Incentive and dopamine sensitization produced by intermittent but not long access cocaine self-administration

Abstract

242 Manuscript -9002ABSTRACT Recent studies suggest that the temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self-administered cocaine to produce addiction-like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of Long Access (LgA) cocaine self-administration, which is widely used to model the transition to addiction, with Intermittent Access (IntA), which is thought to better reflect the pattern of drug use in humans, on the ability of self-administered cocaine to increase dopamine (DA) overflow in the core of the nucleus accumbens (using in vivo microdialysis), and to produce addiction-like behavior. IntA experience was more effective than LgA in producing addiction-like behavior -a drug experience-dependent increase in motivation for cocaine assessed using behavioral economic procedures, and cue-induced reinstatement -despite much less total drug consumption. There were no group differences in basal levels of DA in dialysate, but a single self-administered IV injection of cocaine increased DA in the core of the nucleus accumbens to a greater extent in rats with prior IntA experience than those with LgA or Short Access (ShA) experience, and the latter two groups did not differ. Furthermore, high motivation for cocaine was associated with a high DA response. Thus, IntA, but not LgA, produced both incentive and DA sensitization. This is consistent with the notion that a hyper-responsive dopaminergic system may contribute to the transition from casual patterns of drug use to the problematic patterns that define addiction.

Taking rapid and intermittent cocaine infusions enhances both incentive motivation for the drug and cocaine-induced gene regulation in corticostriatal regions

“…This is especially likely when one considers the very different effects LgA and IntA cocaine experience produce within the dopamine system. Psychostimulant drugs increase immediate early gene expression in part by enhancing dopamine neurotransmission (Ferguson et al, 2003;Graybiel et al, 1990;Ruskin and Marshall, 1994;Young et al, 1991), and LgA cocaine experience promotes tolerance to cocaine's dopamine-elevating effects, while IntA cocaine experience promotes sensitization (Allain et al, 2020;Calipari et al, 2014;Calipari et al, 2013;Ferris et al, 2011;Kawa et al, 2018;Siciliano et al, 2018). A possibility here is that the c-fos mRNA response we measured reflects the neural response not only to cocaine intake, but to the cocaine-paired context/cues as well.…”

“…Our IntA-5s rats also did not escalate their intake over sessions. IntA experience can produce escalation of intake (Allain et al, 2018;Allain and Samaha, 2018;James et al, 2018;Kawa et al, 2016;Kawa et al, 2018;Pitchers et al, 2017a;Pitchers et al, 2017b;Singer et al, 2018). However, here we limited cocaine intake during each IntA session, and this precludes escalation (also see Allain et al, 2018).…”

Hierarchical cue control of drug seeking in the face of cost

“…Furthermore, drug-paired cues evoke dopamine release (Ito et al 2000; Aragona et al 2009), and NAc dopamine signaling is required for drug-associated contextual information to renew cocaine seeking (Chaudhri et al 2009; Saunders et al 2014), suggesting that dopamine may track both proximal and state-level drug related information. Intermittent access to cocaine promotes sensitization of dopamine release and cocaine’s actions on the dopamine transporter in the NAc (Calipari et al 2013, 2015; Kawa et al 2019b). A key future direction will be to assess the impact of cocaine use on in vivo dopamine signaling dynamics during drug self administration and relapse wherein hierarchical cue relationships mitigate behavior.…”

“…A growing body of preclinical work has made use of intermittent access schedules that promote rapid spikes in brain drug levels, which uniquely drive exaggerated motivation and striatal plasticity that is important in addiction (Zimmer et al 2012; Bentzley et al 2013; Calipari et al 2013; Kawa et al 2019b; Allain and Samaha 2019; Carr et al 2020; Samaha et al 2021). Earlier studies demonstrated that the pharmacokinetics of drugs, rather than the absolute amount of a drug, powerfully determines their ability to engage brain reward systems and behavior (Budney et al 1993; Cone 1995; Samaha et al 2002, 2005; Allain et al 2015; Kawa et al 2019a; Canchy et al 2021).…”

Cocaïne en « dents de scie »

“…Lors d'un accès continu à la cocaïne, les niveaux de drogue dans le cerveau restent élevés pendant toute la session d'auto-administration de drogue [7,11], ce qui ne reflète vraisemblablement pas la réalité clinique [4]. Par ailleurs, des rats avec un accès continu à la cocaïne consomment beaucoup plus de drogue que des rats qui ont un accès intermittent à la drogue (jusqu'à 8 fois plus), mais les comportements symptomatiques d'un trouble d'usage de la cocaïne sont d'autant plus présents chez les rats intermittents [2,7,11,[15][16][17][18] (Figure 2). Cela suggère qu'une consommation intermittente de cocaïne est particulièrement efficace pour induire des signes comportementaux pertinents pour l'addiction.…”