Kirsten E. Culver

Compulsive checking behavior of quinpirole-sensitized rats as an animal model of Obsessive-Compulsive Disorder(OCD): form and control

BackgroundA previous report showed that the open field behavior of rats sensitized to the dopamine agonist quinpirole satisfies 5 performance criteria for compulsive checking behavior. In an effort to extend the parallel between the drug-induced phenomenon and human obsessive-compulsive disorder (OCD), the present study investigated whether the checking behavior of quinpirole rats is subject to interruption, which is an attribute characteristic of OCD compulsions. For this purpose, the rats home-cage was placed into the open field at the beginning or the middle of a 2-hr test.ResultsIntroduction of the home-cage reduced checking behavior, as rats stayed inside the cage. After 40 min, checking resurfaced, as quinpirole rats exited the home-cage often. An unfamiliar cage had no such effects on quinpirole rats or saline controls.ConclusionsChecking behavior induced by quinpirole is not irrepressible but can be suspended. Results strengthen the quinpirole preparation as an animal model of OCD compulsive checking.

Effect of nicotine on quinpirole-induced checking behavior in rats: implications for obsessive-compulsive disorder.

BACKGROUND Rats treated chronically in a large, open field with the dopamine D2/D3 receptor agonist quinpirole (QNP) develop compulsive checking behavior as defined by a set of behavioral criteria. This paradigm has been suggested as an animal model of obsessive-compulsive disorder (OCD). Because nicotine blocks various behaviors induced by ontogenetic QNP administration, we asked whether nicotine could attenuate QNP-induced compulsive checking. METHODS Adult male Long-Evans rats (n = 14/group) were treated twice weekly with saline (control), or with QNP (0.5 mg/kg) for 14-16 injections. On the last two injections, rats were pretreated in random order with an acute dose of nicotine (0.3 mg/kg base) or saline 10 min before administration of QNP or saline; and the effects on checking behavior was examined. The effects of chronic QNP treatment on nicotinic receptors in discrete brain regions were also determined. RESULTS Chronic QNP resulted in compulsive checking and increases in cerebellar alpha4beta2 and alpha7 nicotinic receptor densities. Nicotine pretreatment significantly reduced one of the three measures of compulsive checking behavior. CONCLUSIONS Nicotine attenuates some symptoms of compulsive checking in a rat model of OCD; however, the mechanisms of this effect and therapeutic efficacy of nicotinic agonists in OCD require further study.

A switch mechanism between locomotion and mouthing implicated in sensitization to quinpirole in rats.

Abstract Rationale: Chronic treatment with the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D2/D3 dopamine agonist quinpirole. It is unknown whether this blockade occurs via inhibition of the MAO enzyme or by another mechanism. Objectives: While clorgyline and moclobemide are equally effective MAOIs, only clorgyline has a high affinity for the MAOI-displaceable quinpirole binding site (MQB). This study compares the effects of both drugs on quinpirole sensitization. Methods: To examine development of sensitization, rats received clorgyline (1 mg/kg/day), moclobemide (5 mg/kg/day), or vehicle via osmotic mini-pumps and were injected with quinpirole (0.5 mg/kg, s.c.) or saline every 3 days; locomotor and mouthing activity was recorded for each of the eight injections. A similar protocol was used to examine the expression of sensitization in rats previously sensitized to quinpirole. Results: Clorgyline, but not moclobemide, blocked the development of locomotor sensitization to quinpirole. Clorgyline, but not moclobemide, blocked the sensitized locomotor response to quinpirole following the 25th day of treatment. Mouthing showed sensitization in quinpirole-treated rats co-treated with clorgyline, but not moclobemide; this sensitized mouthing was predominantly directed towards self. Clorgyline and moclobemide equally inhibited MAO-A and had equal effects on tissue concentrations of dopamine, 3,4- dihydroxyphenylacetic acid, and serotonin in the striatum. Conclusions: Clorgyline (1) inhibits the development and the maintenance of locomotor sensitization to quinpirole by a mechanism that does not involve MAO and (2) changes the sensitized response to quinpirole from locomotion to mouthing. We suggest that clorgyline affects the response to quinpirole via MQB and that this site acts as a switch that selects the motor pathway for sensitization to quinpirole.

Monoamine oxidase inhibitor sensitive site implicated in sensitization to quinpirole

Clorgyline (1.0 mg/kg/day) administered via osmotic minipumps blocked the development of locomotor sensitization to the dopamine receptor agonist quinpirole (0.5 mg/kg every 3 days for 8 injections). In male rats already well sensitized to quinpirole, the continuous infusion of clorgyline (1.0 mg/kg/day for 28 days) produced a progressive decline in locomotor activity, despite a continued regimen of quinpirole injections (0.5 mg/kg every 3 days). It is suggested that the development, as well as the maintenance, of locomotor sensitization to quinpirole is modulated by the activation of an monoamine oxidase inhibitor-sensitive site. This site may be a dopamine D2 receptor-linked monoamine oxidase inhibitor-displaceable quinpirole binding site, the enzyme monoamine oxidase-A, or other clorgyline binding sites.

Altered dopamine D2-like receptor binding in rats with behavioral sensitization to quinpirole: effects of pre-treatment with Ro 41-1049

Repeated treatment with the dopamine D2/D3 receptor agonist quinpirole produces a sensitized behavioral response in rats manifested as an increase in locomotor activity. Pre-treatment with certain monoamine oxidase inhibitors, such as Ro 41-1049 [N-(2-aminomethyl)-5-(3-fluorophenyl)-4-thiazolecarboxamide HCl], changes the sensitized response from locomotion to stationary, self-directed mouthing. In this study, the effects of quinpirole sensitization, with and without pre-treatment with Ro 41-1049, were determined on dopamine D2-like receptors in the nucleus accumbens and the striatum. Long-Evans rats were pre-treated with Ro 41-1049 (1 mg/kg) 90 min prior to administration of quinpirole (0.5 mg/kg, 8 injections, every 3-4 days). Dopamine D2-like receptor binding was determined 3 days after the last injection by ex vivo radioligand assays using [3H]spiperone and [3H]quinpirole. Densities of [3H]spiperone- and [3H]quinpirole-labeled sites were both increased 32% in the nucleus accumbens of rats with demonstrated locomotor sensitization to quinpirole. In contrast, the density of dopamine D2-like receptors in quinpirole-sensitized rats pre-treated with Ro 41-1049 was not different from saline controls. These findings support the involvement of alterations in dopamine D2-like receptors in the development of locomotor sensitization to quinpirole and suggest that modification of these alterations in dopamine D2-like receptors contributes to the change from sensitized locomotion to mouthing observed when rats are pre-treated with Ro 41-1049.

Effects of hypophysectomy on compulsive checking and cortical dendrites in an animal model of obsessive-compulsive disorder.

Hormones may modulate the symptoms of obsessive–compulsive disorder (OCD), but the evidence is equivocal and not consistent across studies, with findings of hormone-associated increases and decreases of symptoms. To assess whether a strong endocrine influence on OCD exists, the effects of hypophysectomy were examined in an animal model of OCD. The model involves repeated injections of the dopamine D2/D3 receptor agonist, quinpirole, to induce locomotor sensitization and compulsive checking behavior. Intact and hypophysectomized rats were administered quinpirole (0.5 mg/kg×6, twice weekly) or saline and compulsive checking in a large open field was measured according to a standard protocol. Results showed that in hypophysectomized animals, the development of locomotor sensitization was attenuated but the expression of quinpirole-induced compulsive checking was full-blown. Analysis of Golgi-stained neurons showed changes in spine density in Cg3 and Par1 and increased branching of apical dendrites in Cg3. It is suggested that compulsive checking could be coupled with drug-induced increases in Cg3 dendritic branching and that changes in spine density may reflect a compensatory adjustment in dopamine-innervated regions. On the basis of the animal model findings, it is concluded that the presence of OCD checking compulsions is not dependent on pituitary axis hormones.

Hypophysectomy does not block sensitization to the dopamine agonist quinpirole or its modulation by the MAOI clorgyline.

Repeated administration of the dopamine agonist quinpirole induces behavioral sensitization in rats that is characterized by a four- to eight-fold increase in the amount of locomotion compared to an acute dose of quinpirole, in the absence of any increases in mouthing behavior. The monoamine oxidase (MAO) inhibitor, clorgyline, switches behavioral sensitization to quinpirole from that of locomotion to self-directed mouthing. The mechanism by which clorgyline produces this switch in behavioral sensitization is unknown, but is independent of the known effects of clorgyline, namely, inhibition of MAO, inhibition of striatal dopamine uptake, or stimulation of sigma and I(2) receptors. Because clorgyline also inhibits hypothalamo-pituitary-adrenal (HPA) axis function, and increased HPA activity facilitates the behavioral effects of psychostimulant drugs, the effects of clorgyline on quinpirole sensitization are possibly due to an inhibition of HPA function. Therefore, the present study examined whether HPA activity is required for sensitization to quinpirole, and whether clorgyline exerts its effects on quinpirole sensitization via inhibition of HPA function. Control and hypophysectomized rats were administered clorgyline (1 mg/kg, s.c.) or vehicle 90 min before each injection of quinpirole (0.5 mg/kg x 8, twice weekly) or saline. To assess the level of sensitization reached by control and hypophysectomized rats, test injections of quinpirole (0.0, 0.07, and 0.2 mg/kg) were administered. Chronic quinpirole administration produced equivalent levels of locomotor sensitization in control and hypophysectomized rats. Clorgyline was equally effective in blocking the development of locomotor sensitization in control and hypophysectomized rats, and in sensitizing self-directed mouthing. The present study suggests that (1). HPA function is not necessary for the development of quinpirole sensitization and, (2). clorgyline does not produce its effects on behavioral sensitization to quinpirole via an inhibition of HPA activity. Moreover, the observation that quinpirole sensitization develops normally in the absence of any pituitary endocrine function suggests that pituitary-gonadal and pituitary-thyroid axes activity are also not necessary for quinpirole sensitization to occur.