Dopamine 'ups and downs' in addiction revisited

Abstract

Repeated drug use can change dopamine (DA) function in ways that promote the development and persistence of addiction, but in what direction? By one view, drug use blunts DA neurotransmission, producing a hypodopaminergic state that fosters further drug use to overcome a DA deficiency. Another view is that drug use enhances DA neurotransmission, producing a sensitized, hyperdopaminergic reaction to drugs and drug cues. According to this second view, continued drug use is motivated by sensitization of drug 'wanting'. Here we discuss recent evidence supporting the latter view, both from preclinical studies using intermittent cocaine self-administration procedures that mimic human patterns of use and from related human neuroimaging studies. These studies have implications for the modeling of addiction in the laboratory and for treatment.

Keywords: cocaine; dopamine; rat; self-administration; sensitization; tolerance.

Figure 1.. How intermittent- versus long-access cocaine self-administration change dopamine system function.

(A) Representative patterns of cocaine intake, and (B) estimated brain cocaine concentrations in rats self-administering the drug during a long-access (LgA) or intermittent-access (IntA) session (adapted from [13]). (C) Schematic representation of the effects of LgA and IntA cocaine experience on dopamine (DA) system function in the Nucleus Accumbens during the development of addiction. The schematics in (C) represent relative effects in relation to control levels (see below), and summarize effects as measured ex vivo by electrically-evoked DA release and cocaine-induced DA transporter inhibition, and in vivo by cocaine-induced increases in DA concentrations (see text; “Preclinical Models of Addiction: Intermittent Access (IntA)”). The dotted line illustrates control levels, as assessed either in rats with ShA cocaine experience or in cocaine-naïve rats. As shown in (A), under LgA, cocaine is continuously available throughout the session, and rats take cocaine at regular intervals. In contrast, under IntA, cocaine is only available in discrete periods, and rats take cocaine intermittently, which models the intermittency of cocaine use typical in human cocaine users. As shown in (B), LgA produces relatively steady-state brain cocaine concentrations, and IntA produces spiking brain cocaine concentrations. As illustrated in (C), LgA promotes tolerance and a hypodopaminergic state, whereby cocaine-induced DA responses are blunted. The shading illustrates that some studies report unchanged drug-induced DA responses after LgA cocaine experience, relative to control levels. In contrast to LgA, IntA consistently produces sensitization and a hyperdopaminergic state, whereby cocaine-induced DA responses are enhanced. Of note, studies to date have assessed DA responses within the first week of abstinence, and most studies have also focused on cocaine-induced DA responses. In future work, DA responses to drug, cues and under baseline conditions should be examined across the abstinence period.