Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains

Abstract

The primate striatum is composed of limbic, cognitive, and sensorimotor functional domains. Although the effects of cocaine have generally been associated with the ventral striatum, or limbic domain, recent evidence in rodents suggests the involvement of the dorsal striatum (cognitive and sensorimotor domains) in cocaine self-administration. The goals of the present studies were to map the topography of the functional response to cocaine throughout the entire extent of the striatum of monkeys self-administering cocaine and determine whether this response is modified by chronic exposure to cocaine. Rhesus monkeys were trained to self-administer 0.3 mg/kg per injection cocaine for 5 d (initial stages; n = 4) or 100 d (chronic stages; n = 4) and compared with monkeys trained to respond under an identical schedule of food reinforcement (n = 6). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the 5th or 100th self-administration session. In the initial phases of cocaine exposure, self-administration significantly decreased functional activity in the ventral striatum, but only in very restricted portions of the dorsal striatum. With chronic cocaine self-administration, however, the effects of cocaine intensified and spread dorsally to include most aspects of both caudate and putamen. Early experiences with cocaine, then, involve mainly the limbic domain, an area that mediates motivational and affective functions. In contrast, as exposure to cocaine continues, the impact of cocaine impinges progressively on the processing of sensorimotor and cognitive information, as well as the affective and motivational information processed in the ventral striatum.

Figure 1.

Schematic representation of functional domains within three representative levels of the striatum. The three levels represent the rostral precommissural striatum (level +24) where the shell of the accumbens is not present, the caudal precommissural striatum (level +20), and the postcommissural striatum (level +14). Limbic (dark gray), association (light gray), and sensorimotor (white) domains of the striatum are based on its cortical inputs, such that the ventral areas receive projections from limbic cortex and amygdala, the central division receives inputs from association areas of cortex, and the dorsal areas are innervated by sensory and motor related cortices. Adapted from Haber and McFarland (1999).

Figure 2.

Schematic drawing depicting a lateral view of the striatum as it is situated within the entire rhesus monkey brain. The darker gray region represents the caudate, whereas the lighter gray region represents the putamen. Anterior–posterior levels at which rates of local cerebral glucose utilization were measured are represented by the vertical lines. Adapted from Levy et al. (1997).

Figure 3.

Shown are schematic drawings representing the 10 anterior–posterior levels at which rates of glucose utilization were measured in each monkey extending from the rostral precommissural striatum, where the shell of the nucleus accumbens is not present, through the caudal precommissural striatum, where the shell is present, to the postcommissural striatum, where the nucleus accumbens is no longer evident. At each level the portions of the striatum (caudate, putamen, and accumbens) were subdivided further. The ventral striatum included the shell of the nucleus accumbens (1) and the rostral pole-core of the accumbens (2). The putamen was divided into ventral (3), central (4), and dorsal (5) portions. The caudate was divided into ventromedial (6), central (7), dorsomedial (8), and dorsolateral (9) portions.

Figure 4.

Autoradiograms from coronal sections through the rostral precommissural (A), caudal precommissural (B), and postcommissural (C) striatum of a control monkey. The numbers represent the subdivisions of each region in which glucose utilization was measured: ventral striatum: shell of the nucleus accumbens (1) and rostral pole-core of the accumbens (2); putamen: ventral (3), central (4), and dorsal (5) regions; caudate: ventromedial (6), central (7), dorsomedial (8), and dorsolateral (9) portions.

Figure 5.

The effects of cocaine self-administration on rates of local cerebral glucose utilization across the anterior–posterior extent of the core (top) and shell (bottom) subdivisions of the ventral striatum of rhesus monkeys. Rates of glucose utilization of monkeys in the initial (5 d experience) and chronic (100 d experience) stages of self-administration are compared with rates of glucose utilization of control monkeys in which responding was maintained by food. Asterisks mark statistically significant differences (p < 0.05) from control. The vertical line in each panel represents the level of the anterior commissure. Note that glucose utilization is significantly reduced in both shell and core at both time points, but is reduced in the more rostral pole portion of the accumbens only at later time points.

Figure 6.

The effects of cocaine self-administration on rates of local cerebral glucose utilization across the anterior–posterior extent of the dorsolateral (top left), dorsomedial (top right), central (bottom left), and ventromedial (bottom right) subdivisions of the caudate of rhesus monkeys. Rates of glucose utilization of monkeys in the initial (5 d experience) and chronic (100 d experience) stages of self-administration are compared with rates of glucose utilization of control monkeys in which responding was maintained by food. Asterisks mark statistically significant differences (p < 0.05) from control. Daggers (†) mark statistically significant differences (p < 0.05) from initial stage. The vertical line in each panel represents the level of the anterior commissure. Note that glucose utilization is only significantly reduced in the postcommissural caudate at the later time points. Additionally, glucose utilization in the rostral-most levels of the caudate is also affected solely at the later time point.

Figure 7.

The effects of cocaine self-administration on rates of local cerebral glucose utilization across the anterior–posterior extent of the dorsal (top), central (center), and ventral (bottom) subdivisions of the putamen of rhesus monkeys. Rates of glucose utilization of monkeys in the initial (5 d experience) and chronic (100 d experience) stages of self-administration are compared with rates of glucose utilization of control monkeys in which responding was maintained by food. Asterisks mark statistically significant differences (p<0.05) from control. Daggers (†) mark statistically significant differences (p < 0.05) from initial stage. The vertical line in each panel represents the level of the anterior commissure. Note that glucose utilization is only significantly reduced in the postcommissural putamen at the later time points. Additionally, glucose utilization in the rostral-most levels of the putamen is also affected solely at the later time point.

Figure 8.

Schematic representation of the magnitude of the effects of cocaine at three levels of the striatum in the initial (5 d of exposure) and chronic (100 d of exposure) stages of cocaine self-administration. Shown are percentage changes from control, with the lighter blues indicating small changes and the darker blues denoting intense reductions in rates of glucose utilization as compared with rates in food controls. The scale at the right indicates the magnitude of change. The three levels represent the rostral precommissural striatum (level +24), where the shell of the accumbens is not present, the caudal precommissural striatum (level +20), and the postcommissural striatum (level +14). In the initial phases, changes are most intense in the caudal precommissural striatum (level +20), and no changes are observed posterior to the anterior commissure. After continued self-administration experience, the extent of striatum with altered functional activity expands to include both the more rostral precommissural regions and the striatum posterior to the anterior commissure. AC, Anterior commissure.