Dopamine D2 receptor mediation of the discriminative stimulus properties of LY 171555 (quinpirole)

doi:10.1016/0014-2999(86)90016-6

European Journal of Pharmacology

Volume 132, Issue 1, 2 December 1986, Pages 87-91

https://doi.org/10.1016/0014-2999(86)90016-6 Get rights and content

Abstract

The mechanisms subserving the behavioral effects of the putatively selective dopamine D₂ agonist LY 171555 (0.025 mg/kg) were analyzed in rats (N = 23 using a two-lever, water-reinforced drug discrimination task. Substitution (generalization) tests showed that the DA agonist apomorphine mimicked LY 171555 while the selective D₁ agonist SKF 38393 did not. When given in combination with the training drug, haloperidol but not the D₁ antagonist Sch 23390 dose dependently blocked the LY 171555 cue; given alone, Sch 23390 mimicked LY 171555 and haloperidol elicited responding on the saline-appropriate lever. These results suggest that stimulus properties of LY 171555 are mediated primarily by D₂-containing neuronal systems but that the effects of stimulating either D₁ or D₂ receptor subtypes in vivo are complex and interdependent.

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Characterization of the discriminative stimulus effect of quinpirole: Further evidence for functional interaction between central dopamine D<inf>1</inf>/D<inf>2</inf>-receptors
2022, Pharmacology Biochemistry and Behavior
Citation Excerpt :
It has been widely accepted that stimulation of dopamine D1- and D2- receptors is involved in the discriminative stimulus effects of psychostimulants such as methamphetamine and cocaine in rats (Rosenzweig-Lipson and Bergman, 1993; Suzuki et al., 1996; Yoshizawa et al., 2012). On the other hand, dopamine D1-receptor agonists and dopamine D2-receptor agonists do not cross-substitute for each other (Rosenzweig-Lipson and Bergman, 1993; Weathersby and Appel, 1986; Williams and Woolverton, 1990), indicating that they do not share a discriminative stimulus effect. However, the mechanism of the discriminative stimulus effect through the stimulation of dopamine D2-receptors has not yet been fully elucidated.
Dysfunction of the central dopamine D₂-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D₂-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D₂-receptor-containing MSN (D₂-MSN) may be synchronized with the activity of dopamine D₁-receptor-containing MSN (D₁-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D₂-receptor agonist quinpirole to further investigate the “D_1/D₂-MSN” interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D₂-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A_2A-receptor antagonist istradefylline, both of which may act on D₂-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D₁-receptor antagonist SCH23390 and the GABA_B-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D₂-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D₁-receptors and agonistic modulation of GABA_B-receptors may share the discriminative stimulus effect via the activation of central dopamine D₂-receptors.
(S)-amisulpride as a discriminative stimulus in C57BL/6 mice and its comparison to the stimulus effects of typical and atypical antipsychotics
2014, European Journal of Pharmacology
Citation Excerpt :
Haloperidol has been used for the treatment of schizophrenia for over 50 years and has a long history in drug discrimination studies as one of the most often used agents in stimulus antagonism tests. The results of those studies suggest that the stimulus properties of haloperidol include antagonism of D2/3 receptors (e.g. Bristow et al., 1998; Kleven et al., 1990; Millan et al., 2007; Weathersby and Appel, 1986), some degree of antagonism of sigma receptors (e.g. Balster, 1989; Holtzman, 1989; Steinfels et al., 1987), but little or no interaction with serotonin receptors (e.g. Li et al., 2008; Schreiber et al., 1994; White and Appel, 1981, 1982; Young et al., 1982). While haloperidol and amisulpride share high affinity receptor binding at dopamine D2/3 receptors, substitution testing with haloperidol in the (S)-amisulpride-trained animals in the present study produced a maximum of only 45% drug lever responding; testing of higher doses of haloperidol was precluded by suppression of response rates.
Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10 mg/kg, s.c.) from vehicle in a two-lever drug discrimination task for food reward. The (S)-amisulpride stimulus was rapidly acquired and was shown to be dose-related, time dependent (effective between 30 and 120 min) and stereoselective: (S)-amisulpride (ED₅₀=1.77 mg/kg; 4.2 µmol/kg) was about three times more potent than rac-amisulpride (ED₅₀=4.94 mg/kg; 13.4 µmol/kg) and ten times more potent than (R)-amisulpride (ED₅₀=15.84 mg/kg; 42.9 µmol/kg). In tests of stimulus generalization, the (S)-amisulpride stimulus generalized completely to sulpiride (ED₅₀=12.67 mg/kg; 37.1 µmol/kg), a benzamide analog that also is purported to be an atypical antipsychotic, but did not fully generalize to the typical antipsychotic drug haloperidol (maximum of 45% drug-lever responding) nor to the atypical antipsychotic drugs clozapine (partial substitution of 65% drug-lever responding) or aripiprazole (~30% drug-lever responding). These results demonstrated that (S)-amisulpride appears to exert a unique discriminative stimulus effect that is similar to other benzamides, but which differs from other structural classes of antipsychotic drugs.
Drug discrimination in neurobiology
1999, Pharmacology Biochemistry and Behavior
Areas of neurobiological interest are identified towards which drug discrimination (DD) studies have made important contributions. DD allows ligand actions to be analyzed at the whole organism level, with a neurobiological specificity that is exquisite and often unrivalled. DD analyses have thus been made of a vast array of CNS agents acting on receptors, enzymes, or ion channels, including most drugs of abuse. DD uniquely offers access to the study of subjective drug effects in animals, using a methodology that also is transposable to humans and has generated unprecedented models of pathology (e.g., chronic pain, opiate addiction). Parametric studies of such independent variables as training dose and reinforcement provide refined insights into the dynamic psychophysiological mechanisms of both drug effects and behavior. Three different mechanisms have been identified by which discriminative, and perhaps other behaviors, can come about. DD also is superbly sensitive to small, partial activation of molecular substrates; this has enabled DD analyses to pioneer the unravelling of molecular mechanisms of drug action (attributing, f.ex., LSD's particular subjective effects to an unusual, partial activation of 5-HT, and perhaps other receptors). DD has both oriented and served as a tool to conduct drug discovery research (e.g., pirenperone-risperidone, loperamide). The DD response arguably constitutes a quantal, rather than graded, variable, and as such allows a comprehension of molecular, pharmacological, and behavioral mechanisms that would have been otherwise inaccessible. Perhaps most important are the following further contributions. One is the notion that particular, different levels of receptor activation are associated with qualities of neurobiological actions that also differ and are unique, this notion arguably constituting the most significant addition to affinity and intrinsic activity since the earliest theoretical conceptions of molecular pharmacology. Another contribution consists of studies that render redundant the notion of tolerance and identify fundamental mechanisms of signal transduction; these mechanisms account for apparent tolerance, dependence, addiction, and sensitization, and appear to operate ubiquitously in a bewildering array of biological systems.
D<inf>2</inf>-specific discriminative stimuli: Parameters, blocking, and rebound
1995, Pharmacology, Biochemistry and Behavior
This study characterizes the cue properties of quinpirole (LY 171555), a selective D₂ agonist, and the blocking capabilities of spiperone, a selective D₂ antagonist. After rats were trained to discriminate 0.025 mg/kg quinpirole from distilled water, a dose-response curve and time course of the quinpirole discriminative stimulus were determined. The effectiveness of three doses of spiperone in blocking the discriminative stimulus produced by 0.02 mg/kg quinpirole was then assessed. Finally, the time course of spiperone's blocking action was determined. Given the putative selective action of these drugs on D₂ receptors and the parametric data presented here, it was predicted that following chronic treatment with spiperone, a rebound increase in quinpirole-appropriate responding would occur. Neither chronic treatment with spiperone nor chronic treatment with haloperidol produced the predicted changes. This result, however, may be confined to the specific dose and time parameters used.
Postnatal lead exposure induces supersensitivity to the stimulus properties of a D<inf>2</inf>-D<inf>3</inf> agonist
1992, Brain Research
To examine the impact of lead (Pb) exposure during the ontogeny of dopaminergic (DA) systems on resultant DA function, rats were exposed postnatally (0–21 days of age) via the lactating dam to 0, 100 or 350 ppm Pb acetate in drinking water. At 2 months of age, the postnatally Pb-exposed rats were trained to discriminate the stimulus properties of either the D₁ receptor agonist SKF38393 (6.0 mg/kg) or the D₂-D₃ receptor family subtype agonist quinpirole (0.05 mg/kg) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. In each training group, dose-effect curves describing drug lever responding to lower doses of the training drug and to preadministration of selective DA antagonists were obtained to examine Pb-induced changes in DA sensitivity. Doses of other DA agonists were substituted for the training drug to determine the generality of any changes in DA sensitivity, and doses of non-DA compounds were substituted to determine the specificity of any changes in DA sensitivity. In the D₁/saline training condition, Pb exposure was not associated with any specific or consistent changes in DA sensitivity. In contrast, exposure to Pb was associated with D₂-D₃ receptor subtype supersensitivity as was indicated by significantly elevated levels of drug lever responding in the presence of quinpirole and haloperidol and to at least one dose of apomorphine. No differences in the dose-effect curves for either (+)-amphetamine or NMDA were observed in the D₂-D₃-trained control and Pb-exposed groups, but an increase in drug lever responding in the presence of pentobarbital was noted in the Pb-exposed group relative to control. Taken together, these findings are consistent with a Pb-induced functional D₂-D₃ supersensitivity possibly mediated via autoreceptors. Moreover, this functional D₂-D₃ supersensitivity necessarily represents a permanent effect of postnatal Pb exposure since both blood and brain Pb levels were negligible at the time drug discrimination training began.
Stimulus effects of d-amphetamine 1: DA mechanisms
1992, Pharmacology, Biochemistry and Behavior
As part of a continuing effort to assess the role of monoaminergic neuronal systems in the subjective effects of CNS stimulants, 10 rats trained to discriminate 1.0 mg/kg d-amphetamine from saline were treated with compounds that act through different dopaminergic mechanisms. In substitution (generalization) tests, 20 mg/kg of the dopamine (DA) uptake inhibitor GBR 12909 mimicked the training drug completely; at a dose of 15 mg/kg, GBR 12909 substituted for d-amphetamine incompletely. Neither the D₁ agonist SSK&F 38393 (1, 10 mg/kg) nor the D₂ agonist quinpirole (LY 171555; 0.05–0.2 mg/kg) had amphetamine-like effects. When given in combination with the training drug, the D₁ antagonist SCH 23390 blocked the amphetamine cue completely at a dose of 0.05 mg/kg but did not have significant effects at higher or lower doses; the D₂ antagonist metoclopramide did not block d-amphetamine at any dose tested (1–5 mg/kg). These data indicate that: a) The discriminable effects of d-amphetamine are due, at least in part, to inhibition of DA uptake; b) direct stimulation of either D₁ or D₂ receptor sites is not sufficient to evoke d-amphetamine-like responding; and c) blockade of D₁ receptors attenuates the subjective effects of d-amphetamine to a greater extent than blockade of D₂ receptors.

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Short communicationDopamine D2 receptor mediation of the discriminative stimulus properties of LY 171555 (quinpirole)

Abstract

European J. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

Life Sci.

Pharmacol. Biochem. Behav.

Short communication
Dopamine D₂ receptor mediation of the discriminative stimulus properties of LY 171555 (quinpirole)