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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

patients with schizophrenia exhibited more intense craving for cocaine
during the first three days of abstinence compared with cocaine users who
do not have schizophrenia (Carol et al., 2001). The above theoretical
conceptualization is consistent with the first hypothesis discussed at the
beginning of this chapter; that schizophrenia and substance dependence are
different symptomatic expressions of the same neuropathology.
In addition to excess dopamine function in mesolimbic and mesocortical
brain regions, another neurobiological abnormality that characterizes
schizophrenia is decreased functioning of cortical dopaminergic systems. It
has been suggested that this hypofrontality contributes to the cognitive
deficits associated with schizophrenia (Knable & Weinberger, 1997; Dalack,
Healy & Meador-Woodruff, 1998; Hazlett et al., 2000). Atypical antipsychotic
medications that are relatively effective in ameliorating the cognitive deficits
in patients with schizophrenia also increase dopamine activity in the frontal
cortex (Nomikos et al., 1994; Meltzer, Park & Kessler, 1999; Pallanti, Quercioli
& Pazzagli, 1999; Rowley et al., 2000; Cuesta, Peralta & Zarzuela, 2001; Harvey
& Keefe, 2001). Increases in the functioning of the cortical dopaminergic
system can also be induced through administration of a variety of
psychoactive substances that are used by patients with schizophrenia.
Specifically, psychostimulants such as amphetamine, cocaine and nicotine
increase dopamine levels in the frontal cortex (Sorg & Kalivas, 1993; Marshall
et al., 1997; Tanda et al., 1997; Beyer & Steketee 2000; Balla et al., 2001). Indeed,
it has been shown that nicotine administration through tobacco smoking
ameliorated some cognitive deficits of patients with schizophrenia (George
et al., 2002), which have been shown to involve activation of the prefrontal
cortex (Funahashi & Kubota, 1994; Goldman-Rakic, 1995; Kikuchi-Yorioka &
Sawagushi, 2000; Manoach et al., 2000). In conclusion, the above speculation
that psychoactive substances increase the functioning of the frontal cortex,
and thus lead to improved cognitive function in patients with schizophrenia
is consistent with a self-medication hypothesis of comorbidity of
schizophrenia with substance dependence.
Another neurotransmitter system that has recently been strongly
implicated in both schizophrenia and substance dependence is the
glutamatergic system. It has been hypothesized that alterations in
glutamatergic neurotransmission are critically involved in the mediation of
schizophrenia symptoms, based on the well-established observation that
phencyclidine (PCP) administration induces both positive and negative
symptoms of schizophrenia in PCP users and human volunteers, and
exacerbates both positive and negative symptoms in patients with
schizophrenia resembling an acute psychotic episode (Allen & Young, 1978;
Snyder, 1980; Javitt & Zukin, 1991; Duncan, Sheitman & Lieberman, 1999;
Jentsch & Roth, 1999). PCP is a non-competitive antagonist at the N-methyl-
D-aspartate (NMDA) receptor (Lodge & Johnson, 1990) (see Chapter 4). PCP-
induced psychosis can last for weeks despite abstinence (Allen & Young, 1978;
Luisada 1978). Similarly, ketamine, a PCP analogue that exhibits higher

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