in the rat brain

“…Studies by others have shown that the DA response to psychostimulants in addicted, detoxified individuals is impaired [ 46 – 48 ]. Similar conclusions have been drawn from the rat studies by Kuczenski and Segal, who believe that chronic Amph administration leads to decreased DA synthesis and tissue levels of DA [ 44 ]. As mentioned earlier, most studies focus on the acute effects of psychostimulants on the DA system, while the studies assessing the effects of drugs after prolonged abstinence focus on cocaine or methamphetamine (METH) [ 49 – 51 ].…”

“…The current study showed that repeated treatment with Amph-induced sensitization FM of 50-kHz USV rate. Our previous study showed that the rats exhibiting lower sensitivity to the rewarding effects of Amph self-administered more Amph [ 44 ] and the subsequent studies have shown that even a few doses of Amph induce long-term impairment of the DA system [ 45 ]. It seems interesting whether sensitivity to the rewarding effects of Amph is related to the persistence of the disturbances in DA and 5-HT levels after several weeks of the end of Amph administration.…”

“…The doses used were shown to have a rewarding effect and the TIPS procedure induced sensitization. This procedure [ 35 , 44 ], assumes that the first dose of the drug (day 1) induces sensitization, and the second dose (day 7) given after the time required for neurobiological changes to develop (6 days), reveals it [ 35 ]. Under this assumption, sensitization was assessed by the response to the second dose.…”

Mouse and rat ultrasonic vocalizations in neuroscience and neuropharmacology: State of the art and future applications

“…Moreover, and like what has been reported for the emission of 22‐kHz USVs, the emission of 50‐kHz USVs may reveal how individual traits influence the affective properties of drugs, and eventually the development of addictive‐like behaviors. This has been demonstrated in experimental models of amphetamine dependence, where the magnitude of sensitization in the emission of 50‐kHz USVs elicited by passive and repeated administration of amphetamine predicted the subsequent acquisition of amphetamine self‐administration (Taracha et al, 2016).…”

“…Moreover, rats treated with drugs that possess rewarding properties and have abuse potential may emit 50‐kHz USVs when exposed, in drug‐free conditions, to environmental cues previously paired with drug administration, a response that may reflect the presence of increased arousal stimulated by drug‐associated stimuli and the occurrence of environmental conditioning to the affective properties of drugs (Costa et al, 2020; Ma et al, 2010; Simola et al, 2014, 2016). At the same time, it has been demonstrated that the emission of 50‐kHz USVs may not fully overlap with other behaviors that are conventionally evaluated in rat models of drug dependence, such as conditioned place preference (CPP), sensitization in locomotor activity, and drug self‐administration (Browning et al, 2011; Knutson et al, 1998; Maier et al, 2012; Meyer et al, 2012; Simola & Morelli, 2015; Taracha et al, 2016). In this regard, it is noteworthy that drugs that have abuse potential may elicit either aversive or rewarding effects in rats, and that these effects are not necessarily paralleled by the manifestation of behaviors that are thought to mark the presence of drug‐induced modifications in arousal and emotional state (Verendeev & Riley, 2011).…”