Studies estimate that about 70% of the vulnerability for acquiring cocaine dependence is genetically determined10 and genetic factors that enhance cocaine euphoria are likely to increase addiction vulnerability. The availability of D2 receptors on PET is a constitutional trait that varies considerably among individuals, and stimulant-naive individuals with low D2 availability report markedly enhanced euphoria after their first stimulant dose.11 Since low D2 availability has been reported in patients addicted to cocaine,5,12 methamphetamine,13 alcohol(Drug information on alcohol),14 and opioids,5 it may mark an inherited vulnerability to addictive illness.
Studies also demonstrate that low D2 availability can be acquired, since cocaine administration in nonhuman primates produces low D2 availability along with an increased propensity to self-administer cocaine.15 Furthermore, low D2 availability is associated with reduced metabolism in the PFC in cocaine dependence.5 This fascinating marker is among the most promising findings in addiction neurobiology.
Blocking drug euphoria is an established pharmacological strategy to weaken the cycle of addiction. Although cocaine euphoria is associated with increased dopamine(Drug information on dopamine) and glutamate neurotransmission, neither GABA agonists (which reduce dopamine and glutamate release) nor dopamine antagonists convincingly blunt euphoria in controlled studies.3,16 A vaccine that blocks the euphoric effect of cocaine by slowing its passage across the blood-brain barrier is under investigation,17 and 2 separate research groups have reported that modafinil(Drug information on modafinil) blocks cocaine euphoria under controlled conditions.18,19 It is not known how modafinil blocks cocaine euphoria, but its ability to bind the DAT20 might prevent access to cocaine. Modafinil promoted cocaine abstinence in a controlled pilot study,21 and it is currently under investigation in 3 large, government-sponsored clinical trials.
Cocaine withdrawal and hedonic dysregulation
Cocaine users may experience withdrawal symptoms that are opposite those seen during intoxication (Table) and probably reflect brain changes associated with severe addiction.22 Unlike withdrawal symptoms produced by alcohol, sedatives, and opioids, cocaine withdrawal has never been deemed sufficiently protracted or severe to warrant medical detoxification. It was therefore surprising to find that the presence of withdrawal symptoms at treatment onset reliably predicts poor clinical outcome.22 This finding suggests that cocaine withdrawal is just a tip of the iceberg that marks more persistent dysregulation of brain pleasure circuits by chronic exposure to cocaine3; this dysregulation is demonstrated by neuroimaging abnormalities in addicted patients,5 altered neurotransmitter and receptor levels,9 changes in gene expression,23 elevated reward thresholds,24 and even distortions in neuronal morphology associated with the cocaine-addicted brain.25
Evidence that chronic cocaine use produces dopamine hypoactivity is provided by neuroimaging studies in addicted patients26,27 and by several lines of human and animal research that have been reviewed elsewhere.9 Patients with cocaine addiction who have evidence of dopamine hypoactivity have very poor clinical outcomes,28 and dopamine depletion has long been associated with cocaine-induced hedonic dysregulation and baseline craving.29
Chronic cocaine exposure may suppress dopamine activity through dynorphin, an aversive endogenous opioid that inhibits VTA neurons via k-opioid receptors (Figure 2). Autopsy studies show high levels of dynorphin and k-opioid receptors in cocaine abusers,30 as well as dopamine depletion,31 and hedonic dysregulation associated with elevated reward thresholds is produced by k-opioid agonists in animal models.32
Animal studies also demonstrate that chronic exposure to cocaine depletes glutamate33 and elevates GABA34 in the NAc, which would suppress spike formation in this reward region. Dopamine (D2)35 and glutamate (mGluR2/3)36 autoreceptors are also down-regulated after cocaine treatment, perhaps to compensate for dopamine and glutamate depletion. Similarly, the finding of low D2 availability in patients addicted to cocaine5 may reflect autoreceptor down-regulation in response to dopamine hypoactivity.37
Reversing cocaine-induced neuroadaptations with dopamine/glutamate agonists or GABA/dynorphin antagonists might normalize hedonic function and improve clinical outcome. Selective k-opioid antagonists are not currently available, but 2 randomized, placebo-controlled studies of dopamine-enhancing agents have recently been reported. Modafinil (400 mg/d), a weak DAT antagonist, promoted abstinence in cocaine-dependent participants (n = 62),21 as did disulfiram(Drug information on disulfiram) (250 mg/d; n = 121),38 which may increase brain dopamine levels by inhibiting dopamine b-hydroxylase. Conversely, the dopamine antagonist olanzapine(Drug information on olanzapine) (10 mg/d) actually increased cocaine use under controlled conditions (n = 30).39 Hedonic dysregulation resulting from chronic cocaine administration has not been adequately researched, and reliable measures of hedonic function are curiously absent in a scientific community that measures nearly everything else.