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biotech jim

10/10/11 8:32 PM

#128163 RE: genisi #128141

To reply to your questions about addictive potential regarding GABAergic drugs in general and GABAergic sleeping drugs in particular, I first must differentiate "common addiction" as you refer to it from GABA-A receptor addiction.

The so-called common addiction is dopamine based, and involves general addictants such as coacaine and certain types of foods even. I will not go into detail on this aspect.

GABA-A receptor agonists (more scientifically precise positive allosteric activators that require at least some GABA transmitter available for their positive effects on increasing GABA responses on neurons - increasing chloride conductance) have abuse potential, can be addictive and display tolerance over time. (Tolerance means that increasing drug doses are needed to achieve the same pharmacological effect.) I do not want to go into much detail on the addictive potential, as I will refer you to some key literature reviews and also note that the addictive potential is not fully understood in terms of CNS mechanisms, but do also involve activation of midbrain dopamine neurons. Chronic activation of GABA-A receptors by allosteric activators acting at least on subtype 1 receptors are involved, and the story is complex to say the least. Chronic activation is worse than acute activation by the class of benzodiazepine drugs including sleep drugs, but the sleep-inducing drugs have been designed to have short half-lives since drug on board is associated with maintenance of sleep.

Below are 2 general reader reviews on the addictive potential of benzodiazepine and related compounds that act on GABA-A receptors:

Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives.
Longo LP, Johnson B.
Am Fam Physician. 2000 Apr 1;61(7):2121-8. Review.

Addiction: part II. Identification and management of the drug-seeking patient.
Longo LP, Parran T Jr, Johnson B, Kinsey W.
Am Fam Physician. 2000 Apr 15;61(8):2401-8. Review.

Below is a recent review based on animal models (knockouts mostly) that detail some of the current thoughts on the mechanisms of GABA-A receptor-mediated addictive potential:

Hooked on benzodiazepines: GABAA receptor subtypes and addiction.
Trends Neurosci. 2011 Apr;34(4):188-97. Epub 2011 Feb 25.
Tan KR, Rudolph U, Lüscher C.

Finally, here is a review on the 2 most widely used GABA-A receptor active sleep drugs (Ambien and Lunesta, at least Lunesta's racemic version) and their abuse (addictive) potential:

Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data.
Hajak G, Müller WE, Wittchen HU, Pittrow D, Kirch W.
Addiction. 2003 Oct;98(10):1371-8.

I hope this helps. Feel free to ask any additional questions if they arise.