On this model, withdrawal of the benzodiazepine once tolerance has developed would expose the recipient to all the drug-induced alterations in GABA receptors, now no longer opposed by the presence of the drug. The result would be underactivity in the many domains of central function normally modulated by GABA-ergic mechanisms. Since GABA is a universal inhibitor of neural activity and decreases the release of many excitatory neurotransmitters (acetylcholine, noradrenaline, dopamine, serotonin, glutamate)(46), there would be a surge of excitatory nervous activity. Increased release of dopamine, noradrenaline and serotonin has been demonstrated in certain areas of the rat brain during benzodiazepine withdrawal after chronic treatment(47,48). Such increases, coupled perhaps with "downstream" increases in sensitivity of excitatory receptors, may account for many benzodiazepine withdrawal symptoms. The various changes in GABA receptors occurring during tolerance may be slow to reverse after drug withdrawal and may do so at different rates(7), possibly accounting for the variable time of emergence and duration of individual withdrawal symptoms(1,18) and for the sometimes protracted nature of benzodiazepine withdrawal syndrome(1,2). For example, the protracted perceptual and muscular disturbances described above raise the possibility that benzodiazepines are capable of inducing long-term hyperexcitability in central sensory and motor neural pathways.
posted by TedW at 5:15 AM on August 16, 2006