WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D4 receptor activation

Marona‐Lewicka, Danuta; Nichols, David E.

doi:10.1097/fbp.0b013e3283242f1a

Cited by 26 publications

(18 citation statements)

References 16 publications

(19 reference statements)

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“…In vivo administration to rats to test potential treatment of erectile dysfunction [184,185] WAY 100635 16.4 D4 receptor agonist and 5HT1A antagonist; produces discriminative stimulus effects in rats [186,187] PD 168077 8.7 Selective D4 agonist, proerectile effect in rats [188]; tested in mice for memory consolidation studies [189] PNU 96415E 3 Tested for antipsychotic potential [190] Ro 10-5824 5.2 Selective D4 agonist, increases novel exploration in mice [191] NGD 94-1 3…”

Section: Dopamine-related Diseasesmentioning

confidence: 99%

The dopamine D4 receptor: biochemical and signalling properties

Rondou

Haegeman

Craenenbroeck

2010

Cell. Mol. Life Sci.

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Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which belong to the G-protein-coupled receptor superfamily. Besides activating different effectors through G-protein coupling, dopamine receptors also signal through interaction with a variety of proteins, collectively termed dopamine receptor-interacting proteins. We focus on the dopamine D4 receptor, which contains an important polymorphism in its third intracellular loop. This polymorphism has been the subject of numerous studies investigating links with several brain disorders, such as attention-deficit hyperactivity disorder and schizophrenia. We provide an overview of the structure, signalling properties and regulation of dopamine D4 receptors, and briefly discuss their physiological and pathophysiological role in the brain.

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Section: Dopamine-related Diseasesmentioning

confidence: 99%

The dopamine D4 receptor: biochemical and signalling properties

Rondou

Haegeman

Craenenbroeck

2010

Cell. Mol. Life Sci.

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“…Still, several lines of evidence suggest that drugs may have multiple physiologic targets 2-5. Psychiatric medications, for instance, notoriously act through multiple molecular targets and this “polypharmacology” is likely therapeutically essential 6.…”

mentioning

confidence: 99%

Predicting new molecular targets for known drugs

Keiser

Setola²,

Irwin³

et al. 2009

Nature

1,504

1,247

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Whereas drugs are intended to be selective, at least some bind to several physiologic targets, explaining both side effects and efficacy. As many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here, we compared 3,665 FDA-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the β1 receptor by the transporter inhibitor Prozac, the inhibition of the 5-HT transporter by the ion channel drug Vadilex, and antagonism of the histamine H4 receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (< 100 nM). The physiological relevance of one such, the drug DMT on serotonergic receptors, was confirmed in a knock-out mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.

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“…For example, in drug discrimination experiments, WAY-100635 potently blocked the cue produced by full or partial 5-HT 1A agonists (Gommans et al 2000, De Vry et al 1998, Kleven and Koek 1998, Marona-Lewicka and Nichols 2004, Sanchez et al 1996). Nevertheless, we recently demonstrated that at higher doses WAY 100635 produces a robust discriminative stimulus that is insensitive to 5-HT 1A agonist or antagonist treatment, but which can be blocked by dopamine D 4 antagonists (Marona-Lewicka and Nichols, 2009). Moreover, WAY100635 potentiates the temporally-delayed interoceptive cue produced by LSD that is mediated by activation of dopamine D 4 receptors (Marona-Lewicka et al 2009).…”

Section: Introductionmentioning

confidence: 99%

“…For combination tests we chose doses of WAY 100635 previously employed in the drug discrimination assay in our laboratory (Marona-Lewicka and Nichols 2004, 2009): 0.4 mg/kg as the dose that completely blocks a 5-HT 1A -mediated discriminative cue, and 5.4 mg/kg as the dose that generated a robust discriminative stimulus effects in rats that is mediated by activation of dopamine D 4 receptors (Marona-Lewicka and Nichols 2009). We decided also to test several dopamine D 4 receptor selective compounds in substitution and combination tests in (+)-amphetamine-trained rats.…”

Section: Introductionmentioning

confidence: 99%

Potential serotonin 5-HT1A and dopamine D4 receptor modulation of the discriminative stimulus effects of amphetamine in rats

Marona‐Lewicka

Nichols

2011

Behavioural Pharmacology

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Activation of the dopaminergic system underlies the behavioral effects of (+)-amphetamine, and plays the major role in its discriminative stimulus properties. Although serotonin receptors modulate dopamine levels in the brain, and 5-HT1A and 5-HT2 receptor agonists do not mimic (+)-amphetamine, pretreatment with 5-HT2A/2C agonists significantly potentiates the (+)-amphetamine cue. Further, 5-HT2 antagonists do not modify the discriminative stimulus effect of (+)-amphetamine, but 5-HT1A antagonists have never been tested in (+)-amphetamine-trained rats. The present study sought to characterize the effects of the 5-HT1A antagonist WAY 100635 on (+)-amphetamine-induced discriminative stimulus effects. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio (FR) 50, food-reinforced task with (+)-amphetamine sulfate (1.0 mg/kg, i.p., 30 min pretreatment time) as the discriminative stimulus. Substitution and combination tests with WAY 100635 were then performed. WAY 100635 did not produce substitution in amphetamine-trained rats, but significantly increased behavioral disruption. In combination tests 0.4 and 5.4 mg/kg doses of WAY 100635 potentiated the amphetamine cue. We suggest that low doses of WAY 100635 potentiated the (+)-amphetamine cue by blockade of 5-HT1A receptors, but stimulation of the dopamine D4 receptor by higher doses of WAY 100635 may be responsible for potentiation of amphetamine-induced behavioral sensitization. The high percentage of behavioral disruption in substitution tests might suggest that rats trained to discriminate (+)-amphetamine from saline show behavioral sensitization that is not detectable by the drug discrimination assay but may be expressed as hyperactivity and stereotypic behavior that disrupts operant behavior.

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WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D4 receptor activation

Cited by 26 publications

References 16 publications

The dopamine D4 receptor: biochemical and signalling properties

The dopamine D4 receptor: biochemical and signalling properties

Predicting new molecular targets for known drugs

Potential serotonin 5-HT1A and dopamine D4 receptor modulation of the discriminative stimulus effects of amphetamine in rats

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