Dopamine ‘ups and downs’ in addiction revisited

Abstract

Repeated drug use can change dopamine function in ways that promote the development and persistence of addiction. But in what direction? By one view, drug use blunts dopamine neurotransmission, producing a hypodopaminergic state that fosters further drug use to overcome a dopamine deficiency. Another view is that drug use enhances dopamine 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 related human neuroimaging studies. These studies have implications for modeling addiction in the laboratory, and for treatment.

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

“…This intermittency promotes rapid, binge-like drug intake that may better approximate some human drug use patterns. Intermittent self administration of cocaine, alcohol, and opioids, despite resulting in much less total drug intake compared to extended access models, promotes escalation of intake and elevated drug craving ( Simms et al, 2008 ; Zimmer et al, 2012 ; Calipari et al, 2013 ; Kawa et al, 2016 ; O’Neal et al, 2020 ; Fragale et al, 2021 ; Samaha et al, 2021 ). Binge-like self administration can also develop in rats given extended, continuous access to cocaine, and individual differences in binge patterns early in self administration training predict the intensity of future use ( Tornatzky and Miczek, 2000 ; Belin et al, 2009 ).…”

“…Repeated drug exposure, via passive administration or self administration, generally increases DA signaling in the NAc and produces exaggerated drug seeking motivation ( Robinson and Berridge, 2001 ). Recent work, however, highlights how the pattern of drug intake can produce starkly different effects on mesostriatal DA circuits (reviewed in Samaha et al, 2021 ). Extended or long access to drug self administration, which produces escalation of drug intake, craving, and other addiction-like behaviors across a variety of drug types ( Ahmed and Koob, 1998 ; Vanderschuren and Ahmed, 2013 ; Ahmed, 2018 ), is also associated with blunted drug-evoked NAc DA signaling, especially in cocaine use models ( Mateo et al, 2005 ; Calipari et al, 2014 ; Willuhn et al, 2014 ; Siciliano et al, 2015 ).…”

“…The route of delivery affects the pharmacological impact that drugs have on the brain and peripheral physiology, producing unique neurobiological changes and vulnerabilities to addiction-like behaviors ( Jones, 1990 ; Gossop et al, 1992 ; Cone, 1998 ; Allain et al, 2015 ). Intravenous injection and smoking produce the fastest rise and highest drug concentration in the blood, which is associated with greater DA signaling and neural activity in reward circuits ( Samaha et al, 2021 ). Notably, the large majority of drug self administration animal models have relied on intravenous or oral consumption drug delivery, which may obscure unique neurobiological and behavioral adaptations produced by other delivery routes.…”

Restriction of dietary fat, but not carbohydrate, affects brain reward regions in adults with obesity

“…An increase in tonic dopamine during the RF diet may have contributed to the tendency to increase selection of high-fat, high-carbohydrate foods observed during the subsequent ad libitum period. Elevations in tonic dopamine alter the balance with phasic dopamine responses (Grace 2000) and may increase incentive salience (Wise 2013, Samaha, Khoo et al 2020), enhance the ‘wanting’ of foods high in both carbohydrate and fat that are particularly rewarding (DiFeliceantonio, Coppin et al 2018, Perszyk, Hutelin et al 2021), promote selection of these foods previously experienced to deliver reward (Beeler, Daw et al 2010) and reduce the influence of any ensuing negative outcomes on changing behavior (Cox, Frank et al 2015). Thus, our results suggest that diet approaches targeting the reduction of dietary fat may alter brain dopamine in a way that promotes consumption of highly rewarding foods high in both carbohydrate and fat.…”

Neuroplasticity and Multilevel System of Connections Determine the Integrative Role of Nucleus Accumbens in the Brain Reward System

“…Drug abuse changes the effectiveness of DA neurotransmission in synapses of the reward system structures, especially within NAc. The nature of these changes depends on a type of addictive substance [65,68]. The dopaminergic system has a multidirectional effect not only on the neuronal activity but also on the synaptic plasticity and molecular processes related to the gene expression and epigenetic modifications [69,70].…”