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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Altering levels of serotonin produces dysphoric mood in both healthy
individuals (Young et al., 1985; Benkelfat et al., 1994; Ellenbogen et al., 1996)
and those with depression (Shopsin et al., 1975; Shopsin, Friedman
&Gershon, 1976; Delgado et al., 1990, 1991, 1993; Lam et al., 1996; Miller et
al., 1996a), suggesting a role of serotonin in depression (however, not all
studies have reported such effects (Delgado et al., 1994; Heninger et al., 1996).
Finally, chronic treatment with a variety of antidepressant treatments, such
as tricyclics, MAOIs, electroconvulsive therapy, atypical antidepressants and
SSRIs, produce robust changes in serotonin function through both
presynaptic and postsynaptic mechanisms (Willner, 1985; Green, 1987; Blier,
de Montigny & Chaput, 1990; Caldecott-Hazard et al., 1991; Blier & de
Montigny, 1994). The neurochemical changes observed in the serotonin
system consist primarily of changes at the serotonin and serotonin
1A 2A
receptors (Blier & de Montigny, 1994; Stahl, 1994).
Recent experiments with rats provided strong evidence for a link between
psychostimulant and nicotine withdrawal, and depression. The reward
deficits observed during either amphetamine or nicotine withdrawal were
reversed by a drug treatment that increased serotonin function (Allen et al.,
1997), with no effect on the somatic aspects of withdrawal (Harrison, Liem
&Markou, 2001). The reversal of the depression-like aspects of withdrawal
from two different substances (i.e. amphetamine and nicotine) with different
primary mechanisms of action, by a clinically-proven antidepressant
serotonergic drug treatment supports the hypothesis of overlapping
neurobiological abnormalities mediating depressive symptomatology as
observed across psychiatric diagnostic categories (Geyer & Markou, 1995;
Markou, Kosten & Koob, 1998; Geyer & Markou, 2002).
In the case of substance dependence, most available evidence emphasizes
the critical role of dopamine neurotransmission, rather than serotonin, in
the mediation of the acute rewarding effects of several psychoactive
substances, such as stimulants, opioids, nicotine and ethanol (Koob & Le
Moal, 2001). By contrast, a critical role for dopamine in depression has not
been persuasively shown (Markou, Kosten & Koob, 1998), because direct and
indirect dopaminergic agonists do not appear to be effective antidepressant
treatments (Caldecott-Hazard et al., 1991; Caldecott-Hazard & Schneider,
1992; Kapur & Mann, 1992). It may be hypothesized that decreased
dopaminergic neurotransmission may lead to some symptoms of depression,
but that most of the symptoms may be mediated by other neurotransmitter
systems.

Peptide systems
Another intriguing commonality between the neurobiology of depression and
substance dependence is the consistent observation of increased CRF
neurotransmission in both depression (Post et al., 1982; Nemeroff et al., 1984)
and withdrawal from all psychoactive substances investigated thus far

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