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Henry Szechtman - One of the best experts on this subject based on the ideXlab platform.
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A dose-response study of separate and combined effects of the serotonin agonist 8-OH-DPAT and the dopamine agonist Quinpirole on locomotor sensitization, cross-sensitization, and conditioned activity.
Behavioural Pharmacology, 2016Co-Authors: Eric Johnson, Henry SzechtmanAbstract:Chronic treatment with the dopamine D2/D3 agonist, Quinpirole, or the serotonin 1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), induces behavioral sensitization. It is not known whether both drugs produce sensitization through a shared mechanism. Here, we examine whether Quinpirole and 8-OH-DPAT show cross-sensitization and impact sensitization, as would be expected from shared mechanisms. Male rats (N=208) were assigned randomly to 16 groups formed by crossing four doses of Quinpirole (0, 0.03125, 0.0625, or 0.125 mg/kg) with four doses of 8-OH-DPAT (0, 0.03125, 0.625, or 0.125 mg/kg). After a course of 10 drug treatments administered twice per week in locomotor activity chambers, all groups were challenged on separate tests with Quinpirole (0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), or saline, and locomotor activity was evaluated. Challenge tests with Quinpirole and 8-OHDPAT showed no cross-sensitization between the drugs. Chronic Quinpirole (0.125 mg/kg) administration induced a sensitized Quinpirole response that was attenuated dose-dependently by chronic 8-OH-DPAT cotreatment. Cotreatment with Quinpirole (0.0625 mg/kg) and 8-OH-DPAT (all doses) induced Quinpirole sensitization. Chronic 8-OH-DPAT (0.125 mg/kg) induced a sensitized 8-OHDPAT response that was prevented by chronic cotreatment with the lowest but not the highest dose of Quinpirole. Cotreatment with 8-OHDPAT (0.0625) and Quinpirole (0.125 mg/kg) induced sensitization to 8-OH-DPAT. The saline challenge test showed elevated locomotor activity in chronic Quinpirole (0.125 mg/kg) and 8-OHDPAT (0.0625, 0.125 mg/kg) alone groups, and in seven of nine cotreated groups. The absence of cross-sensitization suggests separate mechanisms of sensitization to Quinpirole and 8-OH-DPAT. Cotreatment effects suggest that induction of sensitization can be modulated by serotonin 1A and D2/D3 activity.
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5 ht2a c receptors do not mediate the attenuation of compulsive checking by mcpp in the Quinpirole sensitization rat model of obsessive compulsive disorder ocd
Behavioural Brain Research, 2015Co-Authors: Mark C Tucci, Anna Dvorkingheva, Eric Johnson, Michael Wong, Henry SzechtmanAbstract:Abstract There is emerging evidence for a dopamine (DA)–serotonin (5-HT) interaction underlying obsessive–compulsive disorder (OCD). In the Quinpirole sensitization rat model of OCD, compulsive checking is induced by chronic treatment with the DA agonist Quinpirole, and is attenuated by the 5-HT agonist drug mCPP. However, mCPP has affinity for a number of 5-HT receptor subtypes, and it is unknown by which receptors mCPP exerts its effects on Quinpirole-treated animals. The present study tested in rats whether mCPP activity at 5-HT2A/C receptors mediates the attenuation of compulsive checking in Quinpirole-treated animals. Rats were chronically treated with Quinpirole on the open field for the induction of compulsive checking. Following the induction phase, animals were treated with mCPP (1.25 mg/kg) and the selective 5-HT2A/C receptor antagonist ritanserin (1 mg/kg or 5 mg/kg) to test whether blockade of 5-HT2A/C receptors inhibits attenuation of checking by mCPP. Results showed that as expected, Quinpirole induced compulsive checking, and mCPP reduced its performance. However, 5-HT2A/C receptor blockade by ritanserin did not inhibit the attenuation of compulsive checking by mCPP. These results suggest that the reduction in compulsive checking by mCPP is not mediated by activity at 5-HT2A/C receptors, but by another receptor subtype.
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separate mechanisms for development and performance of compulsive checking in the Quinpirole sensitization rat model of obsessive compulsive disorder ocd
Psychopharmacology, 2014Co-Authors: Mark C Tucci, Anna Dvorkingheva, Renee Sharma, Leena Taji, Paul Cheon, John K Peel, Ashley Kirk, Henry SzechtmanAbstract:Acute administration of serotonergic agonist, meta-chlorophenylpiperazine (mCPP), attenuates performance of compulsive checking in an animal model of obsessive-compulsive disorder (OCD). It is not known whether mCPP has a similar effect on development of compulsive checking. The objective of the study was to examine whether similar mechanisms mediate the development versus the performance of compulsive checking in the rat model. Four groups of male rats (N = 14/group) were tested: two experimental groups co-injected with D2/D3 dopamine agonist Quinpirole (0.25 mg/kg) and mCPP (0.625 mg/kg or 1.25 mg/kg), and two control groups, one co-injected with Quinpirole and saline, the other receiving injections of saline. The time course of development of compulsive checking across injections 1 to 10 in Quinpirole-treated rats was compared to rats co-injected with Quinpirole and mCPP. Results showed that during the course of chronic treatment, mCPP (1.25 mg/kg) significantly attenuated performance of checking behavior. However, when these rats were retested for expression of compulsive checking (that is, with an injection of Quinpirole only), their profile of compulsive checking was no different from the control rats treated throughout with Quinpirole only. Findings show that mCPP inhibits performance of compulsive checking but does not block Quinpirole from inducing the neural substrate underlying this compulsive behavior. Hence, a separate mechanism underlies the induction of compulsive checking and the performance of it. It is suggested that development of the OCD endophenotype reflects neuroplastic changes produced by repeated dopamine D2/D3 receptor stimulation, while stimulation of serotonergic receptors mediates a negative feedback signal that shuts down the motor performance of checking.
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Quinpirole and 8 oh dpat induce compulsive checking behavior in male rats by acting on different functional parts of an ocd neurocircuit
Behavioural Pharmacology, 2013Co-Authors: Ahmad H Alkhatib, Anna Dvorkingheva, Henry SzechtmanAbstract:This study investigated whether the serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) can induce compulsive checking in a large open field, as does the dopamine D2/D3 receptor agonist Quinpirole. To induce compulsive checking, male rats were exposed to eight injections of either 8-OH-DPAT (1 mg/kg), Quinpirole (0.2 mg/kg), or saline. Subsequently, to assess cross-sensitization, rats received an acute challenge of 8-OH-DPAT or Quinpirole. The results showed that treatment with 8-OH-DPAT induces compulsive checking and may have a stronger effect on this behavior compared with Quinpirole. However, there was no cross-sensitization between 8-OH-DPAT and Quinpirole on measures of compulsive checking and locomotion. Moreover, the spatial distribution of locomotor paths in 8-OH-DPAT animals was more confined and invariant than in Quinpirole rats; their rate of locomotor sensitization was also faster than that in Quinpirole animals. Thus, although 8-OH-DPAT and Quinpirole can induce compulsive checking in a large open field, the results suggest that they do so differently. It is suggested that 8-OH-DPAT and Quinpirole probably produce compulsive behavior by acting on different parts of a security motivation circuit underlying obsessive-compulsive disorder. Quinpirole may induce compulsive checking behavior by directly driving dopaminergic activity mediating the motivational drive to check. Conversely, 8-OH-DPAT may perpetuate the activated motivational state by inhibiting the serotonergic-negative feedback signals that normally deactivate the obsessive-compulsive disorder circuit.
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effects of salvinorin a on locomotor sensitization to d2 d3 dopamine agonist Quinpirole
Neuroscience Letters, 2008Co-Authors: Pieter Beerepoot, Vincent M Lam, Alice Luu, Bernice Tsoi, Daniel Siebert, Henry SzechtmanAbstract:Locomotor sensitization induced by the dopamine agonist Quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to Quinpirole. Rats were co-treated with 0.5 mg/kg Quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and Quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to Quinpirole as did U69593, the middle salvinorin A dose had no effect on Quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to Quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of Quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.
Beth Levant - One of the best experts on this subject based on the ideXlab platform.
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Modulation of [3H]Quinpirole Binding in Brain By Monoamine Oxidase Inhibitors: Evidence For a Potential Novel Binding Site1
2016Co-Authors: Beth Levant, Kimberly A Morgan, Jeffrey D. Moehlenkamp, Neda L. Leonard, C. C. ChengAbstract:HJQuinpirole is a dopamine agonist with high affinity for the D2 and D3 dopamine receptor subtypes. A variety of drugs, most notably monoamine oxidase inhibitors (MAOls), inhibit the bind-ing of [H]Quinpirole, but not H]spiperone or [H1(-)-N-n-pro-pylnorapomorphine, in rat striatal membranes by a mechanism that does not appear to involve the enzymatic activity of MAO. This study extends the characterization of MAOI-displaceable [3H}Quinpirole binding in rat brain. Clinically antidepressant MAOIs exhibited selectivity between sites labeled by [H]quin-pirole and H]spiperone as did a number of structurally related propargylamines and N-acylethylenediamine derivatives and other drugs such as debrisoquin and phenylbiguanide. The MAOIs clorgyline and Ro 41-1 049 were the most potent. Anti-depressant MAOls inhibited [H]Quinpirole binding with the fol
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Altered dopamine D2-like receptor binding in rats with behavioral sensitization to Quinpirole: effects of pre-treatment with Ro 41-1049.
European journal of pharmacology, 2008Co-Authors: Kirsten E. Culver, Henry Szechtman, Beth LevantAbstract: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.
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clorgyline induced modification of behavioral sensitization to Quinpirole effects on local cerebral glucose utilization
Brain Research, 2007Co-Authors: Toni L Richards, Thomas L. Pazdernik, Beth LevantAbstract:Sensitization refers to augmented behavioral responses produced by repeated, intermittent injections of dopaminergic psychostimulants. The locomotor manifestations observed after a sensitizing course of Quinpirole, a D2/D3 dopamine agonist, can be modified by the MAOA inhibitor clorgyline, by a mechanism apparently unrelated to its actions on MAOA. Alterations in regional neuronal activity produced by Quinpirole in Quinpirole-sensitized rats with or without clorgyline pretreatment were assessed based on LCGU using the [14C]-2-deoxyglucose (2-DG) method. Adult, male Long–Evans rats (180–200 g, n = 9–10/group) were subjected to an injection of either clorgyline (1.0 mg/kg, s.c.) or saline 90 min prior to an injection of Quinpirole (0.5 mg/kg, s.c.) or saline, 1 set of injections administered every 3rd day for 10 sets. The 2-DG procedure was initiated 60 min after an 11th set of injections in freely moving rats. LCGU was determined by quantitative autoradiography. LCGU was decreased in a number of limbic (nucleus accumbens and ventral pallidum) and cortical (medial/ventral orbital and infralimbic) regions and in the raphe magnus nucleus in Quinpirole-sensitized rats (P < 0.05 vs. saline–saline). Quinpirole-sensitized rats pretreated with clorgyline had similar alterations in LCGU, but LCGU was higher in the locus coeruleus compared to Quinpirole alone (P < 0.05), was not decreased in the raphe magnus nucleus, and was decreased in the piriform cortex and septum. This implicates altered activity of the noradrenergic, serotonergic, olfactory, and limbic systems in the modified behavioral response to Quinpirole with clorgyline pretreatment.
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clorgyline induced modification of behavioral sensitization to Quinpirole effects on local cerebral glucose utilization
Brain Research, 2007Co-Authors: Toni L Richards, Thomas L. Pazdernik, Beth LevantAbstract:Sensitization refers to augmented behavioral responses produced by repeated, intermittent injections of dopaminergic psychostimulants. The locomotor manifestations observed after a sensitizing course of Quinpirole, a D2/D3 dopamine agonist, can be modified by the MAOA inhibitor clorgyline, by a mechanism apparently unrelated to its actions on MAOA. Alterations in regional neuronal activity produced by Quinpirole in Quinpirole-sensitized rats with or without clorgyline pretreatment were assessed based on LCGU using the [14C]-2-deoxyglucose (2-DG) method. Adult, male Long–Evans rats (180–200 g, n = 9–10/group) were subjected to an injection of either clorgyline (1.0 mg/kg, s.c.) or saline 90 min prior to an injection of Quinpirole (0.5 mg/kg, s.c.) or saline, 1 set of injections administered every 3rd day for 10 sets. The 2-DG procedure was initiated 60 min after an 11th set of injections in freely moving rats. LCGU was determined by quantitative autoradiography. LCGU was decreased in a number of limbic (nucleus accumbens and ventral pallidum) and cortical (medial/ventral orbital and infralimbic) regions and in the raphe magnus nucleus in Quinpirole-sensitized rats (P < 0.05 vs. saline–saline). Quinpirole-sensitized rats pretreated with clorgyline had similar alterations in LCGU, but LCGU was higher in the locus coeruleus compared to Quinpirole alone (P < 0.05), was not decreased in the raphe magnus nucleus, and was decreased in the piriform cortex and septum. This implicates altered activity of the noradrenergic, serotonergic, olfactory, and limbic systems in the modified behavioral response to Quinpirole with clorgyline pretreatment.
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differences in Quinpirole induced local cerebral glucose utilization between naive and sensitized rats
Brain Research, 2003Co-Authors: Toni L Carpenter, Thomas L. Pazdernik, Beth LevantAbstract:Abstract Dopaminergic psychostimulants produce behavioral responses of greater magnitude with repeated, intermittent administration, than a single, acute dose, a phenomenon known as ‘sensitization’. Alterations in regional neuronal activity produced by Quinpirole, a D 2 /D 3 agonist, in Quinpirole-naive and Quinpirole-sensitized rats 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 3rd day; controls and Quinpirole-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 43 brain regions by quantitative autoradiography. In Quinpirole-naive rats, Quinpirole decreased LCGU in the caudate/putamen (84% of control), lateral habenula (80% of control), and motor cortex (79% of control). In sensitized rats, Quinpirole decreased LCGU in the nucleus accumbens core and shell (77 and 83% of control, respectively) and ventral pallidum (82% of control) as well as in the caudate/putamen (86% of control), lateral habenula (77% of control), and motor cortex (79% of control). This suggests that decreased neuronal activity in the nucleus accumbens and ventral pallidum may underlie the augmented behavioral response to Quinpirole in sensitized animals.
Russell W. Brown - One of the best experts on this subject based on the ideXlab platform.
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ontogenetic Quinpirole treatment produces long lasting decreases in the expression of rgs9 but increases rgs17 in the striatum nucleus accumbens and frontal cortex
European Journal of Neuroscience, 2007Co-Authors: Amanda M Maple, Joshua P. Parlaman, Marla K. Perna, Gregg D. Stanwood, Russell W. BrownAbstract:Ontogenetic treatment of rats with the dopamine D 2 -like receptor agonist Quinpirole produces a significant increase in dopamine D 2 receptor sensitivity that persists throughout the animal's lifetime, a phenomenon known as D 2 priming. The present study was designed to investigate the effects of priming of the D 2 receptor on the expression of three different members of the regulator of G-protein signaling (RGS) family: Rgs4, Rgs9 and Rgs17. Male offspring were ontogenetically treated with Quinpirole or saline from postnatal days (P)1-21 and raised to adulthood. On ∼P65, animals were given an acute quinipirole injection (0.1 mg/kg) and the number of yawns was recorded for 1 h after the injection. Yawning has been shown to be a behavioural event mediated by the dopamine D 2 /D 3 receptor. Animals ontogenetically treated with Quinpirole demonstrated a significant 2.5-fold increase in yawning as compared to controls. Rgs transcripts were analysed through in situ hybridization several weeks later. Rats ontogenetically treated with Quinpirole demonstrated a significant decrease in Rgs9 expression in the frontal cortex, but a more robust decrease in the striatum and nucleus accumbens as compared to controls. Regarding Rgs17, ontogenetic Quinpirole produced a modest but significant increase in expression in the same brain areas. There were no significant differences in Rgs4 expression produced by drug treatment in any of the brain regions analysed. This study demonstrates that ontogenetic Quinpirole treatment, which results in priming of the D 2 receptor, results in significant decreases in Rgs9, which has been shown to regulate G-protein coupling to D 2 receptors.
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Ontogenetic Quinpirole treatment produces long-lasting decreases in the expression of Rgs9, but increases Rgs17 in the striatum, nucleus accumbens and frontal cortex.
The European journal of neuroscience, 2007Co-Authors: Amanda M Maple, Joshua P. Parlaman, Marla K. Perna, Gregg D. Stanwood, Russell W. BrownAbstract:Ontogenetic treatment of rats with the dopamine D(2)-like receptor agonist Quinpirole produces a significant increase in dopamine D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon known as D(2) priming. The present study was designed to investigate the effects of priming of the D(2) receptor on the expression of three different members of the regulator of G-protein signaling (RGS) family: Rgs4, Rgs9 and Rgs17. Male offspring were ontogenetically treated with Quinpirole or saline from postnatal days (P)1-21 and raised to adulthood. On approximately P65, animals were given an acute quinipirole injection (0.1 mg/kg) and the number of yawns was recorded for 1 h after the injection. Yawning has been shown to be a behavioural event mediated by the dopamine D(2)/D(3) receptor. Animals ontogenetically treated with Quinpirole demonstrated a significant 2.5-fold increase in yawning as compared to controls. Rgs transcripts were analysed through in situ hybridization several weeks later. Rats ontogenetically treated with Quinpirole demonstrated a significant decrease in Rgs9 expression in the frontal cortex, but a more robust decrease in the striatum and nucleus accumbens as compared to controls. Regarding Rgs17, ontogenetic Quinpirole produced a modest but significant increase in expression in the same brain areas. There were no significant differences in Rgs4 expression produced by drug treatment in any of the brain regions analysed. This study demonstrates that ontogenetic Quinpirole treatment, which results in priming of the D(2) receptor, results in significant decreases in Rgs9, which has been shown to regulate G-protein coupling to D(2) receptors.
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adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with Quinpirole possible roles of acetylcholine function and neurotrophic factor expression
European Journal of Neuroscience, 2004Co-Authors: Russell W. Brown, Michael T Williams, Kenyatta D Thompson, Kimberly N Thompson, Jeffrey J Ward, Stephanie K Thacker, Richard M KostrzewaAbstract:Increases in dopamine D(2) receptor sensitivity are known to be common in drug abuse and neurological disorders. Past data from this laboratory have shown that long-term increases in D(2) sensitivity can be produced by Quinpirole treatment (a D(2)/D(3) agonist) during early development. The present investigation was designed to test the hypothesis that nicotine administration in adulthood would reduce both cognitive and skilled reaching impairments produced by increases in D(2) sensitivity. Female Sprague-Dawley rats were treated with Quinpirole (1 mg/kg) or saline from postnatal day 1 (PD 1) to PD 21. Beginning in adulthood (PD 61), rats were treated with nicotine (0.3 mg/kg free base) or saline twice daily for 14 consecutive days before behavioural testing commenced. Animals neonatally treated with Quinpirole demonstrated performance deficits on the Morris water task and a skilled reaching task compared to controls. Deficits on both tasks were completely alleviated by adulthood nicotine treatment. Animals neonatally treated with Quinpirole demonstrated a significant 36% decrease of ChAT in the hippocampus compared to saline controls that was partially eliminated by nicotine. Additionally, neonatal Quinpirole produced a significant decrease in hippocampal NGF content compared to controls, however, nicotine failed to alleviate this decrease in NGF. The results of this investigation demonstrate that long-term increases in dopamine D(2) receptor sensitivity produce significant decreases in hippocampal cholinergic and NGF expression that may result in cognitive impairment. Nicotine alleviates both cognitive and skilled reaching impairments caused by increases in D(2) sensitivity, but the mechanism through which nicotine is acting is currently unknown.
Ronald P Hammer - One of the best experts on this subject based on the ideXlab platform.
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camp response element binding protein phosphorylation in nucleus accumbens underlies sustained recovery of sensorimotor gating following repeated d2 like receptor agonist treatment in rats
Biological Psychiatry, 2011Co-Authors: Alison K Berger, Ronald P Hammer, Thomas A Green, Steven J Siegel, Eric J NestlerAbstract:Background Prepulse inhibition (PPI) is a cross-species measure of sensorimotor gating. PPI deficits are observed in humans and rats upon acute treatment with dopamine D 2 -like receptor agonists and in patients with schizophrenia. Repeated treatment with a D 2 -like agonist, however, reverses PPI deficits and increases cyclic adenosine monophosphate (cAMP) signaling in the nucleus accumbens (NAc). This study examined the short- and long-term effects on PPI of treatment with Quinpirole and ropinirole, dopamine D 2 /D 3 receptor agonists, and the molecular mechanism by which they occur. Methods PPI was assessed in adult male Sprague–Dawley rats following acute and chronic treatment with Quinpirole or ropinirole and 1, 2, 3, and 4 weeks after termination of repeated ropinirole treatment. Finally, the effect of dominant negative mutant cAMP response element binding protein (CREB) overexpression in the NAc on PPI following chronic Quinpirole treatment was assessed. Results Acute Quinpirole produced dose-dependent PPI deficits, whereas ropinirole caused consistent PPI reduction at all but the highest dose. Repeated ropinirole treatment significantly increased PPI compared with acute treatment, and increased CREB phosphorylation in NAc neurons. Subsequent ropinirole challenge had no effect as long as 28 days later, at which time NAc CREB phosphorylation had normalized. Overexpression of dominant negative mutant CREB prevented PPI recovery induced by chronic Quinpirole treatment. Conclusions Chronic Quinpirole or ropinirole treatment produces sustained PPI recovery; CREB activity in the NAc is required to induce PPI recovery but not to maintain it. The results suggest that transcriptional regulation by CREB mediates long-lasting changes occurring within NAc circuits to promote recovery of sensorimotor gating.
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Repeated Quinpirole Treatment Increases cAMP-Dependent Protein Kinase Activity and CREB Phosphorylation in Nucleus Accumbens and Reverses Quinpirole-Induced Sensorimotor Gating Deficits in Rats
Neuropsychopharmacology, 2004Co-Authors: Kerry E Culm, Natasha Lugo-escobar, Bruce T Hope, Ronald P HammerAbstract: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 D_2-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 μM), or SKF 82958- (10 μM) 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.
Trevor W Robbins - One of the best experts on this subject based on the ideXlab platform.
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d2 receptors and cognitive flexibility in marmosets tri phasic dose response effects of intra striatal Quinpirole on serial reversal performance
Neuropsychopharmacology, 2019Co-Authors: Nicole K Horst, Bianca Jupp, Angela C Roberts, Trevor W RobbinsAbstract:Behavioral flexibility, which allows organisms to adapt their actions in response to environmental changes, is impaired in a number of neuropsychiatric conditions, including obsessive-compulsive disorder and addiction. Studies in human subjects and monkeys have reported correlations between individual differences in dopamine D2-type receptor (D2R) levels in the caudate nucleus and performance in a discrimination reversal task, in which established contingent relationships between abstract stimuli and rewards (or punishments) are reversed. Global genetic deletion of the D2R in mice disrupts reversal performance, indicating a likely causal role for this receptor in supporting flexible behaviors. To directly examine the specific role of caudate D2-type receptors in reversal performance, the D2/3/4R agonist Quinpirole was infused via chronic indwelling cannulae into the medial caudate of male and female marmoset monkeys performing a touchscreen-based serial discrimination reversal task. Given prior evidence for dose-dependent effects of Quinpirole and other dopaminergic drugs, a full dose-response curve was established. Individually, marmosets displayed marked differences in behavioral sensitivity to specific doses of intra-caudate Quinpirole. Collectively, they exhibited a behaviorally specific bi-phasic deficit in reversal learning, being consistently impaired at both relatively low and high doses of Quinpirole. However, intermediate doses of intra-caudate Quinpirole produced significant improvement in reversal performance. These data support previous human and monkey neuroimaging studies by providing causal evidence of a U-shaped function describing how dopamine modulates cognitive flexibility in the primate striatum.
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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
Behavioural Brain Research, 2014Co-Authors: Dawn M Eagle, Cristie Noschang, Lauresophie Camilla Dangelo, Christie A Noble, Marie Louise Dongelmans, David E H Theobald, Gonzalo P Urcelay, Sharon Moreinzamir, Trevor W RobbinsAbstract: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 (0.5 mg/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.
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dopamine d2 d3 receptor agonist Quinpirole impairs spatial reversal learning in rats investigation of d3 receptor involvement in persistent behavior
Psychopharmacology, 2009Co-Authors: Vasileios Boulougouris, Anna Castane, Trevor W RobbinsAbstract:Dopamine is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. We investigated the effects of systemic administration of the D2/D3 receptor agonist Quinpirole (0.1, 0.3 mg/kg), the D2/D3 receptor antagonist raclopride (0.1, 0.3 mg/kg), the selective D3 antagonist nafadotride (0.3, 1.0 mg/kg), and combined administration of raclopride (0.1 mg/kg) or nafadotride (1.0 mg/kg) with Quinpirole (0.3 mg/kg) on spatial discrimination and reversal learning. Rats were trained on an instrumental two-lever spatial discrimination and reversal learning task. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a reversal was introduced. None of the drugs altered performance during retention of the previously reinforced contingencies. Quinpirole (0.3 mg/kg) significantly impaired reversal learning by increasing both trials and incorrect responses to criterion in reversal phase, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, neither raclopride nor nafadotride when administered alone altered reversal performance. However, raclopride blocked the Quinpirole-induced reversal deficit, whereas combined administration of nafadotride and Quinpirole affected not only performance during the reversal but also the retention phase. The reversal impairment resulting from co-administration of nafadotride and Quinpirole was associated with both perseverative and learning errors. Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.
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dopamine d2 d3 receptor agonist Quinpirole impairs spatial reversal learning in rats investigation of d3 receptor involvement in persistent behavior
Psychopharmacology, 2009Co-Authors: Vasileios Boulougouris, Anna Castane, Trevor W RobbinsAbstract:Rationale Dopamine is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. Objectives We investigated the effects of systemic administration of the D2/D3 receptor agonist Quinpirole (0.1, 0.3 mg/kg), the D2/D3 receptor antagonist raclopride (0.1, 0.3 mg/kg), the selective D3 antagonist nafadotride (0.3, 1.0 mg/kg), and combined administration of raclopride (0.1 mg/kg) or nafadotride (1.0 mg/kg) with Quinpirole (0.3 mg/kg) on spatial discrimination and reversal learning. Materials and methods Rats were trained on an instrumental two-lever spatial discrimination and reversal learning task. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a reversal was introduced. Results None of the drugs altered performance during retention of the previously reinforced contingencies. Quinpirole (0.3 mg/kg) significantly impaired reversal learning by increasing both trials and incorrect responses to criterion in reversal phase, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, neither raclopride nor nafadotride when administered alone altered reversal performance. However, raclopride blocked the Quinpiroleinduced reversal deficit, whereas combined administration of nafadotride and Quinpirole affected not only performance during the reversal but also the retention phase. The reversal impairment resulting from co-administration of nafadotride and Quinpirole was associated with both perseverative and learning errors. Conclusions Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.
