The Neurobiology of Cocaine Dependence and Its Clinical Implications

Cocaine dependence is a devastating disorder that is associated with a host of medical and psychosocial risks. This complex disorder is made up of distinct clinical components that are interwoven into a cycle of addiction (Figure 1). Cocaine activates ancient pleasure centers that dominate our thoughts, behaviors, and priorities, producing a pleasure-reinforced compulsion to use the drug. Repeated use dysregulates brain pleasure centers and paves the way to addiction through craving and impaired hedonic function.¹ Euphoria and craving drive the cycle of addiction through positive and negative reinforcement, respectively, and they provide targets for pharmacological interventions.

Cocaine may also dysregulate neurons in the prefrontal cortex (PFC), which is the part of the brain that weighs the motivation to use cocaine. PFC dysfunction, in turn, may contribute to loss of control and denial. Human and animal research has identified neuronal mechanisms that underlie many of the clinical aspects of cocaine dependence, support a disease concept,and provide guidance for urgently needed pharmacological treatments.²

Cocaine-induced euphoria
Cocaine produces pleasure that far exceeds the normal range of human experience and becomes inexorably crystallized in memory. The lure of cocaine euphoria should never be underestimated in clinical practice; its sheer power is illustrated by the fact that laboratory animals with unrestricted access to cocaine will self-administer until death. Cocaine produces a brief rush of pleasure and a constellation of stimulant effects (Table)³ that notably includes sexual arousal. Indeed, several lines of evidence indicate that cocaine activates sex reward circuits in the brain.³ Within minutes, cocaine pleasure gives way to intense craving that drives characteristic cocaine binges. As cocaine addiction progresses, individuals become increasingly willing to risk family turmoil, job loss, incarceration, medical problems, and even death in pursuit of the drug.

Cocaine euphoria has traditionally been ascribed to increased dopamine(Drug information on dopamine) neurotransmission in the nucleus accumbens (NAc), a "universal addiction site" where addictive drugs and natural rewards (eg, sexual behaviors) have long been known to increase dopamine levels.¹ Dopamine is released into the NAc by axons from the ventral tegmentum area (VTA), a reward-related midbrain region that also innervates the PFC, amygdala, and other limbic sites. Target neurons in the NAc have long axons that project to distant regions and release endogenous opioids (enkephalin or dynorphin) and γ-aminobutyric acid (GABA). These neurons have massive dendritic trees that can accommodate projections from as many as 400,000 neurons located in the PFC and other conscious structures,⁴ enabling the NAc to funnel, process, and transmit cortical information throughout reward-related circuits.

Cocaine increases synaptic dopamine levels in the NAc by blocking the dopamine transporter (DAT), a reuptake site that normally serves to clear dopamine from the synapse. Positron emission tomography (PET) demonstrates a close correlation between cocaine euphoria and the rate by which cocaine effectively binds the DAT.⁵ This explains why rapid routes of administration (eg, smoking, injecting) are associated with intense euphoria. PET studies using [¹¹C] raclopride, a radioligand that competes with dopamine at D₂ receptors, further demonstrate that stimulant euphoria is closely correlated with dopamine neurotransmission.⁵

Although this and other evidence for dopamine involvement in cocaine euphoria is compelling, glutamate is also important. Mice bred to lack the glutamatergic mGluR5 receptor will not self-administer cocaine, despite elevated dopamine levels in the NAc.⁶ Furthermore, it has recently been demonstrated that dopamine VTA neurons also release glutamate⁷ and form glutamatergic synaptic connections in the NAc.⁸ These and other findings suggest that cocaine euphoria requires concurrent glutamate and dopamine neurotransmission.⁹