Neurobiologic Processes in Drug Reward and Addiction

Abstract

Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These"hard-wired"changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.

Relapse to smoking during unaided cessation: clinical, cognitive and motivational predictors

“…This system is activated during drug craving and shows structural and functional abnormalities in current and former users of many addictive substances including nicotine (e.g. Adinoff, 2004;Rose et al, 2007). Volkow et al (2009) argue that addicts' reward systems are hyporeactive and thus respond weakly to non-drug reinforcers, but, through a history of associative learning, respond disproportionately strongly to cues paired repeatedly with drug use.…”

The Role of Acetylcholine in Cocaine Addiction

“…From a clinical perspective, this neurobiologic interconnectiveness suggests that a combination of cholinergic and dopaminergic modulation may be the optimal treatment approach for the cocaine-dependent patient. For example, most studies of DA agonists have not provided strong signals in the treatment of cocaine dependence (Adinoff, 2004). The addition of a cholinomimetic may enhance the effects of a dopaminergic agonist in the NAc.…”

“…Dopamine (DA) has been identified as the critical neurotransmitter in the reward circuitry mediating substance abuse and the primary focus of preclinical research and clinical treatment interventions (Adinoff, 2004;Di Chiara et al, 2004;Self, 2004). DA levels abruptly increase following the administration of many drugs of abuse, including cocaine, and cocaine is no longer self-administered in animal models of addiction following DA receptor blockade within the nucleus accumbens (NAc) (Chang et al, 1994).…”

Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression

“…Increases in nucleus accumbens neuron activity and dopamine release are observed during expectations and experience of rewards (Adinoff, 2004;de la Fuente-Fernandez et al, 2002;Doyon et al, 2005;Schultz, 2004). Converging evidence of the accumbens' role in reward processing comes from neuroimaging studies, which show increases in ventral striatal activity associated with euphoric responses to dextroamphetamine (Drevets et al, 2001), cocaine-induced euphoria (Breiter et al, 1997), monetary reward (Cohen et al, 2005;Knutson et al, 2001a;O'Doherty et al, 2001), pleasurable responses to music (Blood and Zatorre, 2001), and viewing attractive faces (Aharon et al, 2001).…”