Repetitive behaviors in monkeys are linked to specific striatal activation patterns

Abstract

The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomotor stimulants. We have developed a primate model for analyzing the neurobiology underlying such drug-induced behavioral changes. We performed ethogram-based behavioral assays on squirrel monkeys given single or multiple cocaine treatments, and in the same monkeys made anatomical plots of striatal neurons that were activated to express early-gene proteins. A final cocaine challenge after chronic intermittent exposure to cocaine induced highly patterned behavioral changes in the monkeys, affecting individual behavioral motifs in distinct ways. In the striatum, the challenge dose induced striosome-predominant expression combined with intense dorsal early-gene expression, especially in the putamen. These patterns of gene expression were highly predictive of the levels of stereotypy exhibited by the monkeys in response to cocaine challenge. The total levels of expression, on the other hand, appeared to reflect increased spontaneous behavioral activation during the drug-free period after the cocaine exposure. We suggest that in the primate, compartmentally and regionally specific striatal activation patterns contribute to the striatal modulation of psychostimulant-induced behaviors. These observations in nonhuman primates raise the possibility that monitoring such basal ganglia activity patterns could help to delineate the neural mechanisms underlying drug-induced repetitive behaviors and related syndromes in which stereotypies are manifest.

Figure 1.

Squirrel monkeys exhibit a range of stereotypic behaviors in response to cocaine exposure. A, Treatment protocols for the monkeys of the saline, acute cocaine, and chronic cocaine groups. B, Bar graphs illustrate the level of stereotypy expressed in monkeys of the chronic saline, acute cocaine, and chronic cocaine groups, as determined by ethogram analysis (Table 1). Asterisks indicate significance values for the stereotypy scores of monkeys of the chronic saline group (^**p = 0.01) and the acute cocaine group (^***p = 0.001) relative to the stereotypy scores for monkeys of the chronic cocaine group. C, Bar graphs illustrate the levels of individual behaviors exhibited by monkeys of the saline, acute cocaine, and chronic cocaine groups. Asterisks indicate significance values for the individual behavioral scores for the chronic cocaine group relative to the scores for the acute cocaine group.

Figure 2.

A single dose of cocaine induces early-gene expression in the squirrel monkey caudate nucleus (CN) and putamen (P), and repeated daily doses shift the expression pattern toward one of striosome predominance and accentuated dorsal expression. Illustrations indicate Fos-positive striatal neurons as small black dots. Asterisks indicate examples of striosomes, which are shown in outline. A, Monkey M4, chronic saline group; B, monkey M7, acute cocaine group; C, monkey M3, chronic cocaine group; and D, monkey M5, chronic cocaine group. Note in C the striosome-predominant patterns of Fos expression and in D the dorsal cap of strong labeling together with heightened striosomal labeling. Illustrations also show low levels of Fos expression in ventral striatum (VS).

Figure 3.

Cocaine-induced patterns of Fos expression in rostral striatum differ for squirrel monkeys given saline, acute cocaine, or acute and repeated exposures to the cocaine before challenge. A, Low density of Fos-positive neurons (black dots) in rostral striatum of squirrel monkey M4, treated with saline; B, higher density of Fos-positive neurons in monkey M9, treated with single injection of cocaine after 16 d of saline treatment and 7 d of drug abstinence; and C, accentuation of Fos expression in striosomes and far dorsal putamen in monkey M5, from the chronic cocaine group (16 d cocaine, 1 week abstinence period, final cocaine challenge). Asterisks indicate examples of striosomes.

Figure 4.

Heightened striosomal distributions of early-gene products Fos and JunB occur in the striatum of squirrel monkeys given a cocaine challenge after repeated daily cocaine treatments and drug abstinence. Photomicrographs illustrate serially adjacent sections immunostained for Fos-like immunoreactivity (A), enkephalin-like immunoreactivity (B), and JunB-like immunoreactivity (C). Striosomes are identifiable as enkephalin-poor zones (examples shown by asterisks). Scale bar, 1 mm.

Figure 5.

Fos expression patterns in the striatum shift after repeated cocaine treatment relative to patterns in acute cocaine group. A, Dorsal to ventral Fos expression ratio in the putamen. B, Dorsal to ventral Fos expression in the caudate nucleus. C, Fos expression in the nucleus accumbens. Asterisk indicates significance level of p ≤ 0.02.

Figure 6.

Heightened numbers of Fos-positive neurons in striosomes and the dorsal part of the caudate-putamen complex predict the levels of behavioral stereotypy induced by cocaine exposure. Graphs illustrate regression analyses of behavioral stereotypy scores (y-axes) in relation to density of striatal Fos expression (x-axes) for Fos expression in striosomes (A), extrastriosomal matrix (B), and dorsal cap of the caudate nucleus and putamen (C). Spearman correlation coefficients for each analysis are shown by r values together with corresponding p values.

Figure 7.

Total density of Fos-positive neurons in the caudate nucleus of the squirrel monkey is correlated with the levels of spontaneous stereotypic behavior exhibited after treatment during the drug-free period of abstinence (A) but not with the baseline activity of monkeys before treatment (B). The graphs show regression analyses of the behavioral scores (y-axes) in relation to the density of Fos expression in the caudate nucleus (x-axes).