Neuroendocrine pathways in benzodiazepine dependence: new targets for research and therapy

Benzodiazepines are known to modulate the activity of the hypothalamo-pituitary-adrenocortical (HPA) axis by antagonizing the effects of corticotropin-releasing factor (CRH). Besides regulating the HPA axis CRH evolves properties of a neurotransmitter in the limbic system that is closely involved in the delivery of the emotional consequences of the stress response. At a superordinated level Neuropeptide Y (NPY) and Cholecystokinin (CCK) affect the release of CRH and modulate thereby the intensity of the physiological stress response. Benzodiazepine treatment interferes not only with the release of CRH but also with the release of NPY and CCK. Alterations in the intracortical ratio of NPY, CCK and CRH are correlated with behavioural changes like increased respectively decreased anxiety and subsequent alterations in the activity of the HPA axis. Recent research offers the possibility that the alterations of plasma levels of these neuropeptides are not only a secondary phenomenon due to drug intake, but that low levels of those neuropeptides that modulate anxiety and fear can possibly explain addiction to substances that counterbalance these deficits. Depending on the available results possible implications of NPY and CCK on benzodiazepine addiction and withdrawal symptoms are reviewed, thereby providing topics for further research.