The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD

Abstract

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial.

Keywords: Checking; Dopamine; Obsessive-compulsive disorder; Rat.

Fig. 1

(a–d) The observing response task. (a) Training 1. The observing lever (i) on the back panel of the box was retracted. Rats were trained to press two levers (ii) on the front panel of the chamber. A light was illuminated above each lever to indicate ‘active’ status (iii). Completion of lever-presses requirement gave a food pellet in a central food well (iv). (b) Training 2: lever discrimination. One front-panel lever was active and the light above was illuminated (v); the other lever was inactive and the light above was unlit. The active-lever and illuminated-light location switched on a pre-determined schedule (vi). (c) Observing response task. Both levers were extended but neither light was lit above (vii). The observing lever was extended, and a single press on the observing lever (viii) illuminated the light above the active lever for 15 s. (d) Extra observing lever presses (EOLPs) (ix); when the active-lever light was already illuminated had no further consequence, but was recorded. (e) Elevated plus maze. (f) Diagram of marble-burying cage showing the position of the marble array. 20 mm marbles were arranged 6 cm apart along the short wall of the cage. (g) Flowchart of task components in the observing response task, showing active/inactive lever press, observing lever press (OLP) and extra observing lever press (EOLP).

Fig. 2

During active-lever light illumination, percentage of active lever presses (%ActiveCS) for high- and low-checkers. Black bars denote pre- and post-treatment phases, when rats were tested in the absence of quinpirole. Grey bars denote the 10 day quinpirole-administration period. Data are shown for pre-treatment, during 10 days of quinpirole administration (Q1–10), and for both early (PQ1–10) and late (PQ49–58) post-quinpirole periods (in the absence of further quinpirole administration). Error bars represent + 1 s.e.m. Asterisks denote differences between high and low Checker groups *p < 0.05, **p < 0.01.

Fig. 3

Performance measures on the observing response task [schedule FT90s, VR10–20, OLP FR1 (15s)], for vehicle (white bars) and quinpirole (filled bars) treated rats. Black bars denote pre- and post-treatment phases, when rats were tested in the absence of quinpirole. Grey bars denote the 10 day quinpirole-administration period. Data are shown for pre-treatment, during 10 days of quinpirole administration (Q1–10), and for both early (PQ1–10) and late (PQ49–58) post-quinpirole periods (in the absence of further quinpirole administration). (a) observing lever presses; OLPs, (b) non-functional extra observing lever presses; EOLPs, (c) active lever presses, (d) inactive lever presses, (e) rewards, (f) percentage of active lever presses when the active-lever light was illuminated %ActiveCS, (g) EOLPs relative to duration of active-lever light illumination EOLPinCS and (h) percentage of active lever presses when the active-lever light was off %ActiveCSoff. Error bars represent + 1 s.e.m. Asterisks denote differences between vehicle and quinpirole treatment groups *p < 0.05, **p < 0.01.

Fig. 4

Performance measures on the observing response task, showing the difference between low (a, c, e, g, i) and high-checkers (b, d, f, h, j), [schedule FT90s, VR10–20, OLP FR1 (15s)], for vehicle (white bars) and quinpirole (filled bars) treated rats. Black bars denote pre- and post-treatment phases, when rats were tested in the absence of quinpirole. Grey bars denote the 10 day quinpirole-administration period. Data are shown for pre-treatment, during 10 days of quinpirole administration (Q1–10), and for both early (PQ1–10) and late (PQ49–58) post-quinpirole periods (in the absence of further quinpirole administration). (a, b) OLPs, (c, d) EOLPs, (e, f) active lever presses, (g, h) inactive lever presses, (i, j) rewards. Error bars represent + 1 s.e.m. Asterisks denote differences between vehicle and quinpirole treatment groups *p < 0.05, p < 0.01.

Fig. 5

Single-day extinction. (a) OLPs, (b) EOLPs, (c) active lever presses, (d) inactive lever presses, (e) rewards, (f) %ActiveCS, (g) EOLPinCS for the quinpirole-treated (QNP) and vehicle-treated (VEH) rats. Error bars represent + 1 s.e.m.

Fig. 6

Effects of increasing response requirement/uncertainty from VR10–20 to VR10–100. (a) OLPs, (b) EOLPs, (c) active lever presses, (d) inactive lever presses, (e) rewards, (f) %ActiveCS. Error bars represent ±1s.e.m. Asterisks denote differences between vehicle and quinpirole treatment groups *p < 0.05.

Fig. 7

Increasing uncertainty of active lever location [from FT90s to VT20–120s], for a low response requirement (VR10–20) and a high response requirement (VR10–70). Data are shown for low-checkers (a, c, e, g, i) and high-checkers (b, d, f, h, j). (a,b) OLPs, (c, d) EOLPs, (e, f) active lever presses, (g, h) inactive lever presses, (i, j) rewards, (f) %ActiveCS. Error bars represent + 1 s.e.m. $ denotes difference between FT and VT condition, $p < 0.05, $$p < 0.01.

Fig. 8

Effects of sulpiride (vehicle, 20 and 60 mg/kg, i.p) on observing response task measures for the quinpirole-treated (QNP) and vehicle-treated (VEH) rats. (a) OLPs, (b) EOLPs, (c) active lever presses, (d) inactive lever presses, (e) rewards, (f) %ActiveCS. Error bars represent + 1 s.e.m. Asterisks denote difference between sulpiride dose and vehicle **p < 0.01.

Fig. 9

Baseline-dependent effects of sulpiride on observing and extra observing lever presses. (a,b) Difference in observing lever responses during sulpiride (60 mg/kg) treatment compared with vehicle, plotted against baseline OLPs (during the no-drug baseline sessions in the sulpiride test phase of the experiment) for (a) quinpirole and (b) vehicle treated rats. (c,d) Difference in extra observing lever responses during sulpiride (60 mg/kg) treatment compared with vehicle, plotted against baseline EOLPs for (c) quinpirole and (d) vehicle treated rats. There was a significant negative correlation between EOLPs response to sulpiride and baseline EOLPs for the quinpirole-treated rats.