5-HT2 Receptor Antagonism Reduces Hyperactivity Induced by Amphetamine, Cocaine, and MK-801 But Not D1 Agonist C-APB

O’Neill, Michael F.; Heron-Maxwell, C.; Shaw, Gillian

doi:10.1016/s0091-3057(98)00240-8

Cited by 122 publications

(69 citation statements)

References 31 publications

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“…Elevated locomotor activity is one of the more consistent behavioral phenotypic traits of DAT KO mice (Giros et al, 1996;Spielewoy et al, 2000;Gainetdinov et al, 2001); in the present study, these mice exhibited levels of activity in a novel environment, that is, their total distance traveled two to three times those of WT and HT mice. The finding that M100907 can reverse hyperactivity selectively in DAT KO mice, which have elevated synaptic levels of dopamine (Gainetdinov et al, 1999), complements earlier reports that M100907 reverses the behavioral hyperactivity induced by indirect dopamine agonists, such as cocaine, d-amphetamine and GBR 12909, in both rats and mice Carlsson, 1995;Kehne et al, 1996;O'Neill et al, 1999;McMahon and Cunningham, 2001). Although the between-cohorts design of the locomotor tasks in the present study, using different cohorts of mice with different doses, precluded an explicit test of dose-dependency of M100907, the greater relative effect size of the highest dose strongly suggests that behavioral effects were dose related.…”

Section: Discussionsupporting

confidence: 78%

“…It is unlikely that M100907 exerts its actions directly at dopamine receptors, as the compound exhibits a low binding affinity for these receptors . Furthermore, M100907 was unable to reverse the hyperlocomotor effects of the direct D 1 agonist C-APB (O'Neill et al, 1999) in WT mice, while a dose of M100907 as high as 32 mg/kg was ineffective in countering the behavioral effects of the direct D 2 agonist apomorphine in mice. Studies using in vivo techniques, such as cerebral microdialysis, have suggested that M100907 can reduce impulse-dependent dopamine release in the rat medial prefrontal cortex (Pehek et al, 2001), while the selective 5-HT 2A receptor antagonist SR 46349B attenuated amphetamine-induced dopamine release in the nucleus accumbens and dorsal striatum (Porras et al, 2002).…”

Section: Discussionmentioning

confidence: 93%

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The Selective Serotonin-2A Receptor Antagonist M100907 Reverses Behavioral Deficits in Dopamine Transporter Knockout Mice

Barr

Lehmann-Masten

Paulus

et al. 2003

Neuropsychopharmacol

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A hyperdopaminergic state in humans has been hypothesized to contribute to the pathology of a number of psychiatric illnesses, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Mice that display elevated synaptic levels of dopamine due to a genetically engineered deletion of the dopamine transporter (DAT) model behavioral deficits that simulate the above conditions. As novel treatment strategies for these disorders have focused on the serotonin (5-HT) 2A receptor, we determined the capacity of the highly selective 5-HT 2A receptor antagonist M100907 to reverse behavioral deficits in DAT knockout (KO) mice. Prior to drug treatment, DAT KO mice exhibited increased levels of locomotor activity and highly linearized movement in a novel environment, as well as reduced prepulse inhibition (PPI) of acoustic startle, compared to wild-type littermates. Treatment with M100907 (0.3-1.0 mg/ kg, but not 0.1 mg/kg) reversed locomotor deficits in DAT KO mice. Similarly, treatment with 1.0 mg/kg M100907 reversed the PPI deficits in DAT KO mice. These data indicate that selective 5-HT 2A receptor antagonists, such as M100907, may represent a class of drugs that can be used to treat conditions in which a chronic, elevated dopaminergic tone is present and contributes to abnormal behavior and sensorimotor gating deficits.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 93%

The Selective Serotonin-2A Receptor Antagonist M100907 Reverses Behavioral Deficits in Dopamine Transporter Knockout Mice

Barr

Lehmann-Masten

Paulus

et al. 2003

Neuropsychopharmacol

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“…However, in the case of NDMC this level of occupancy is not achieved even at the high dose of 100 mg/kg observed up to 360-min post-treatment. 5-HT 2 receptor antagonism (O'Neill et al, 1999) and muscarinic M 1 agonism are known to inhibit AIL and it is likely that they could have influenced inhibition of AIL, although at a very high dose.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Natesan

Reckless

Barlow

et al. 2006

Neuropsychopharmacol

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There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT 2 antagonist and as a partial agonist to dopamine D 2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D 2 and 5-HT 2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT 2 (64-79%), but minimal D 2 occupancy (o15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

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“…86 5HT2A receptors that localize on dopaminergic neurons inhibit dopamine firing, whereas 5HT2A antagonists induce dopamine release and reduce dopamine-induced hyperactivity in rodents. 87,88 The serotonergic modulation of dopaminergic function is also supported by the analysis of DAT-KO mice, in which hyperlocomotion is reversed by selective 5HT2A antagonists and the effects of psychostimulant treatments depend on the serotonin system. 34,88 Therefore, our results contribute to growing evidence, suggesting that the serotoninergic system may indirectly affect ADHD by modulating dopamine neurotransmission.…”

Section: Ht2amentioning

confidence: 98%

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB

et al. 2007

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Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P = 0.00053; odds ratio (OR) = 2.17) and childhood ADHD (P = 0.0017; OR = 1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P = 0.0029; OR = 1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P = 0.0036; OR = 1.63) and children (P = 0.0084; OR = 1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.

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5-HT2 Receptor Antagonism Reduces Hyperactivity Induced by Amphetamine, Cocaine, and MK-801 But Not D1 Agonist C-APB

Cited by 122 publications

References 31 publications

The Selective Serotonin-2A Receptor Antagonist M100907 Reverses Behavioral Deficits in Dopamine Transporter Knockout Mice

The Selective Serotonin-2A Receptor Antagonist M100907 Reverses Behavioral Deficits in Dopamine Transporter Knockout Mice

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB

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