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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

drinking and will operantly respond to oral ethanol in amounts that produce
pharmacologically meaningful blood alcohol concentrations. Compared with
non-preferring rats, alcohol-preferring rats are less sensitive to the sedative/
hypnotic effects of ethanol, develop tolerance more quickly to high doses of
ethanol, and show signs of physical dependence after withdrawal (McBride
& Li, 1998). Ethanol increases the sensitivity of animals to brain stimulation
reward, (Kornetsky et al., 1988), place preference conditioning (Grahame et
al., 2001), and drug discrimination (Hodge et al., 2001).

Mechanism of action
Ethanol increases the inhibitory activity mediated by GABA-A receptors and
decreases the excitatory activity mediated by glutamate receptors, especially
the NMDA receptors. These two mechanisms of action may be related to the
general sedative effect of alcohol and impairment of memory during periods
of intoxication. GABA-A receptors are sensitive to ethanol in distinct brain
regions and are clearly involved in the acute effects of ethanol, ethanol
tolerance and dependence, and ethanol self-administration (Samson &
Chappell, 2001; McBride, 2002). GABA-A receptor activation mediates many
of the behavioural effects of ethanol including motor incoordination,
anxiolysis and sedation (Grobin et al., 1998).
The reinforcing effects produced by ethanol are probably related to
increased firing rate of ventral tegmental area (VTA) dopamine neurons
(Gessa et al., 1985), and dopamine release in the nucleus accumbens (Di
Chiara & Imperato, 1988a), probably as a secondary consequence of activation
of the GABA system or stimulation of endogenous opioids (O´Brien, 2001).
The increase in dopamine activity occurs only while blood concentration of
ethanol is rising. The increase in mesolimbic dopamine is critical to the
reinforcing effects of psychoactive substances (see Chapter 3).
Imaging studies of brain metabolism show that alcohol decreases
metabolic activity in occipital brain regions and increases metabolism in the
left temporal cortex (Wang et al., 2000; Fig. 4.1)

Tolerance and withdrawal
Ethanol induces diverse types of tolerance. Among them is behavioural
tolerance which refers to adaptive learning to overcome some of the effects
of ethanol (Vogel-Sprott & Sdao-Jarvie, 1989). Both operant and associative
learning can play a major role in the development of tolerance to alcohol
and cross-tolerance to other drugs. Most of the neural mechanisms related
to learning and memory are now known to be involved in the development
and retention of tolerance (Kalant, 1998). Metabolic tolerance also occurs,
and is a function of the upregulation of metabolic enzymes in the liver, with
the result that an increased dose or more frequent use of alcohol is required
to obtain the desired psychopharmacological effects.

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