M100,907, a selective 5-HT2A antagonist, attenuates dopamine release in the rat medial prefrontal cortex

Pehek, Elizabeth A.; McFarlane, Hewlet G.; Maguschak, Kimberly A.; Price, Bernadette; Pluto, Charles P.

doi:10.1016/s0006-8993(00)03004-3

Cited by 113 publications

(68 citation statements)

References 32 publications

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“…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). The authors of these studies have posited that the 5-HT 2A receptor exerts a minimal influence on basal dopamine efflux, hence explaining why no effects of M100907 were observed in WT animals in the present study, but may modulate dopamine release under conditions when the mesocortical system is stimulated.…”

Section: Discussionmentioning

confidence: 99%

“…M100907 has been shown to elicit a positive response in a large number of preclinical paradigms designed to detect antipsychotic activity . Several of these rodent paradigms indicate that M100907 can reverse the behavioral effects of an acute hyperdopaminergic state that has been induced by amphetamines , potentially through modification of stimulated release of dopamine in the medial prefrontal cortex (Pehek et al, 2001) and nucleus accumbens shell (Marcus et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Thus, a role for presynaptic regulation of DA release cannot be discounted. We have previously shown that intracortical infusions of the 5-HT2A antagonist M100907 block local potassium (K + )-stimulated DA release in the PFC (Pehek et al, 2001). Since high K + stimulates transmitter release by depolarizing nerve terminals, it is possible that M100907 may have acted to block DA efflux through actions on 5-HT2A receptors localized presynaptically on DA terminals.…”

Section: -Ht2amentioning

confidence: 99%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

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526

311

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The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. There are at least 14 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

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“…D 4 receptor activation attenuates both GABAmediated inhibition of medial prefrontal cortex pyramidal neurons and N-methyl-D-aspartic-acid-mediated synaptic responses (Seamans et al 2001;Wang et al 2002Wang et al , 2003. Another mechanism for 5-HT 2A interactions with dopaminergic systems that has been proposed includes the possibility that 5-HT 2A receptors might act as presynaptic heteroreceptors on dopamine axon terminals (Pehek 1996;Pehek et al 2001), a hypothesis that finds support in the study by Miner et al (2003), showing that in the prefrontal complex (PFC), some 5-HT 2A receptors are localized on dopaminergic terminals. Thus, dopamine D 4 receptors are co-localized in some of the same cortical layers where 5-HT 2A receptors are highly expressed and might directly or indirectly modulate 5-HT 2A receptor function.…”

Section: Discussionmentioning

confidence: 99%

“…For example, it is well documented that activation of the 5-HT 2A receptor can modulate dopamine levels or physiological responses mediated by dopaminergic systems (Alex and Pehek 2007;Lucas and Spampinato 2000;Pehek et al 2001;Vollenweider et al 1999;Yan 2000). In addition, it has been reported previously that pretreatment with 5-HT 2A agonists can potentiate the discriminative stimulus effects of amphetamine (Marona-Lewicka and Nichols 1997), methamphetamine (Munzar et al 1999(Munzar et al , 2002, and cocaine (Munzar et al 2002) in rats.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

2008

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Rationale Lysergic acid diethylamide (LSD) differs from other types of hallucinogens in that it possesses direct dopaminergic effects. The exact nature of this component has not been elucidated. Objective The present study sought to characterize the effects of several dopamine D 4 agonists and antagonists on the discriminative stimulus effect of LSD at two pretreatment times and 2,5-dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT 2A/2C agonist. Materials and methods Male Sprague-Dawley rats were trained in a two-lever, fixed ratio (FR) 50, food-reinforced task with LSD-30 (0.08 mg/kg, i.p., 30-min pretreatment time), LSD-90 (0.16 mg/kg, i.p., 90-min pretreatment time), and DOI (0.4 mg/kg, i.p., 30-min pretreatment time) as discriminative stimuli. Substitution and combination tests with the dopamine D 4 agonists, ABT-724 and WAY 100635, were performed in all groups. Combination tests were run using the dopamine D 4 antagonists A-381393 and L-745,870 and two antipsychotic drugs, clozapine and olanzapine. Results WAY 100635 produced full substitution in LSD-90 rats, partial substitution in LSD-30 rats, and saline appropriate responding in DOI-trained rats. ABT-724 partially mimicked the LSD-90 and LSD-30 cues, but produced no substitution in DOI-trained rats. In combination tests, both agonists shifted the dose-response curve of LSD leftward, most potently for the LSD-90 cue. The D 4 antagonists significantly attenuated both the LSD-90 and LSD-30 cue, but had no effect on the DOI cue. Conclusion Dopamine D 4 receptor activation plays a significant modulatory role in the discriminative stimulus effects in LSD-90-trained rats, most markedly for the later temporal phase of LSD, but has no effect on the cue produced by DOI.

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M100,907, a selective 5-HT2A antagonist, attenuates dopamine release in the rat medial prefrontal cortex

Cited by 113 publications

References 32 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

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

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