Research report
Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder

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Abstract

Rats treated chronically with the dopamine D2/D3 receptor agonist quinpirole develop locomotor sensitization and exhibit compulsive checking of specific places in an open-field arena, a behavioral profile that may represent an animal model of obsessive-compulsive disorder. However, it is not known how compulsive checking develops across quinpirole injections nor whether checking behavior possesses a particular temporal structure. Male rats received quinpirole (0.5 mg/kg, twice weekly × 10) or an equivalent regimen of saline and were placed in a large open field for 55 min where their behavior was digitally tracked for subsequent analysis of checking behavior using existing and newly developed computer software. Results showed that the measures of compulsive checking did not follow a singular profile across injections: some remained constant and others changed monotonically reaching their near-maximum levels after about 5–7 quinpirole injections. Moreover, results showed that checking behavior was organized into bouts of checking, with the number of bouts, as well as the rate of checking within a bout, increasing across injections to reach near maximal levels after about 5–7 administrations of quinpirole. Finally, quinpirole-treated rats showed a paucity of long inter-bout intervals. These results suggest that (a) compulsive checking emerges from the operation of at least two underlying processes: a regulated process and a process of sensitization that intensifies the performance of checking behavior; and (b) quinpirole treatment may attenuate a sense of satiety that could underlie the compulsive nature of checking. Finally, because key variables measured using the newly developed algorithms showed the expected profile, the present study provides validation for the use of this methodology for the analysis of checking behavior.

Introduction

Rats treated chronically with the dopamine D2/D3 receptor agonist quinpirole (QNP) develop locomotor sensitization [2], [12], [20], [26] and exhibit compulsive checking of specific places in an open-field arena, a behavioral profile that may represent an animal model of OCD [8], [11], [19]. The usefulness of this model is further supported by the finding that the clinically effective serotonin uptake inhibitor clomipramine partially attenuates QNP-induced compulsive checking [19].

In the quinpirole model, compulsive checking was evaluated following the 10th drug injection, when the rats were already well-sensitized to the locomotor enhancing effects of quinpirole [16], [19], [20]. Although the morphogenesis of the motor rituals under quinpirole had been described [1], there is no information on the development of checking behavior across sessions and thus, it is unknown whether checking behavior is a single phenomenon or the result of several underlying processes. Therefore, the first purpose of the present study was to examine the development of compulsive checking behavior across quinpirole injections.

A second purpose of the present study was to evaluate whether or not checking behavior exhibits a temporal structure. Such information would be particularly relevant in light of a recent theory that described OCD as a disturbance of the security motivation system. In that theory, OCD is seen as the result of a failure to shut down the activated security motivation, a failure that occurs because performance of security-related behaviors such as checking do not generate the normal “satiety” feedback signal that indicates task completion [21], [27], [28]. The presence of a temporal structure in checking would be informative as to whether or not there is evidence of a satiety-like state produced by security-motivated checking behavior.

Finally, the present study had an additional objective. Thus far measures of checking behavior were obtained in our lab through manual scoring of videotape records of the rats’ behavior. Here, we sought to establish whether the same findings would be observed by using an automated method, both by having the videotapes tracked by commercial software [13], [15] and by having the obtained tracks analyzed by a combination of available [4] and custom-developed software.

Section snippets

Subjects

Twenty-four experimentally naive male Long-Evans rats (Charles-River, Canada) weighing 200–250 g at the start of treatment were used. Rats were individually housed in a temperature-controlled colony room (22 °C) under a 12 h light–dark cycle, with free access to food and water. Rats were allowed to acclimatize to the colony room for 1 week following arrival and were handled 2 min daily for 7 days before the start of the experiment. All treatment and testing was conducted during the light hours.

Locomotion and spatial dispersion

Fig. 1 shows that the distance travelled by quinpirole-treated rats increased as a function of repeated quinpirole injections, confirming the presence of the expected locomotor sensitization to quinpirole [16], [20]. As shown in Table 1, the fitted asymmetric sigmoid curve suggests that the half-maximum response was reached after 4.1 (±0.3) quinpirole injections, that the maximum response was more than six-fold of the acute response, and that the slope of the curve was 3.4 (±0.6), values that

Discussion

The present study showed that in addition to the well-established sensitization of locomotor distance to repeated injections of quinpirole [2], [12], [20], [26], there was also a sensitization of the spatial dispersion and organization of locomotor trajectories. Moreover, the study revealed that compulsive checking behavior underwent orderly changes across injections but the pattern shown by the measures of checking behavior was more complex, with some measures changing monotonically across

Acknowledgments

We thank Dr Ilan Golani, Department of Zoology, Tel-Aviv University for making available the SEE software package used in analysis of locomotor data, Dr Antonio Páez, School of Geography and Geology, McMaster University for suggesting the use of the standard deviational ellipse to measure spatial distribution of trajectories; Jasmine K. Aujla and Sarah Harvey for help in running the animals, and Savio Yu and Dawn Graham for assistance in processing the data. This study was supported by

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