Selective Alleviation of Compulsive Lever-Pressing in Rats by D1, but not D2, Blockade: Possible Implications for the Involvement of D1 Receptors in Obsessive–Compulsive Disorder

Abstract

Rats undergoing extinction of lever-pressing for food after the attenuation of an external feedback for this behavior exhibit excessive lever-pressing unaccompanied by an attempt to collect a reward. This behavior may be analogous to the excessive and unreasonable behavior seen in obsessive-compulsive disorder. In the present study, we tested the hypothesis that the compulsive behavior induced by signal attenuation is mediated via D 1 rather than D 2 receptors. Administration of 0.005, 0.01 and 0.03 mg/kg of the D 1 antagonist SCH 23390 reduced the number of compulsive lever-presses without affecting the number of lever-presses followed by an attempt to collect a reward. In contrast, administration of 0.005, 0.01, 0.024, 0.036 and 0.05 of the D 2 antagonist haloperidol dose-dependently decreased both types of lever-presses. In addition, haloperidol at doses that decreased lever-pressing in the post-training signal attenuation procedure (0.036 and 0.05 mg/kg) had a similar effect in regular extinction, whereas an SCH 23390 dose that decreased compulsive lever-pressing in the post-training signal attenuation procedure (0.01 mg/kg) had no effect on regular extinction. On the basis of electrophysiological data on the response of dopamine neurons to the omission of an expected reward, these results were interpreted as suggesting that compulsive lever-pressing depends on a phasic decrease in the stimulation of D 1 receptors. The implications of these results for the pathophysiology and treatment of obsessive-compulsive disorder are discussed.

The Role of the Striatum in Compulsive Behavior in Intact and Orbitofrontal-Cortex-Lesioned Rats: Possible Involvement of the Serotonergic System

“…These findings are in accordance with the differential efficacy of these drugs in alleviating obsessions and compulsions in OCD patients (Zohar et al, 1992;Piccinelli et al, 1995;Dolberg et al, 1996). Compulsive lever-pressing is also sensitive to manipulations of the OFC (FlaisherGrinberg et al, 2008;Joel et al, 2005a, b;Joel and Klavir, 2006) and of the dopaminergic and serotonergic systems (Flaisher-Grinberg et al, 2008;Joel and Doljansky, 2003), in line with different lines of evidence implicating these systems in the pathophysiology of OCD (for review see Stein, 2000;Aouizerate et al, 2004).…”

“…We have named this behavior 'compulsive' lever-pressing because it may be analogous to the excessive and unreasonable behavior seen in OCD. Compulsive lever-pressing is abolished by the SSRIs fluoxetine, paroxetine, and fluvoxamine, but not by the anxiolytic drug, diazepam, the antipsychotic, haloperidol, or the tricyclic antidepressant, desipramine Joel and Doljansky, 2003;Joel et al, 2004). These findings are in accordance with the differential efficacy of these drugs in alleviating obsessions and compulsions in OCD patients (Zohar et al, 1992;Piccinelli et al, 1995;Dolberg et al, 1996).…”

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

“…Haloperidol (VetMarket) and paroxetine (Unipharm, Ramat-Gan, Israel) were prepared as previously described (Brimberg et al, 2007;Joel and Doljansky, 2003), and injected i.p. 60 and 30 min, respectively, before behavioral assessment.…”

Obsessive–Compulsive Disorder

“…Although the precise mechanism of influence remains in question (Pauls, 2008), the serotonergic and dopaminergic systems have most reliably been implicated. Of interest, animal models of compulsive behavior have variably offered support for the critical role of both systems in OCD presentation (e.g., Campbell et al, 1999;Joel & Doljansky, 2003;Joel, Doljansky & Schiller 2005;Tsaltas et al, 2005). In addition, the unparalleled efficacy of serotonin reuptake inhibitors in the pharmacological treatment of OCD (e.g., Goodman, Price, Rasmussen, Delgado et al, 1989; has implicated both the serotonergic system and -due to serotonin-dopamine interaction and presumed secondary effects on dopamine releasethe dopaminergic system (Westenberg, Fineberg, & Denys, 2007).…”