Cocaine Dependence - Mechanism of Dependence

Mechanism of Dependence

It is speculated that cocaine's intense addictive properties stem partially from its DAT-blocking effects (in particular, increasing the dopaminergic transmission from ventral tegmental area neurons). However, a study has shown that mice with no dopamine transporters still exhibit the rewarding effects of cocaine administration. Later work demonstrated that a combined DAT/SERT knockout eliminated the rewarding effects. The rewarding effects of cocaine are influenced by circadian rhythms, possibly by involving a set of genes termed "clock genes".

There is a correlation between a variant of the CAMK4 gene and cocaine addiction; a German study found that addicts were 25% more likely to have a variant of the gene than people who did not use cocaine.

However, chronic cocaine addiction is not solely due to cocaine reward. Chronic repeated use is needed to produce cocaine-induced changes in brain reward centers and consequent chronic dysphoria. Dysphoria magnifies craving for cocaine because cocaine reward rapidly, albeit transiently, improves mood. This contributes to continued use and a self-perpetuating, worsening condition, since those addicted usually cannot appreciate that long-term effects are opposite those occurring immediately after use.

Research has shown that chronic cocaine use reduces the expression of a protein, called Rac1, known to regulate brain plasticity, producing a greater sensitivity to the rewarding effects of cocaine. This results in large increase in the number of physical protrusions or spines that grow out from the neurons in the reward center of the brain.