This is in contrast to cocaine abuse, where administration is less intense and frequent (American Psychiatric Association 2000).
According to the 2007 results from the National Survey on Drug Use and Health, 1.6 million Americans abused or were dependent on cocaine during the previous year, underscoring the need for treatment of cocaine dependence. The hallmark of cocaine dependence, and perhaps its most problematic aspect, is the propensity to ► relapse. Cocaine dependent individuals undergo treatment and abstinence from drug use and yet still face considerable desire to consume the drug (craving) and there are high rates of return to drug use (relapse). Clearly, the brains of such individuals have been altered by the repeated drug use such that the individuals have diminished control over their behavior. In addition, drug-seeking will take priority over the pursuit of natural rewards, i.e., reduced drive to obtain natural rewards. The transition from cocaine use to cocaine dependence takes place in different stages. The initial stage is characterized by repetitive, social use of the drug and changes in neural chemistry are largely due to the pharmacological action of the drug itself (Fig. 1). The second stage is defined by persistent changes in the brain circuits that regulate cognitive and emotional responses to environmental stimuli.
Cocaine Dependence. Fig. 1. The transition from cocaine use to cocaine dependence and the relationship with neuroplasticity. Social use can lead to regulated relapse, which can progress into compulsive relapse. This is typified by stable cocaine-induced neuroplasticity and the individual has "learned" to become addicted.
This is accompanied by regulated relapse where the individual consciously decides to relapse. It is therefore a declarative decision-making process to engage in cocaine-taking behavior. Eventually, regulated relapse can progress into compulsive relapse which is a procedural decision-making process and the individual relapses with relatively less consideration of environmental contingencies. Compulsive relapse can be triggered by environmental cues or stressors that were previously associated with drug use (Kalivas and O'Brien 2008). At this stage the cocaine-dependent brain exhibits stable cocaine-induced ► neuroplasticity and the individual has "learned" to become addicted. Accordingly, over the past two decades, a shift has occurred, in which drug addiction is now viewed as a disorder of learning and memory and motivation (Hyman 2005).
Cocaine can be insufflated (intranasal), inhaled (smoked, "freebased," "crack"), or injected. Smoked (freebase, crack) cocaine is derived from cocaine hydrochloride (HCl) using ammonia or sodium bicarbonate. This converts cocaine HCl into freebase cocaine, since most of the HCl form is destroyed by heat. Users report a greater "high" for smoked cocaine versus intranasal cocaine and a faster subjective "peak" versus intravenous and intranasal cocaine. Both the "high" and "feel of drug'' peak faster for smoked (1-2 min) compared to intravenous (3-4 min) and intranasal cocaine (10-15 min). By contrast, intravenous cocaine provides the highest blood levels, but it has been suggested that smoked cocaine reaches sooner in the brain. The user initially experiences a euphoric state which is soon followed by cocaine-induced dysphoria. This dys-phoric feeling contributes to the repeated use of cocaine, since the user wants to re-experience the initial euphoric rewarding state. Even though cocaine withdrawal lacks overt physical manifestations compared to some other drugs of abuse, the user is subjected to severe psychological withdrawal symptoms. Cocaine dependence often shares comorbidity with other psychiatric disorders (Vocci and Ling 2005). The self-medication hypothesis has been proposed as a possible explanation for cocaine dependence and depression comorbidity, but it does not explain the majority of cocaine dependence.
Different routes of administration are associated with specific side effects. For instance, intranasal cocaine administration could lead to septal necrosis and palatal perforation. Smoking freebase cocaine volatizes the drug and exposes the lungs directly to the smoked mixture, thereby increasing the risk of adverse pulmonary effects and complications. These include interstitial pneu-monitis, fibrosis, pulmonary hypertension, alveolar hemorrhage, asthma exacerbation, barotrauma, thermal airway injury, hilar lymphadenopathies, and bullous emphysema either directly due to the drug itself or associated cutting substances such as talc, silica, and lactose. Intravenous cocaine administration could lead to HIV, hepatitis, and systemic infections such as abscesses and bacteremia due to needle sharing and lack of sterile injection techniques.
After acute administration, there is an increase in dopaminergic neurotransmission in the mesolimbic ► dopamine pathway of the ventral tegmental area (VTA) and the ► nucleus accumbens (NAc), which is followed by the release of dopamine in the NAc, a reward-related brain structure. In addition, cocaine also inhibits the ► dopamine transporter (DAT), by blocking reuptake and thereby increasing extracellular dopamine. The VTA-NAc pathway also mediates the effects of natural rewards such as food and sex. Chronic cocaine use leads to an impaired dopamine system and the baseline levels of dopamine are reduced. Over time, repeated cocaine administration will lead to a sensitized dopaminer-gic response to the drug or to drug-associated cues from the VTA-NAc, while natural rewards will become less effective in increasing dopaminergic transmission (Koob and Le Moal 2008). In addition, the amplitude and duration of the dopamine release is greater after cocaine administration compared to natural rewards (Fig. 2). Furthermore, there is an increase in dopaminergic neurotransmission from the VTA to the ► prefrontal cortex
Cocaine Dependence. Fig. 2. Hypothetical histogram illustrating the changes in dopamine release to biological and cocaine reward. Repeated cocaine administration will lead to a sensitized dopaminergic response to the drug or to drug-associated cues, while natural rewards will become less effective in increasing dopaminergic transmission. Furthermore, the amplitude and duration of the dopamine release is greater after cocaine administration compared to natural rewards.
(PFC) and basolateral ► amygdala (BLA). At a molecular level, D1 and D2 receptors exert opposite effects: D2 receptors respond to numerous environmental stimuli while D1 receptors only respond to the strongest stimuli. Chronic cocaine administration promotes a shift toward a D1-like state. This is accomplished in part through an induction of AGS3 (activator of G protein signaling-3), a protein which is a negative regulator of Gi and therefore of D2 signaling.
In addition to having effects on the dopaminergic system, chronic cocaine use also causes reduced basal activity in the glutamatergic pathway from several areas of the PFC to the NAc. These areas include the anterior cingu-late and orbitofrontal cortices and contribute to executive functions, such as working memory, attention, and behavioral inhibition. The PFC-NAc pathway also mediates the impulsivity and compulsivity to engage in drug taking. Cortical neurons show a decrease in basal glutamatergic neurotransmission, while being hypersensitive to cocaine and cocaine-associated cues. The increase in glutamatergic neurotransmission from the PFC to the NAc corresponds to the increase in dopaminergic neurotransmission from the VTA to the PFC, BLA, and NAc. Human neuroimaging data have confirmed that there is a general reduction in cortical cellular metabolism and blood flow (Goldstein and Volkow 2002). Given the importance of the anterior cingulate cortex in regulating biologically motivated behaviors, and activation of the ventral orbital cortex, this hypofron-tality has been characterized as a strong indicator of the reduced ability of addicts to regulate drug-seeking. Presentation of a cue previously associated with cocaine use activates the PFC, including the anterior cingulate and ventral orbital cortices. This activity is positively correlated with the intensity of the cue-induced desire for the drug and is larger than the activation of the PFC in control subjects after presentation of natural reward-related cues. By contrast, presentation of the same natural reward-related cues to cocaine addicts results in reduced PFC activity compared to controls. This is in accordance with the dogma that addicts show an impaired response to natural rewards.
On a cellular level, dysregulation of glutamatergic neurotransmission due to downregulation of the cystine-glutamate exchanger (system xc-) and presynaptic ► metabotropic glutamate receptors (mGluR's) has been established in preclinical models of cocaine dependence. Cells use cystine to synthesize the intracellular antioxidant glutathione by exchanging the uptake of one cystine for the release of one molecule of intracellular ► glutamate into the extracellular space. The nonsynaptic glutamate in the extracellular space stimulates inhibitory presynaptic
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