Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function

Palfreyman, Michael G.; Schmidt, Christopher J.; Sorensen, Stephen M.; Dudley, Mark W.; Kehne, John H.; Moser, Paul; Gittos, Maurice W.; Carr, Albert A.

doi:10.1007/bf02245008

Cited by 119 publications

(62 citation statements)

References 28 publications

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“…Some studies suggest that, like the acute treatment, chronic 5-HT3 antagonism (using DAU 6215 or zatosetron) does not affect the number of spontaneously active DA neurons in the SNpc (Rasmussen et al, 1991;Prisco et al, 1992) or the concentration of DA in the striatum . Other studies see a decrease in the number of spontaneously active DA neurons in the SNpc in response to chronic treatment with the 5-HT3 antagonist MDL 73147EF (Sorenson et al, 1989;Palfreyman et al, 1993). It is possible that this discrepancy is caused by the different selectivities of the antagonists used.…”

Section: Nigrostriatal Pathwaymentioning

confidence: 96%

“…Supporting this lack of effect, the 5-HT3 antagonists ICS 205-930 and metoclopramide do not affect the 5-HT-stimulated release of [ 3 H]DA from NA slices (Jacocks and Cox, 1992). There is, however, consensus that chronic 5-HT3 antagonism causes decreased DA in rat NA and decreases DA cell firing rate in the VTA (Sorenson et al, 1989;Rasmussen et al, 1991;Prisco et al, 1992;Palfreyman et al, 1993). Antipsychotic drugs also are known to decrease mesolimbic DA activity after chronic use.…”

Section: Mesolimbic Pathwaymentioning

confidence: 99%

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Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

536

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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Section: Nigrostriatal Pathwaymentioning

confidence: 96%

Section: Mesolimbic Pathwaymentioning

confidence: 99%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

536

311

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“…Similarly, local application of 5-HT or 5-HT agonists have been shown to reduce (de Belleroche and Gardiner 1982) and facilitate dopamine efflux in the nucleus accumbens (Guan and McBride 1989;Parson and Justice 1993). In respect to the 5-HT 2 receptor agonist properties of psilocybin, it is of particular note that 3,4-methylenedioxymethamphetamine (MDMA), a potent 5-HT releasing agent, has been shown to increase impulse-mediated striatal dopamine release through 5-HT 2 receptor activation (Schmidt et al 1992;Palfreyman et al 1993;Schmidt et al 1994;Yamamoto et al 1995;Gudelsky and Nash 1996). Thus, 5-HT 2A receptors located on dopaminergic and/or GABAergic neurons within the striatum and nucleus accumbens might provide an anatomical substrate for a serotonin-mediated psilocybin-induced dopamine release (Palacios et al 1991).…”

Section: The Modulating Effects Of Serotonin On Dopamine Neurotransmimentioning

confidence: 99%

5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride

Vollenweider

1999

Neuropsychopharmacology

263

138

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The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [ 11 C]raclopride to D 2 -dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n ϭ 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HTPsilocybin, a potent indoleamine hallucinogen and 5-HT receptor stimulating agent, has been reported to produce a psychosis-like syndrome in man resembling the first manifestation of schizophrenia in certain respects [for review see (Fischman 1983;Gouzoulis-Mayfrank et al. 1998)]. Particularly, ego-disorders (Rüm-mele and Gnirss 1961;Vollenweider et al. 1997), affective changes (Rümmele and Gnirss 1961), loosened associations (Spitzer et al. 1996) and perceptual alterations commonly seen in psilocybin-induced psychosis are also observed in incipient acute schizophrenic stages (Bowers and Freedman 1966;Heimann, 1986;Gouzoulis et al. 1994). In support of these suggested clinical similarities, we recently found that psilocybin produced a marked prefrontal and anterior cingulate activation in normal subjects comparable to the hyperfrontal pattern observed in some (Cleghorn et al. 1989;Ebmeier et al. 1993Ebmeier et al. , 1995Catafau et al. 1994 1994;Ebmeier et al. 1995;Sabri et al. 1997) but not all (Andreasen et al. 1992;Buchsbaum et al. 1992;Liddle et al. 1992;Siegel et al. 1993) acute schizophrenic patients. A number of functional animal studies have suggested that indoleamine (psilocybin, LSD) and phenylethylamine (DOI, mescaline) hallucinogens produce their psychotomimetic effects primarily through excessive stimulation of 5-HT, and 5-HT 2A receptors in particular (McKenna et al. 1989;Pierce and Peroutka 1989;Aghajanian 1994;Sipes and Geyer 1994;Padich et al. 1996). This assumption was corroborated in a recent human study demonstrating that the psychotomimetic effects of psilocybin can be blocked dose-dependently by pretreatment with the preferential 5-HT 2A receptor antagonist ketanserin (Vollenweider et al. 1998). However, pretreatment with the D 2 -antagonist haloperidol also reduces some of the positive symptoms of psilocybin psychosis. This raises the possibility that symptoms of psilocybin are secondary responses to increased dopaminergic transmission (Vollenweider et al. 1998).Hence, a contribution of the dopamine systems to the effects of psilocybin, presumably through a serotonindopamine interaction, cannot be ruled out. Functional interactions between central serotonin (5-HT) and dopamine (DA) systems have been well documented. Electrophysiological, biochemical, and behavioral evidence suggests that the ascending serotonergic pathways from the medial and dorsal raphe modulate or control the function of the mesolimbic and mesostriatal dopamine systems (Joyce 1993;Zazpe et al. 1994;Kapur and Remington 1996). The modulating effect of serotonin on striatal dopamine release...

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“…The putative antipsychotic drug R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907) is a highly selective 5-HT 2A receptor antagonist with significantly greater affinity (4500-fold) for the 5-HT 2A receptor over the D 2 receptor (Palfreyman et al, 1993;de Paulis, 2001), which may underlie its ability to achieve a high level of receptor occupancy in the absence of extrapyramidal-like symptoms in humans (Andree et al, 1998). M100907 has been shown to elicit a positive response in a large number of preclinical paradigms designed to detect antipsychotic activity .…”

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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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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Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function

Cited by 119 publications

References 28 publications

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride

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

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