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6. CONCURRENT DISORDERS

selectivity than PCP for the NMDA receptor (Lodge & Johnson, 1990), also
induces psychosis-like effects in healthy volunteers (Newcomer et al., 1999),
and exacerbates symptoms in patients with schizophrenia (Lahti et al., 1995;
Malhotra et al., 1997). Based on the above, it is speculated that decreased
glutamatergic actions at NMDA receptors may mediate symptoms of
psychosis. In support of the argument that PCP- and ketamine-induced
psychoses are neurobiologically similar to schizophrenia, data exist showing
that PCP and ketamine effects are reversed by atypical antipsychotic
medications in both humans and in animal subjects (Malhotra et al., 1997),
but not by the typical neuroleptic haloperidol (Lahti et al., 1995).
If decreased glutamatergic neurotransmission is involved in schizophrenia,
then the administration of psychoactive substances such as cocaine,
amphetamine and nicotine would reverse this deficit by acutely enhancing
glutamatergic neurotransmission in limbic areas. It has been shown that
administration of NMDA receptor antagonists together with psychoactive
substances blocks the development of behavioural sensitization (see Chapter
3) to the locomotor-activating effects of psychoactive substances, such as
cocaine (Kalivas & Alesdatter, 1993; Wolf & Jeziorski, 1993) and nicotine
(Shoaib & Stolerman, 1992); and the development and/or expression of
dependence on opioids (Gonzalez et al., 1997), ethanol (Liljequist, 1991) and
benzodiazepine (Steppuhn & Turski, 1993). These findings suggest that
glutamatergic actions at NMDA receptors are involved in the development
of substance dependence. This hypothesis is supported by data
demonstrating that acute administration of psychoactive substances, such
as cocaine or amphetamine, increases glutamate levels in the VTA and the
nucleus accumbens which in turn increases dopaminergic neurotransmission
in limbic areas, such as the nucleus accumbens (Smith et al., 1995; Kalivas
&Duffy, 1998) that partly mediates the rewarding effects of psychoactive
substances (Koob, 1992; Koob et al., 1993; Wise, 1998). In turn, this enhanced
glutamatergic neurotransmission would lead to alterations in dopaminergic
neurotransmission (increases or decreases depending on the brain site) that
would produce rewarding effects, but may potentially worsen some
symptoms of schizophrenia if indeed hyperdopaminergia is one of the core
abnormalities of schizophrenia.
One brain site where the multiple interactions discussed above may occur
is the VTA (Mogenson, Jones & Yim, 1980). Glutamatergic afferents to the VTA,
originating in the prefrontal cortex, increase firing of dopamine neurons in
the VTA, which results in increased dopamine levels in the nucleus accumbens
(Kalivas, Duffy & Barrow, 1989; Suaud-Chagny et al., 1992; Taber & Fibiger,
1995). There are presynaptic α7 nicotinic acetylcholine receptors located
upon these glutamatergic afferents (Mansvelder & McGehee, 2000), that when
stimulated increase glutamate release. This enhanced glutamate release then
acts at NMDA and non-NMDA receptor sites on postsynaptic dopamine
neurons and increases their firing rate (Fu et al., 2000; Grillner & Svensson,
2000; Mansvelder & McGehee, 2000). These interactions between glutamate

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