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PubMed1993

Low-dose quinpirole ontogenically sensitizes to quinpirole-induced yawning in rats.

It is known that dopamine (DA) receptors can be sensitized by repeated treatments with quinpirole during postnatal development. This study was undertaken to determine whether low-dose quinpirole treatments might sensitize receptors to quinpirole-induced yawning behavior. Rats were treated with quinpirole HCl (50 micrograms/kg per day) or saline at four different periods of ontogeny: a) the 10th day of gestation to day of birth; b) 1st-11th days after birth; c) 12th-22nd days from birth; or d) 23rd-33rd days from birth. The numbers of yawns occurring in 1 h after a challenge dose of quinpirole HCl (50 micrograms/kg, IP) was determined at 6 weeks. Rats exposed prenatally to quinpirole demonstrated increased numbers of yawns following the third dose of quinpirole (2-day interval between doses). In rats exposed postnatally to quinpirole, there was a 70-300% increase in the yawning response, with the greatest response occurring in the group treated with quinpirole from birth to 11 days from birth. The findings demonstrate that quinpirole receptors are sensitized by a low dose of quinpirole, 60-fold lower than previously shown. It is suggested that sensitized receptors are of the DA D3 subclass.

Animals↗
PubMed2004

Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats.

Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D2-like receptor agonists such as quinpirole reduces PPI, but tolerance occurs upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c.), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 microM), or SKF 82958- (10 microM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased cAMP-dependent protein kinase (PKA) activity. Phosphorylation of cAMP response element-binding protein (CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the cAMP analog, Sp-cAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment. Thus, repeated quinpirole treatment increases NAc PKA activity and CREB phosphorylation, and this neuroadaptive response might facilitate the recovery of sensorimotor gating in schizophrenia.

Acoustic Stimulation↗
PubMed2005

Altered quinpirole-induced local cerebral glucose utilization in anterior cortical regions in rats after sensitization to quinpirole.

Dopaminergic psychostimulants produce behavioral responses of greater magnitude with repeated, intermittent administration, than a single, acute dose, a phenomenon known as "sensitization." Most studies of sensitization have focused on the "motive circuit"; however, some additional anterior cortical regions also appear to be affected. In this study, alterations in regional neuronal activity in anterior cortical brain areas produced by quinpirole, a D(2)/D(3) agonist, were assessed on the basis of local cerebral glucose utilization (LCGU) using the [(14)C]-2-deoxyglucose (2-DG) method. Adult, male Long-Evans rats (180-200 g, n = 7-9/group) were subjected to ten injections of quinpirole (0.5 mg/kg, s.c.) administered every third day; controls and drug-naive rats received saline. Locomotor activity was quantitated after injections one and ten to confirm sensitization. The 2-DG procedure was initiated 60 min after an 11th injection in freely moving rats. LCGU was determined in 11 anterior cortical brain regions by quantitative autoradiography. In drug-naive rats, quinpirole decreased LCGU in the cingulate cortex-area 3 (-16%) and infralimbic cortex (-16%). In sensitized rats, quinpirole decreased LCGU in the cingulate cortex-area 1 (-19%), frontal cortex-area 3 (-19%), lateral orbital cortex (-18%), medial/ventral orbital cortex (-17%), and parietal cortex (-17%) as well as in the cingulate cortex-area 3 (-19%) and infralimbic cortex (-20%); (all P < 0.05 v. control). This suggests that decreased neuronal activity in the cingulate cortex-area 1, frontal cortex-area 3, lateral orbital cortex, medial/ventral orbital cortex, and parietal cortex, in addition to altered activity in the motive circuit, may underlie the augmented behavioral response to quinpirole in sensitized animals.

Animals↗
PubMed2001

Modulation of [3H]quinpirole binding at striatal D2 dopamine receptors by a monoamine oxidaseA-like site: evidence from radioligand binding studies and D2 receptor- and MAO(A)-deficient mice.

[3H]Quinpirole is a dopamine agonist with high affinity for the D2 and D3 dopamine receptors. A variety of monoamine oxidase inhibitors (MAOIs) inhibit equilibrium binding of [3H]quinpirole binding in rat striatal membranes suggesting that MAOIs interact with a novel binding site that is labeled by [3H]quinpirole or that allosterically modulates [3H]quinpirole binding. To determine whether the D2 receptor is essential for [3H]quinpirole binding and/or modulation of [3H]quinpirole binding by MAOIs, D2 receptor-deficient mice were studied. [3H]Quinpirole binding was decreased in D2 receptor-deficient mice to 3% of that observed in wild-type controls indicating that [3H]quinpirole binding is associated with the D2 dopamine receptors. Then, in an attempt to label the site mediating the modulation of [3H]quinpirole binding, binding of the MAOI [3H]Ro 41-1049 was characterized in rat striatal membranes. [3H]Ro-41-1049 labeled a single binding site with a pharmacological profile with respect to MAOIs that was similar to both [3H]quinpirole binding (Spearman r=0.976) and MAO(A) activity. To determine whether MAO(A) plays a role in the modulation of [3H]quinpirole binding by MAOIs, MAO(A)-deficient mice were examined. In these mice, [3H]Ro-41-1049 binding was decreased to 7% of wild-type control. [3H]Spiperone binding was unaltered. Spiperone-displaceable [3H]quinpirole binding was decreased to 43% of wild-type control; however, the remaining [3H]quinpirole binding in MAO(A)-deficient animals was inhibited by Ro 41-1049 similar to wild-type. [3H]Ro-41-1049 binding was not decreased in D2 receptor-deficient mice. These data suggest that [3H]Ro-41-1049 labels multiple sites and that MAOIs modulate [3H]quinpirole binding to the D2 receptor via interactions at a novel, non-MAO binding site with MAO(A)-like pharmacology.

Animals↗
PubMed2004

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.

Animals↗
PubMed1987

Cardiovascular characterization of the DA2 dopamine receptor agonist quinpirole in rats.

In normotensive anesthetized rats, 15-min IV infusions of quinpirole (2.5-40.0 micrograms/kg/min) produced dose-related, rapidly appearing, and long-lasting decreases in mean carotid artery BP and HR. Hemodynamically, the hypotensive effects of quinpirole (10.0 micrograms/kg/min) were due to a fall in total peripheral vascular resistance inasmuch as CO did not undergo significant changes. Mesenteric, hindquarter, and renal blood flows were, respectively, reduced, unchanged, and increased by quinpirole; thus, the renal vascular resistance fell more than either the total peripheral or hindquarter vascular resistance. Biochemically, the hypotensive effects of quinpirole were accompanied by a decrease in the plasma level of norepinephrine and plasma renin activity. The peak fall in blood pressure produced by quinpirole was not significantly modified by atenolol, idazoxan, ranitidine, SCH 23390 (DA1 dopamine receptor antagonist), enalapril, or SK&F 100273 (V1 vasopressin receptor antagonist), but was entirely blocked by S-sulpiride or removal of autonomic nerve drive to the cardiovascular system with chlorisondamine. The effect of quinpirole on systemic and regional vascular resistances was antagonized by S-sulpiride. Furthermore, SK&F 100273 prevented the fall in mesenteric flow produced by quinpirole. Intracerebroventricular injection of quinpirole (10.0 micrograms/kg over 2 min) in saline- or SK&F 100273-pretreated rats produced the same hypotensive effects as an identical IV dose of the compound. In pithed rats, quinpirole (10 micrograms/kg/min IV over 15 min) decreased pressor responses to electrical stimulation of spinal cord outflow without affecting those to exogenously injected angiotensin II, B-HT 920, cirazoline, norepinephrine, or 5-hydroxytryptamine. This inhibitory effect was antagonized by S-sulpiride. The bradycardia produced by quinpirole in intact rats was mediated by the autonomic nervous system inasmuch as it was slightly modified by bilateral vagotomy, partly reduced by atenolol, and entirely prevented by pithing even when the low HR of the last preparation had been raised by IV infusion of isoprenaline. Furthermore, S-sulpiride, but not SCH 23390 or idazoxan, antagonized this effect. In pithed rats, quinpirole similarly inhibited the tachycardic responses elicited by electrical stimulation of either the spinal cord outflow (preganglionic) or postganglionic cardioaccelerator nerve fibers. This effect of quinpirole was susceptible to S-sulpiride but not idazoxan blockade. Finally, in conscious spontaneously hypertensive rats (SHR) but not in normotensive rats, quinpirole (10 micrograms/kg/min IA over 15 min) lowered blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Central effects of quinpirole on blood pressure of spontaneously hypertensive rats.

The i.v. administration of the dopamine D-2 receptor agonist quinpirole induced a rapid increase in blood pressure in spontaneously hypertensive rats (SHR). Heart rate showed little change. The pressor response to quinpirole was similar in SHR and normotensive Wistar-Kyoto rats (WKY) at doses of 0.03 to 0.3 mg/kg but, at 1 mg/kg, quinpirole induced a greater increase in blood pressure in SHR than in WKY. In contrast, although both strains showed a decreased locomotor activity after administration of 0.01 to 0.05 mg/kg of quinpirole, only in WKY was activity enhanced by 0.25 to 1.25 mg/kg of quinpirole. The i.v. administration of the dopamine agonists apomorphine, N-propylnorapomorphine and (R)-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine, but not the putative presynaptic D-2 agonist (S)-(-)-3-(3-hydroxyphenyl)-N- propylpiperidine, induced pressor responses in SHR comparable to those after quinpirole administration. The pressor effect of quinpirole was enhanced by pretreatment with the peripheral D-2 antagonist domperidone, but blocked by the centrally acting dopamine antagonists haloperidol or sulpiride. In SHR, which were pretreated centrally with pertussis toxin, quinpirole induced a significantly smaller increase in blood pressure than in control SHR. Pretreatment centrally with 6-hydroxydopamine had no effect on the pressor action of quinpirole in SHR. Thirty minutes after i.v. administration of quinpirole, an additional injection of quinpirole did not significantly change blood pressure. Increasing the interval between two subsequent injections of quinpirole showed that this desensitization slowly reversed, but only after 24 hr had the pressor response to quinpirole fully recovered.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

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

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 clorgy-line, 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 clorgy-line affects the response to quinpirole via MQB and that this site acts as a switch that selects the motor pathway for sensitization to quinpirole.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Ontogenetic homologous sensitization to the antinociceptive action of quinpirole in rats.

Repeated postnatal treatment of rats with the dopamine receptor agonist, quinpirole results in exaggeration of selected behaviors that are induced by quinpirole in adulthood. To determine whether the antinociceptive response to quinpirole could be similarly enhanced, rats were treated daily from birth with quinpirole HCl (3.0 mg/kg per day i.p. x 28 days) and their response time in the hot plate analgesia test was determined at 4 months. An acute dose of quinpirole HCl (100 or 1000 micrograms/kg i.p.) produced an analgesic response in the neonatally primed rats and in the vehicle controls. More significantly, the effect was substantially greater in the quinpirole-primed group at each of these two doses of quinpirole. This effect of quinpirole was fully attenuated in both groups by treatment with the dopamine receptor antagonist, spiperone HCl (0.30 mg/kg i.p., 1 h before quinpirole). The analgesic effect of morphine sulfate (6.0 mg/kg i.p.) was not greater in the quinpirole-primed group. These findings demonstrate that the ontogenetic sensitization of quinpirole receptors results in enhanced antinociceptive responses to quinpirole in adulthood. This animal model may be useful for studying the involvement of dopamine systems in algesia and analgesia.

Aging↗
PubMed2003

Clorgyline-induced switch from locomotion to mouthing in sensitization to the dopamine D2/D3 agonist quinpirole in rats: role of sigma and imidazoline I2 receptors.

RATIONALE: The monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D(2)/D(3) dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. Clorgyline has a high affinity for imidazoline I(2) and sigma receptors, which could account for its effects on quinpirole sensitization. OBJECTIVES: To examine whether the effect of clorgyline on quinpirole sensitization is attributed to stimulation of either I(2) or sigma receptors. METHODS: In one experiment, rats received injections of the I(2) receptor agonist 2-BFI (0.2 mg/kg, IP) or vehicle, 90 min prior to each injection of quinpirole (0.5 mg/kg, SC, x 8, twice weekly) or saline. A similar protocol was used to examine the effects of the MAOI Ro 41-1049 (10 mg/kg, SC) on quinpirole sensitization. Unlike clorgyline, Ro 41-1049 has no affinity for sigma or I(2) sites. An initial experiment demonstrated that intermittent injections of clorgyline (1 mg/kg, SC) are as effective as a continuous clorgyline administration (1 mg/kg per day via osmotic mini-pump) on quinpirole sensitization. RESULTS: Like clorgyline, Ro 41-1049, but not 2-BFI, blocked the development of quinpirole-induced locomotor sensitization and induced instead sensitization of self-directed mouthing. CONCLUSIONS: Because Ro 41-1049 produced the same effects as clorgyline, and 2-BFI had no effects on quinpirole sensitization, it is unlikely that clorgyline exerts its effects via an action at sigma or I(2) receptors. Our results are consistent with the suggestion that clorgyline and Ro 41-1049 affect the behavioral response to quinpirole via the MAOI-displaceable quinpirole binding (MQB) site, and the hypothesis that the MQB site selects what motor output becomes sensitized to repeated injections of quinpirole.

Animals↗
PubMed1997

Pretreatment with quinpirole inhibits the central antihypertensive effects of rilmenidine and alpha-methyldopa in conscious rats.

Treatment of conscious spontaneously hypertensive rats (SHR) with the dopamine D2 receptor agonist quinpirole causes a short-lasting pressor response and apparent desensitisation to the effects of subsequent injections of quinpirole or central antihypertensives such as clonidine. In the present study, a number of aspects of this apparent desensitisation were investigated. Thirty minutes after intravenous injection of quinpirole into spontaneously hypertensive rats, treatment with the dopamine D2 receptors antagonist raclopride caused a significant fall in blood pressure. At this time point, circulating levels of vasopressin were not significantly different compared to controls. In Brattleboro rats, the pressor response to quinpirole was reduced in the first 15 min after injection, but not difference in blood pressure was observed at later time points. In SHR which had been treated with quinpirole, the central antihypertensive effects of rilmenidine or alpha-methyldopa were significantly inhibited. By contrast, the bradycardia induced by these drugs was similar in quinpirole-treated rats and controls. Quinpirole pretreatment caused an enhancement of the hypotension but a reduction of the reflex tachycardia after intravenous treatment with hydralazine. In SHR treated with methylatropine and quinpirole, the upper plateau of the sympathetic baroreceptor-heart rate reflex curve was reduced. These results show that treatment with quinpirole has marked effects on central sympathetic vasomotor mechanisms which are the target of antihypertensive drugs such as rilmenidine and alpha-methyldopa. At least some of these effects may occur at the level of the sympathetic baroreflex. Moreover, while the effects of quinpirole on sympathetic regulation are prolonged, the initial pressor response is counteracted by an as yet unidentified compensatory mechanism which can be unmasked when quinpirole is displaced from its receptor by dopamine D2 receptor antagonist treatment.

Animals↗
PubMed2003

Behavioral sensitization to quinpirole is not associated with increased nucleus accumbens dopamine overflow.

This study assessed the relationship between extracellular nucleus accumbens (NAc) dopamine (DA) concentrations and sensitized locomotor activation following repeated administration of the DA D2-like receptor agonist quinpirole. Locomotor activity measures and nucleus accumbens microdialysis samples were collected concurrently in response to the first (acute) and tenth (repeated) quinpirole injection (0.5 mg/kg s.c., every other day). Results indicate that acute quinpirole produced locomotor activation and that repeated quinpirole resulted in locomotor sensitization. Acute quinpirole significantly decreased the detection of extracellular concentrations of DA and the DA metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAc. Following repeated quinpirole, basal NAc DA levels were decreased, whereas basal DOPAC levels were increased. Nevertheless, quinpirole challenge elicited a significant decrease in DA, DOPAC and HVA following repeated treatment. In addition, although acute quinpirole did not affect NAc levels of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA), quinpirole challenge produced a significant increase in 5-HIAA levels following repeated treatment. Taken together, these data indicate that functional DA autoreceptor subsensitivity is not a necessary condition for the expression of behavioral sensitization to quinpirole. Instead, it appears that behavioral sensitization to quinpirole occurs predominantly as a consequence of neuroadaptations that are post-synaptic to DA release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Interaction of the dopamine D2 receptor agonist quinpirole with sympathetic vasomotor tone and the central action of rilmenidine in conscious rabbits.

Previous studies in conscious rats have shown that systemic administration of the dopamine D2 receptor agonist quinpirole causes a centrally-mediated increase in blood pressure which is associated with increased plasma levels of noradrenaline and adrenaline. In addition, treatment with quinpirole caused a marked inhibition of the antihypertensive effect of centrally-acting sympatho-inhibitory drugs such as clonidine, rilmenidine and alpha-methyldopa, suggesting an interaction at the level of sympathetic vasomotor tone. The main aim of the present study was investigate in conscious rabbits the effect of quinpirole on renal sympathetic nerve activity. In addition, we studied the effect of pretreatment with quinpirole on responses to additional quinpirole injections or rilmenidine treatment. Quinpirole treatment caused a prolonged dose-dependent increase in blood pressure and heart rate. Additional injection of quinpirole, 30 min after the first treatment, caused a significantly smaller pressor response (7+/-2 vs. 17+/-2 mm Hg). Injection of rilmenidine caused a larger decrease in blood pressure in rabbits which had been pretreated with quinpirole than in controls (-28+/-3 vs. -14+/-3 mm Hg). Total renal sympathetic nerve activity was markedly increased by quinpirole treatment (3.5-fold), an effect which could be attributed to both increased amplitude and increased frequency of the renal nerve signal. After a second injection of quinpirole, 30 min after the first treatment, only total renal sympathetic nerve activity and amplitude were increased and the effects were reduced. These results show marked actions of quinpirole on renal sympathetic nerve activity in conscious rabbits. However, the previously described apparent desensitisation to the antihypertensive effect of rilmenidine could not be observed in rabbits, suggesting marked species differences in the mechanism and site of action of rilmenidine.

Adrenergic alpha-Agonists↗
PubMed1991

Downregulation of stereotyped behavior and production of latent locomotor behaviors in mice treated continuously with quinpirole.

D1 and D2 dopamine receptors mediate different behavioral effects in animals. We have attempted to selectively modulate dopamine-mediated behaviors by continuously administering D2 agonists to mice. Acute administration of the D2 agonist quinpirole caused dose-related stereotyped effects; no locomotor or grooming behavior was apparent. Continuously infusing quinpirole with implanted Alzet minipumps initially produced stereotyped behavior, but this stereotypy decreased by 2 hours, and was completely absent from 3 hours to 6 days of infusion. Within 1 day after implanting quinpirole, there appeared a significant locomotor behavior that continued for the 6 days of infusion. Acute challenge doses of quinpirole given either 6 days after infusing quinpirole or 12 hours after removing the quinpirole implant failed to elicit any stereotyped behavior and did not alter the locomotor behavior. By contrast, acute challenge injections with the D1 agonist SKF 38393 administered 12 hours after removing the quinpirole implant produced a characteristic grooming response. In an attempt to learn the mechanism of the behavioral effects induced by the continuous administration of quinpirole, the actions of relatively selective D1 and D2 antagonists were examined. The D2 antagonist sulpiride inhibited the stereotypy but not the locomotion induced by quinpirole. By contrast, the D1 antagonist Sch 23390 blocked the locomotion but not the stereotypy induced by quinpirole. These results indicate that chronic administration of quinpirole causes two separate behavioral effects: (1) a downregulation of stereotypy, perhaps by downregulating D2 receptors; and (2) the development of locomotion, which appears to involve both the downregulation of D2 receptors and an activation of D1 dopaminergic mechanisms.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Mapping quantitative trait loci that regulate sensitivity and tolerance to quinpirole, a dopamine mimetic selective for D(2)/D(3) receptors.

Acute sensitivity and tolerance to quinpirole (a dopamine mimetic with selectivity for D(2)/D(3) dopamine receptors) were evaluated in the C57BL/6J and DBA/2J inbred strains of mice, 24 of their BXD recombinant inbred strains, and 233 F(2) mice. Baseline locomotor activity, locomotor activity following 0.03 mg/kg quinpirole (and 0. 01 mg/kg in BXD mice), body temperature following 1 mg/kg quinpirole, and hypothermic tolerance following 2 or 3 days of quinpirole administration were evaluated. Quantitative trait locus (QTL) analysis was employed to identify genetic determinants of baseline locomotor activity and five behavioral responses to quinpirole. We examined correlated allelic variation in genetic markers of known chromosomal location with variation in each of these phenotypes. We definitively mapped a QTL on Chromosome (Chr) 9 linked to the D(2) dopamine receptor gene, Drd2, for hypothermic sensitivity to quinpirole, and identify a suggestive QTL in the same chromosomal region for tolerance to quinpirole after repeated treatments. Suggestive QTLs were also identified on Chr 19 for sensitivity and tolerance to quinpirole-induced hypothermia and for baseline locomotor activity; on Chr 15 for locomotor sensitivity to quinpirole; and on Chr 13 and 5 for baseline locomotor activity. Our results indicate that genetic differences in quinpirole sensitivity and tolerance are associated with QTLs near Drd2, and that baseline locomotor activity is associated with a suggestive QTL in proximity to the dopamine transporter gene Dat1. These data suggest that the genes influencing locomotor activity, dopamine mimetic sensitivity, and tolerance do not overlap completely.

Animals↗
PubMed1995

The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies, co-administered with quinpirole in primate and rodent models of Parkinson's disease.

The effects of co-administration of quinpirole with benzazepine D1 dopamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co-administration of SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) strongly potentiated the contralateral circling induced by quinpirole. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Co-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contrast, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disability. Co-administration of high doses of SKF 82958 and more especially SKF 83959 and SKF 80723, with quinpirole induced hyperexcitability and seizures. Oral activity and grooming were unaltered following the co-administration of benzazepine derivatives with quinpirole. The ability of some benzazepine D1 DA agonists to prolong the antiparkinsonian effects of quinpirole in the MPTP-treated marmoset may indicate a role for certain D1 DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepines with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimulate AC. These observations further implicate a behavioural role for D1 DA receptors not linked to AC.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Role of the renin-angiotensin system in the compensation of quinpirole-induced blood pressure decrease.

The dopamine D(2)-like receptor agonist quinpirole has been reported to lower blood pressure. This effect appears to be mediated via activation of presynaptic D(2)-like receptors inhibiting the stimulated neural norepinephrine release. The aim of the present study was to investigate the role of renal nerves and the renin-angiotensin system (RAS) in the blood pressure lowering effect of quinpirole. Therefore, clearance experiments using different doses of quinpirole (0.3 to 100 microg/kg/min) were performed in thiopental-anesthetized rats with intact kidneys (INN) or 5 to 7 days after bilateral renal denervation (DNX). The functional involvement of the RAS in the blood pressure lowering effect of quinpirole was determined in rats pretreated with a subpressor dose of angiotensin II (10 microg/kg/min) or in rats pretreated with the angiotensin II (AT(1)) receptor antagonist losartan, in a subdepressor dose (10 microg/kg/min). Quinpirole dose-dependently decreased mean arterial blood pressure (MAP) by up to 29%. This blood pressure lowering effect of quinpirole was observed at lower doses in DNX rats when compared with INN animals (ED(50): 0.98 microg/kg/min in DNX vs. 6.02 microg/kg/min in INN animals). Quinpirole in a dose of 3 microg/kg/min, which did not affect MAP in vehicle treated INN rats, significantly reduced MAP in rats with losartan pretreatment. In DNX rats pretreated with angiotensin II the MAP-response to the infusion of 3 microg/kg/min quinpirole was clearly attenuated in comparison with untreated DNX animals. Our data show that stimulation of dopamine D(2)-like receptors dose-dependently decreased blood pressure, which was potentiated by both interruption of the renal innervation and AT(1) receptor blockade, while exogenous ANG II restored the enhancement of the blood pressure response to quinpirole. We conclude that the increased vasodilatory effect of quinpirole after renal denervation might depend on a decreased activity of the RAS.

Anesthesia↗
PubMed1991

Dopamine receptors labelled by [3H]quinpirole.

Since quinpirole (or LY171555) has a high affinity for dopamine D2 receptors, and since the high-affinity state of D2 appears to be the functional state of D2, we prepared [3H]quinpirole to investigate its suitability for labelling the high-affinity state of the D2 receptor. The dissociation constant of [3H]quinpirole binding to canine striatum homogenate was 3.9 nM in the absence of NaCl and 6.8 nM in the presence of NaCl. Only 50% of the total binding was specifically displaced by 10 microM S-sulpiride. The data are consistent with the conclusion that much or most of the [3H]quinpirole binds to the high-affinity state of the D2 receptor, since dopamine D2 agonists and antagonists were the most potent in inhibiting the binding of this ligand, because the density of binding sites was 8-9 pmol/g, about half that for [3H]spiperone, and because the density was reduced by 70% in the presence of guanylylimidodiphosphate. Since quinpirole has a reported Ki value of 5.1 nM for dopamine D3 receptors, similar to the quinpirole Ki value of 4.8 nM for the high-affinity state of the dopamine D2 receptor, it appears that [3H]quinpirole with its Kd of 3.9-6.8 nM could label both these two dopamine receptors. However, since the spiperone and haloperidol Ki values against [3H]quinpirole were the same as their values at dopamine D2 receptors rather than dopamine D3 receptors, it appears that [3H]quinpirole predominantly labels dopamine D2 receptors in the canine striatum. The guanine nucleotide-insensitive component of [3H]quinpirole binding (about 30%) may be to dopamine D3 receptors.

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