Functional Organization of the 
Striatum: Relevance to Actions of 
Psychostimulant Drugs of Abuse 
Charles R Gerfen 
Recent advances in understanding the functional organization of the basal 
ganglia may provide some insight into the cellular and molecular action 
of certain drugs of abuse. For example, the psychomotor stimulant effects 
of cocaine (e.g., euphoria, locomotion, stereotypy) are thought to be mediated 
primarily by dopaminergic mechanisms in brain regions such as the striatum, 
including the nucleus accumbens (DeWit and Wise 1977; Pettit et al. 1984; 
Roberts et al. 1977). Dopaminergic afferents to the striatum are directed 
principally to the medium spiny neurons (Freund et al. 1984), which constitute 
90 to 95 percent of the striatal neurons and give rise to the major striatal 
efferent pathways (Somogyi et al. 1981). On the basis of their axonal 
projections, striatal outputs are divided into two types: those that project to 
the globus pallidus and those that project to the entopeduncular nucleus/ 
substantia nigra complex (Kawaguchi et al. 1990). Neurons contributing to 
both pathways contain glutamic acid decarboxylase (Kita and Kitai 1988) and 
use y-aminobutyric acid (GABA) as a transmitter (Chevalier et al. 1985), but 
each contains different neuropeptides. For example, the majority of striatonigral 
neurons contain dynorphin and substance P (Brownstein et al. 1977; Gerfen 
and Young 1988; Vincent et al. 1982), whereas the majority of striatopallidal 
neurons contain enkephalin (Haber and Nauta 1983). Pharmacological and 
lesion studies have demonstrated that dopamine differentially modulates the 
expression of these peptides as determined by changes in immunoreactivity 
(Hong et al. 1978, 1985; Li et al. 1987, 1988; Voorn et al. 1987) or mRNA levels 
(Bannon et al. 1986; Gerfen et al. 1991; Morris et al. 1988; Young et al. 1986). 
The contrasting effects of dopamine on peptide mRNA regulation appear to be 
dependent on the differential expression of the D1 and D2 dopamine receptors 
on striatonigral and striatopallidal neurons, respectively (Gerfen et al. 1990). 
Thus, dopamine-induced alterations in striatal peptide mRNA levels provide a 
paradigm to study receptor-mediated regulation of specific subtypes of striatal 
output neurons. 
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