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6. CONCURRENT DISORDERS

rewarding effects of most psychoactive substances (Koob, 1992; Koob et al.,
1993; Wise, 1998), and possibly drug craving (Markou et al., 1993; Self, 1998;
Kilts et al., 2001), although “memory” systems may also be critically involved
in craving and dependence (Holden, 2001; Vorel et al., 2001) (see Chapter 3).
It has been shown that administration of most psychoactive substances, such
as cocaine, amphetamine, nicotine and opioids, increases dopamine levels
in the nucleus accumbens (e.g. DiChiara et al., 1999) (see Chapters 3 and 4).
Moreover, similar increases in dopamine levels are seen in the amygdala, a
limbic brain site believed to be involved in the rewarding effects of
psychoactive substances and interconnected with the nucleus accumbens.
Increased functioning of the mesolimbic dopamine system has long been
implicated in the pathophysiology of schizophrenia (Snyder, 1976; Carlsson,
1977). Neuroleptic antipsychotic medications are dopamine receptor
antagonists, and thus, their therapeutic effects are believed to involve
dampening of an overactive dopaminergic system (Carlsson, 1978).
Consistent with this notion is the finding that administration of high doses
of psychostimulant drugs that increase dopamine levels in the nucleus
accumbens can induce a transient psychotic state in healthy individuals (Bell,
1965; Angrist & Gershon, 1970; Griffith et al., 1972). Thus it has been argued
that the overactive dopamine systems, or hyperdopaminergia, of patients with
schizophrenia renders them more likely to seek and use psychoactive
substances, and to be more susceptible to their rewarding effects (Chambers,
Krystal & Self, 2001).
In addition, developmental abnormalities in the hippocampus and the
prefrontal cortex associated with schizophrenia may further contribute to
the malfunctioning of the nucleus accumbens system (Chambers, Krystal
&Self, 2001). There is accruing evidence that patients with schizophrenia
exhibit a disruption in the distribution of cells in the hippocampus (Scheibel
& Conrad, 1993; Fatemi, Earle & McMenomy, 2000; Webster et al., 2001), and
reductions in hippocampal volume (Bogerts et al., 1993; Razi et al., 1999;
Heckers, 2001; Rajarethinam et al., 2001). In the healthy brain, glutamate
projections from the hippocampus and the prefrontal cortex have been shown
to modulate both the activity of dopamine neurons in the nucleus accumbens
(together with inputs from other brain sites such as the amygdala, the
thalamus and the entorhinal cortex) and the behavioural output of the
nucleus accumbens (Wilkinson et al., 1993; Grace, 1995; Finch,1996; Blaha
et al., 1997; Mittleman, Bratt & Chase, 1998; Legault, Rompre & Wise, 2000). It
is hypothesized that in schizophrenia there is malfunction of the normal
inhibitory glutamatergic control exerted by projections from the
hippocampus and the prefrontal cortex on the nucleus accumbens, resulting
in increased drug-seeking and drug-taking behaviour. That is, the
neuropathology of schizophrenia may contribute to the vulnerability to
substance use, and eventually dependence, by increasing the sensitivity of
patients with schizophrenia to the positive rewarding effects of psychoactive
substances. In support of this hypothesis preliminary data indicated that

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