Scientific Understanding of Consciousness
Benzodiazepines and Opioid Drug Abuse
Nature 463, 743-744 (11 February 2010)
Neuroscience: Lack of inhibition leads to abuse
Arthur C. Riegel & Peter W. Kalivas
Chronic drug use can lead to addiction, which is initiated by specific brain circuits. The mystery of how one class of drugs, the benzodiazepines, affects activity in this circuitry has finally been solved.
Common illnesses such as anxiety disorders, insomnia and even muscle spasms are treated with benzodiazepine drugs, of which diazepam (Valium) is perhaps the best known. But both conventional benzodiazepines and newer benzodiazepine-like compounds (such as zolpidem) are addictive. This limits the therapeutic potential of an otherwise safe class of drugs that has broad clinical applications.
Most addictive substances activate the same brain circuitry: the dopaminergic system, which is also stimulated by natural rewards, such as food and sex. Benzodiazepines stimulate this circuitry, but the underlying mechanism was unknown, prompting speculation that benzodiazepine addiction involves systems distinct from those involved in dependence on other addictive drugs.
Recent research reports that the missing link connecting benzodiazepines to the dopaminergic circuitry is a select group of GABAA receptors (γ-aminobutyric acid type A receptors) that reside on inhibitory interneurons. These interneurons coordinate the output of dopaminergic neurons in the ventral tegmental area (VTA) of the brain. In inhibitory interneurons, benzodiazepines increase the stimulation of GABAA receptors that contain α1 subunits. This reduces activity in the interneurons and thereby increases excitability in VTA dopaminergic cells.
In general, the urge to self-administer an addictive drug is initiated in the VTA by the 'strengthening' of excitatory glutamatergic synapses to dopaminergic neurons. Such strengthening increases the chance that the synapse will release glutamate and is caused by the recruitment of new AMPA receptors to glutamatergic synapses on dopaminergic neurons.
The location of α1-containing GABAA receptors within the VTA's microcircuitry is on the inhibitory interneurons — the same class of cells targeted by opioid drugs such as morphine. In fact, much of morphine's addictive potential is attributed to the inhibition of interneurons in the VTA.
Taken together, the data suggest that the activation of α1-containing GABAA receptors by benzodiazepines calms GABAergic interneurons, reducing their overall inhibitory output. Consequently, dopaminergic neuron firing increases in the VTA, which elevates the number of AMPA receptors in the membranes of the excited dopaminergic neurons and strengthens the excitatory synapses that favour addiction. This general disinhibition mechanism is analogous to that involved in opioid drug abuse.
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