Central amygdala, dynorphins, CRF and negative addiction - re cocaine

http://www.sciencedaily.com/releases/2013/06/130612144735.htm

cocaine-induced changes in this brain system contribute to anxiety-like behavior and other unpleasant symptoms of drug withdrawal -- symptoms that typically drive an addict to keep using. When the researchers blocked specific brain receptors called kappa opioid receptors in this key anxiety-mediating brain region, the rats' signs of addiction abated.

While changes in these pleasure-seeking brain networks may dominate the early period of drug use, scientists have been finding evidence of changes in the "negative" motivational circuitry as well -- changes that move a person to take a drug not for its euphoric effects but for its (temporary) alleviation of the anxiety-ridden dysphoria of drug withdrawal...George F. Koob, chair of TSRI's Committee on the Neurobiology of Addictive Disorders, has argued that these "dark side" brain changes mark the transition to a more persistent drug dependency. 

Found abundantly in the central amygdala, CRF receptors become persistently overactive there as drug use increases, and that overactivity helps account for the negative symptoms of drug withdrawal.

The central amygdala also contains a high concentration of a class of neurotransmitters called dynorphins, which bind to kappa opioid receptors. Much like the CRF system, the dynorphin/kappa opioid system mediates negative, dysphoric feelings -- and there have been hints from previous studies that CRF doesn't work alone in producing such feelings during addiction.

Blocking negative-motivational factors such as the kappa opioid and CRF systems also has the potential advantage that it spares the positive motivational pathways -- the targets of older addiction therapies such as naltrexone. "We need to keep our positive motivational pathways intact so that they can signal the many normal rewarding events in our lives," said Roberto. By contrast, she suspects, our negative motivational pathways involving CRF and kappa opioid receptors become abnormally active only in disease states such as addiction, and thus may be blocked more safely.