neurons. In the ventral striatum, which includes the nucleus accumbens, the 
cocaine-induced effects are more subtle and complex. Here dynorphin mRNA 
levels show the largest increase compared with the other peptide mRNAs, but 
this increase is considerably less pronounced than in the dorsal striatum. Both 
substance P and enkephalin mRNA levels show a slight, significant, cocaine- 
induced elevation in the nucleus accumbens. Ventral striatal neurons that 
express substance P project to the ventral pallidum (Haber and Nauta 1983); 
however, it has not been established whether these neurons belong to a set 
that coexpresses either enkephalin or dynorphin and that provides axon 
collaterals to both the ventral pallidum and substantia nigra. Nonetheless, the 
elevation in dynorphin, substance P, and enkephalin mRNA levels suggests 
that gene regulation is increased, albeit only modestly, in most output neurons 
in the nucleus accumbens during cocaine self-administration. This is in contrast 
to the dorsal striatum, where cocaine self-administration results in a rather 
selective and substantial increase in gene regulation in striatonigral neurons, 
thus generating a relative imbalance between striatonigral and striatopallidal 
neurons compared with the control condition. 
As has been demonstrated with other pharmacologic manipulations of the 
striatal dopaminergic system, cocaine appears to alter the relative balance of 
function of striatopallidal and striatonigral neurons. A model for dopamine’s 
functional effects in the dorsal striatum has been proposed that suggests that 
this neurotransmitter modulates the balance of activity in the striatopallidal 
and striatonigral output systems (Albin et al. 1989; Gerfen et al. 1990). The 
consequences of altering the balance in these output pathways are related to 
the ultimate effects on the activity of GABAergic neurons in the entopeduncular 
nucleus and substantia nigra. Increased striatopallidal activity results in an 
increase in the activity of nigral GABAergic neurons by way of the intervening 
subthalamic nucleus (Kita and Kitai 1987). Conversely, increased striatonigral 
activity directly inhibits nigral GABAergic neurons (Chevalier et al. 1985). The 
behavioral consequences of opposed modulation of GABAergic nigral neurons 
are generally modeled on the concept that the tonic inhibitory output of these 
neurons is interrupted by inhibitory inputs to these neurons from the striatum 
during movements (Chevalier et al. 1985; Deniau and Chevalier 1985). This 
disinhibitory process has been best characterized for eye movements by 
Hikosaka and Wurtz (1 983a, 1 983b, 1 983c, 1 983d) who, in a series of elegant 
studies, showed that visual-, memory-, and reward-contingent eye movements 
are correlated with pauses in the tonic activity of nigral GABAergic neurons and 
increased activity in superior colliculus neurons. Akinesia that accompanies 
Parkinson’s disease has been related to increased striatopallidal activity and 
the resultant increase in excitatory subthalamic inputs to nigral GABAergic 
neurons, which then predominates over the disinhibitory mechanisms required 
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