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

Abstract

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.

Pilot trial of gabapentin for the treatment of benzodiazepine abuse or dependence in methadone maintenance patients

“…While the direct effects of BZDs are GABA-related, the withdrawal syndrome may be in part be mediated by calcium channel (20) and glutamatergic (21) mechanisms. In addition, neuroendocrine pathways, including regulation of the hypothalamo-pituitary-adrenocortical axis by corticotropin-releasing factor, may be involved in the mechanism of BZD dependence (22). …”

Neuroleptic Malignant Syndrome—An 11-Year Longitudinal Case-Control Study

“…10 Our finding of BDZs increasing the risk of NMS could perhaps be partly explained by a cessation or a decrease of BDZs when patients were admitted, causing an increased glutamanergic activity that was previously controlled with the positive allosteric modulation of the BDZs. 42 Another possible explanation may be found in the confounding by indication; for example, patients treated with BDZs are somehow systematically different from patients who are not treated with BDZs, not corrected for by the matching of control subjects. However, owing to methodological limitations of the study design, the conclusions of a possible relation between lithium, BDZs, and the risk of developing NMS have to be conservative.…”

Differential effects of allopregnanolone on the escalation of cocaine self-administration and sucrose intake in female rats

“…Drugs that facilitate GABA A neurotransmission antagonize the effects of CRF (Heberlein et al 2008) and inhibit cocaine-induced extracellular dopamine in the nucleus accumbens and striatum in rodents (Dewey et al 1997; Finlay et al 1992; Giorgetti et al 1998; Morgan and Dewey 1998). Furthermore, administration of GABAergic drugs (e.g., topiramate and baclofen) attenuated cocaine self-administration in rats (Campbell et al 1999, 2002) and have shown some similar results in treating drug dependence in humans (Kalivas 2007; Karila et al 2008; Ling et al 1998; Reis et al 2008; Shoptaw et al 2003).…”