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Mechanisms of Benzodiazepine Addiction

Mechanisms of Benzodiazepine Addiction (Left Image) Both inhibitory interneurons (labeled GABA) and dopaminergic neurons (labeled DA) are subject to the restraining influence of the inhibitory neurotransmitter GABA. A key difference, however, is that GABA influences the inhibitory interneurons largely via the alpha-1 subset of GABAA receptors and the dopaminergic neurons largely via the alpha-3 subtype. (Right Image) Benzodiazepines currently on the market do not interact strongly with alpha-3 GABAA receptors on dopaminergic neurons and so have no direct impact on dopamine release. However, the drugs do interact strongly with alpha-1 GABAA receptors, thereby curtailing inhibitory interneurons’ release of GABA into synapses with dopaminergic neurons. The net result is a lessening of GABA restraint on the dopaminergic neurons and an increase in dopamine release.

This illustration provides diagrams of neurotransmitter release at synapses in the presence or absence of benzodiazapines. The first diagram shows that in the absence of benzodiazapines, GABA released from an axon of a neuron earlier in the pathway binds to an alpha-1 GABAA receptor on an inhibitory interneuron. Synapses on the axon of that interneuron then release GABA that binds to an alpha-3 GABAA receptor at a synapse of a dopamine neuron. The binding reduces that neuron’s dopamine release at its axonal synapse. The second illustration shows that benzodiazapines currently on the market bind to the alpha-1 GABAA receptor on an inhibitory interneuron, reducing GABA binding there and subsequent GABA release by that neuron. Without the normal GABA influence, the dopamine neuron releases more dopamine than in the first diagram.

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