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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Mechanism of action
Benzodiazepines act by binding to a specific binding site on the GABA-A
receptor complex, which facilitates the effects of GABA on the opening of
the chloride channel (Haefely, 1978). Barbiturates also bind to a separate
specific site on the GABA-A receptor and directly open the chloride channel
(Nutt & Malizia, 2001). Benzodiazepines do not directly open the channel,
but they modulate the ability of GABA to do so, thus less GABA than usual
is required to open the channel (Barnard et al., 1998). The effects of
benzodiazepines on endogenous GABA function makes them safer in large
doses than the barbiturates and alcohol. The latter directly open the chloride
channel and therefore can have effects in excess of the naturally occurring
effects of GABA.
The increase in chloride conductance following opening of the chloride
channel hyperpolarizes the cell, making it less likely to fire an action potential
(see Chapter 2). Because GABA controls neuronal excitability in all brain
regions, increasing GABA function is the mechanism by which sedatives and
hypnotics have their characteristic effects of sedation, amnesia and motor
incoordination (Nutt & Malizia, 2001).
Like other dependence-producing drugs, there is also evidence that
sedatives and hypnotics affect the mesolimbic dopamine system
(Feigenbaum & Yanai, 1983), leading to their reinforcing effects and enhancing
the motivation to repeat their use.
Similarly to alcohol, the benzodiazepine lorazepam decreases metabolic
activity in the occipital cortex, increases activity in the temporal cortex, and
also decreases thalamic metabolism, as measured by positron emission
tomography (Wang et al., 2000).

Tolerance and withdrawal
Tolerance to the effects of sedatives/hypnotics develops rapidly, and increased
doses are required to maintain the same level of effect. Tolerance develops to
the pleasurable and sedative effects, as well as to the effects of benzodiazepines
and barbiturates on motor coordination. Tolerance to the anticonvulsant effects
does not appear to occur (Jacobs & Fehr, 1987). There is also a high degree of
cross-tolerance between sedatives/hypnotics, including alcohol.
Upon withdrawal of sedatives and hypnotics, certain effects are observed
which are opposite to those of the drug. Thus, increased arousal, anxiety,
restlessness, insomnia and excitability are characteristic withdrawal
symptoms (Nutt & Malizia, 2001). In severe cases, seizures can occur.
There is evidence that chronic treatment with benzodiazepines alters the
composition of GABA-A receptor subunits (Holt, Bateson & Martin, 1996),
which may also be due to changes in receptor coupling and function. This
results in tolerance in the presence of benzodiazepines, and withdrawal
symptoms when benzodiazepines are removed.

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