Chronic treatment with a serotonin2 receptor (5-HT2R) agonist modulates the behavioral and cellular response to (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA]

Ross, Julie D.; Herin, David V.; Frankel, Paul S.; Thomas, Mary L.; Cunningham, Kathryn A.

doi:10.1016/j.drugalcdep.2005.06.004

Cited by 18 publications

(19 citation statements)

References 61 publications

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“…5-HT 2A receptors play an important role in the regulation of stress, mood and impulse control (Kroeze et al, 2002; Magalhaes et al, 2010) and the behavioral effects of several drugs of abuse (Bubar and Cunningham, 2006; Filip et al, 2006; Ross et al, 2006). 5-HT 2A receptors are the most abundant serotonin receptor in prefrontal cortex (PFCx) and are predominantly expressed in pyramidal neurons (Jones et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT_2A) receptor activity via ERK1/2 signaling

Franklin

Carrasco

2012

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Recent behavioral studies suggest that non-selective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT2A receptors. Here, we present experimental evidence that rats treated with a non-selective cannabinoid receptor agonist (CP 55,940, 50μg/kg, 7 days) showed increases in 5-HT2A receptor protein levels, 5-HT2A receptor mRNA levels, and 5-HT2A receptor-mediated phospholipase C Beta (PLCβ) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by Gαi/o class of G-proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5-HT2A receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid-induced upregulation of 5-HT2A receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5-HT2A receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5-HT2A receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety & depression and schizophrenia. Therefore, these results might provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans.

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Section: Introductionmentioning

confidence: 99%

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT_2A) receptor activity via ERK1/2 signaling

Franklin

Carrasco

2012

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“…To validate the ability of the rAAV construct to establish expression of 5-HT 2A R and Flag within the VTA, we employed immunohistochemical techniques using diaminobenzidine detection and light microscopy as described previously (Allen and MacPhail, 1991; Ross et al, 2006; Shank et al, 2007). Briefly, sections were blocked with a solution containing 1.5% normal goat serum (Vector Laboratories, Burlingame, CA, USA) in PBS with 0.4% Triton-X (PBS-T; Sigma), followed by incubation in PBS-T containing a polyclonal antibody for either the 5-HT 2A R (1:1000; courtesy of Dr. Bryan Roth, Case Western University Cleveland, OH, USA; Garlow et al, 1993; Roth et al, 1995; Cornea-Hebert et al, 2002; Nocjar et al, 2002; Bubar et al, 2005; Ross et al, 2006) or Flag peptide (1:1000; Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, sections were blocked with a solution containing 1.5% normal goat serum (Vector Laboratories, Burlingame, CA, USA) in PBS with 0.4% Triton-X (PBS-T; Sigma), followed by incubation in PBS-T containing a polyclonal antibody for either the 5-HT 2A R (1:1000; courtesy of Dr. Bryan Roth, Case Western University Cleveland, OH, USA; Garlow et al, 1993; Roth et al, 1995; Cornea-Hebert et al, 2002; Nocjar et al, 2002; Bubar et al, 2005; Ross et al, 2006) or Flag peptide (1:1000; Sigma). Sections were washed in PBS, incubated in PBS-T containing biotinylated goat-anti-rabbit IGg (1:400; Vector), incubated in an avidin-biotin-horseradish peroxidase complex (Vector), washed in TRIS buffer and developed in 3,3′-diaminobenzidine (0.5 mg/ml; Sigma) with 0.005% H 2 O 2 .…”

Section: Methodsmentioning

confidence: 99%

Elevated Expression of Serotonin 5-HT2A Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine

Herin¹,

Bubar²,

Seitz³

et al. 2013

Front. Psychiatry

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The dopamine mesocorticoaccumbens pathway which originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens and prefrontal cortex is a circuit important in mediating the actions of psychostimulants. The function of this circuit is modulated by the actions of serotonin (5-HT) at 5-HT2A receptors (5-HT2AR) localized to the VTA. In the present study, we tested the hypothesis that virally mediated overexpression of 5-HT2AR in the VTA would increase cocaine-evoked locomotor activity in the absence of alterations in basal locomotor activity. A plasmid containing the gene for the 5-HT2AR linked to a synthetic marker peptide (Flag) was created and the construct was packaged in an adeno-associated virus vector (rAAV-5-HT2AR-Flag). This viral vector (2 μl; 109–10 transducing units/ml) was unilaterally infused into the VTA of male rats, while control animals received an intra-VTA infusion of Ringer’s solution. Virus-pretreated rats exhibited normal spontaneous locomotor activity measured in a modified open-field apparatus at 7, 14, and 21 days following infusion. After an injection of cocaine (15 mg/kg, ip), both horizontal hyperactivity and rearing were significantly enhanced in virus-treated rats (p < 0.05). Immunohistochemical analysis confirmed expression of Flag and overexpression of the 5-HT2AR protein. These data indicate that the vulnerability of adult male rats to hyperactivity induced by cocaine is enhanced following increased levels of expression of the 5-HT2AR in the VTA and suggest that the 5-HT2AR receptor in the VTA plays a role in regulation of responsiveness to cocaine.

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“…At the same time, the available data concerning the effects of chronic recep tor activation on the expression of the 5 НТ 2А receptor gene are controversial. In the studies performed by dif ferent research groups, chronic administration of DOI either had no effect on the expression of the 5 НТ 2А receptor gene [16], or downregulated its expression [17]. There is hardly any information available on the effects of the activation of the chronic 5 НТ 2А recep tor on 5 HT metabolism and on the expression of genes that encode the key enzyme of 5 HT biosynthe MOLECULAR BIOLOGY Vol.…”

Section: Introductionmentioning

confidence: 99%

Involvement of 5-HT2A receptors in genetic mechanisms of autoregulation of brain 5-HT system

et al. 2012

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The brain serotonin (5 HT) system has been implicated in the pathophysiology of anxiety, depression, drug addiction, and schizophrenia. 5 HT 2A receptors are involved in the mechanisms of stress induced psychopathology and impulsive behavior. In this work, we investigated the role of 5 HT 2A receptors in the autoregulation of the brain 5 HT system. Chronic treatment with DOI, a 5 HT 2A receptor agonist (1.0 mg/kg, i.p./14 days), produced a considerable decrease in the number of 5 HT 2A receptor mediated head twitches in AKR/J mice, indicating the desensitization of 5 HT 2A receptors. Chronic DOI treatment did not affect the expression of the 5 HT 2A receptor gene in the midbrain, hippocampus and frontal cortex. At the same time, an increase in the expression of the gene encoding a key enzyme of 5 HT synthesis, tryptophan hydroxylase 2 (TPH 2), accompanied with an increase in TPH 2 activity and 5 HT levels, and decreased expression of the serotonin transporter (5 HTT) gene were observed in the midbrain of DOI treated mice. These results provide new evidence of receptor-gene cross talk in the brain 5 HT system and implication 5 HT 2A receptors in the autoregulation of the brain 5 HT system. : chronic DOI treatment, 5 HT 2A receptor, 5 HT transporter, tryptophan hydroxylase 2 gene expression, tryptophan hydroxylase 2 activity, 5 HT and 5 HIAA levels, mice UDC 577.21; 577.25 Abbreviations: 5 HT, serotonin; 5 HT 2A receptor, subtype 2A serotonin receptor; 5 HT 1A receptor, subtype 1A serotonin receptor; DOI, (±) 1 (2,5 dimethoxy 4 iodophenyl) 2 amino propane hydrochloride; DHBA, 3,4 dihydroxybenzylamine hydrobromide; rPol II, RNA polymerase II; 5 HIAA, 5 hydroxy indolacetic acid; TPH 2, tryptophan hydroxylase 2; 5 HTT, sero tonin transporter; RT, reverse transcription; PCR, polymerase chain reaction; HPLC, high performance liquid chromatography.

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Chronic treatment with a serotonin2 receptor (5-HT2R) agonist modulates the behavioral and cellular response to (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA]

Cited by 18 publications

References 61 publications

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT_2A) receptor activity via ERK1/2 signaling

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT_2A) receptor activity via ERK1/2 signaling

Elevated Expression of Serotonin 5-HT2A Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine

Involvement of 5-HT2A receptors in genetic mechanisms of autoregulation of brain 5-HT system

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Chronic treatment with a serotonin2 receptor (5-HT2R) agonist modulates the behavioral and cellular response to (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA]

Cited by 18 publications

References 61 publications

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT2A) receptor activity via ERK1/2 signaling

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT2A) receptor activity via ERK1/2 signaling

Elevated Expression of Serotonin 5-HT2A Receptors in the Rat Ventral Tegmental Area Enhances Vulnerability to the Behavioral Effects of Cocaine

Involvement of 5-HT2A receptors in genetic mechanisms of autoregulation of brain 5-HT system

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Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT_2A) receptor activity via ERK1/2 signaling

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT_2A) receptor activity via ERK1/2 signaling