The role of the striatum in compulsive behavior in intact and orbitofrontal-cortex-lesioned rats: possible involvement of the serotonergic system

Abstract

In the signal attenuation rat model of obsessive-compulsive disorder (OCD), 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We have recently found that lesions to the rat orbitofrontal cortex (OFC) led to an increase in compulsive lever-pressing that was prevented by systemic administration of the selective serotonin reuptake inhibitor paroxetine, and paralleled by an increase in the density of the striatal serotonin transporter. This study further explored the interaction between the OFC, the striatum, and the serotonergic system in the production of compulsive lever-pressing. Experiment 1 revealed that OFC lesions decrease the content of serotonin, dopamine, glutamate, and GABA in the striatum. Experiment 2 showed that intrastriatal administration of paroxetine blocked OFC lesion-induced increased compulsivity, but did not affect compulsive responding in intact rats. Experiments 3 and 4 found that pre-training striatal lesions had no effect on compulsive lever-pressing, whereas post-training striatal inactivation exerted an anticompulsive effect. These results strongly implicate the striatum in the expression of compulsive lever-pressing in both intact and OFC-lesioned rats. Furthermore, the results support the possibility that in a subpopulation of OCD patients a primary pathology of the OFC leads to a dysregulation of the striatal serotonergic system, which is manifested in compulsive behavior, and that antiobsessional/anticompulsive drugs exerts their effects, in these patients, by normalizing the dysfunctional striatal serotonergic system.

Figure 1

A schematic diagram of the organization of a trial in each of the different training stages of the post-training signal attenuation procedure. HL, houselight; RI, random interval; ^*on the first day of lever-press training (day 5) this time limit was 15 s.

Figure 2

A photomicrograph of a (a, b) coronal section taken through the orbitofrontal cortex (OFC) from a representative OFC-lesioned rat (a, arrowheads indicate lesion location) and sham-operated rat (b), and (c) a coronal section taken through the striatum of a representative cannula-implanted rat showing the cannula tract (Experiment 2).

Figure 3

(a) Schematic reconstructions of coronal sections (Paxinos and Watson, 2005) showing the largest (gray shading) and smallest (black shading) extents of the OFC lesion in common for all rats in the lesion group. Numbers in each section indicate the A-P level anterior to the bregma. (b) A schematic representation of the injection cannulae placements in a coronal section (Paxinos and Watson, 2005) in the striatum of paroxetine-injected rats. The locations of the injector tips are represented by black dots. The number indicates the distance anterior to the bregma (Exp. 2).

Figure 4

The mean and standard error of the mean number of (a) extra lever-presses that were followed by an attempt to collect a reward (ELP-C), and (b) extra lever-presses that were not followed by an attempt to collect a reward (ELP-U) in the test of intrastriatal vehicle-injected (empty bars) and paroxetine-injected (filled bars) rats sustaining either OFC or sham lesion (Experiment 2). ^*p<0.05.

Figure 5

(a, b) A photomicrograph of a coronal section taken from a representative (a) striatal-lesioned rat and (b) sham-operated rat (Exp. 3). (c) A schematic reconstruction of a coronal section (Paxinos and Watson, 2005) showing the largest (gray shading) and smallest (black shading) extents of the striatal lesion in common for all rats in the lesion group. The number indicates the distance anterior to the bregma (Exp. 3). (d) A photomicrograph of a coronal section taken through the striatum of a representative cannula-implanted rat showing the cannula tract (Exp. 4). (e) A schematic representation of the injection cannulae placements in a coronal section (Paxinos and Watson, 2005) in the striatum of the striatal-inactivated rat. The locations of the injector tips are represented by black dots. The number indicates the distance anterior to the bregma (Exp. 4).

Figure 6

The mean and standard error of the mean number of (a, c) extra lever-presses that were followed by an attempt to collect a reward (ELP-C) and (b, d) extra lever-presses that were not followed by an attempt to collect a reward (ELP-U) in the test of the regular extinction (RE) or post-training signal attenuation (PTSA) procedures in (a, b) sham-operated and striatal-lesioned rats (Experiment 3) and (c, d) vehicle-injected and striatal-inactivated rats (Experiment 4). ^*p<0.001.