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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

and dopamine systems, and nicotinic acetylcholine receptors are particularly
relevant because of the extremely high rate of smoking among patients with
schizophrenia. In addition to increased glutamate release in the VTA, nicotine
also increases glutamate release in other limbic sites, such as the nucleus
accumbens (Reid et al., 2000), the prefrontal cortex (Gioanni et al., 1999) and
the hippocampus (Gray et al., 1996). Finally, there is preclinical and clinical
evidence to suggest that some forms of cognitive deficits that patients with
schizophrenia exhibit may depend critically on α7 nicotinic acetylcholine
receptors in the hippocampus (Adler et al., 1998). Although nicotine has low
affinity for α7 nicotinic acetylcholine receptors (Clarke et al., 1985), it may
activate these α7 receptors in the hippocampus, which leads to increased
glutamate release to counteract this deficit (Dalack, Healy & Meador-
Woodruff, 1998), and thus leads to self-medication through smoking. All of
the above data suggest ways by which the use of psychoactive substances
would self-medicate symptoms of schizophrenia by enhancing glutamatergic
neurotransmission in order to counteract a possible hypoglutamatergia that
may characterize this disease.
The above represents a small subset of sites and mechanisms where the
effects of psychoactive substances and the neurobiology of schizophrenia
may overlap and/or interact to lead to the high degree of comorbidity between
the two disorders. Although many of the above neurobiological mechanisms
are speculative and most of the studies were conducted in the USA, the recent
attention to the issue of comorbidity has led to the initiation of multiple
preclinical and clinical studies. These studies will directly investigate the
neurobiology of how and why so many patients with schizophrenia use
psychoactive substances compared with people without schizophrenia or
patients having any other psychiatric disorder, in different countries and
settings.

Depression

The comorbidity of depression with substance use is of great importance
because of the high overall lifetime prevalence of affective and mood
disorders. Approximately 8–13% of the general population experience
clinical depression in their lifetime (Regier et al., 1990; Kessler et al., 1994).
The comorbidity with substance use is 32% with an odds ratio of 2.6. That
is, individuals with an affective disorder are 2.6 times more likely to use
psychoactive substances than those without affective disorder (Regier et
al., 1990). Considering the various affective disorders separately, bipolar
disorder has the highest comorbidity value, with more than 60% of those
suffering from this illness using psychoactive substances compared with
more than 27% of those suffering from unipolar major depression. The
discussion below will focus on unipolar major depression because it is the
most common among affective disorders (Regier et al., 1990; Kessler et al.,
1994).

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