Investigation of the mechanisms mediating MDMA 'Ecstasy'-induced increases in cerebro-cortical perfusion determined by btASL MRI.

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Title:	Investigation of the mechanisms mediating MDMA 'Ecstasy'-induced increases in cerebro-cortical perfusion determined by btASL MRI.
Authors:	Rouine, J, Kelly, M., Jennings-Murphy, C., Duffy, P., Gorman, I., Gormley, S., Kerskens, C., Harkin, Andrew
Source:	Psychopharmacology. May2015, Vol. 232 Issue 9, p1501-1513. 13p.
Subjects:	Ecstasy (Drug), Perfusion, Magnetic resonance imaging of the brain, Pharmacology, Dopaminergic mechanisms, Propylamine, Chlorophenylalanine
Abstract:	Rationale: Acute administration of the recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has previously been shown to increase cerebro-cortical perfusion as determined by bolus-tracking arterial spin labelling (btASL) MRI. Objectives: The purpose of the current study was to assess the mechanisms mediating these changes following systemic administration of MDMA to rats. Methods: Pharmacological manipulation of serotonergic, dopaminergic and nitrergic transmission was carried out to determine the mechanism of action of MDMA-induced increases in cortical perfusion using btASL MRI. Results: Fenfluramine (10 mg/kg), like MDMA (20 mg/kg), increased cortical perfusion. Increased cortical perfusion was not obtained with the 5-HT receptor agonist 2,5-dimethoxy-4-iodophenyl-aminopropane hydrochloride (DOI) (1 mg/kg). Depletion of central 5-HT following systemic administration of the tryptophan hydroxylase inhibitor para-chlorophenylalanine ( pCPA) produced effects similar to those observed with MDMA. Pre-treatment with the 5-HT receptor antagonist metergoline (4 mg/kg) or with the 5-HT reuptake inhibitor citalopram (30 mg/kg), however, failed to produce any effect alone or influence the response to MDMA. Pre-treatment with the dopamine D receptor antagonist SCH 23390 (1 mg/kg) failed to influence the changes in cortical perfusion obtained with MDMA. Treatment with the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole (7-NI) (25 mg/kg) provoked no change in cerebral perfusion alone yet attenuated the MDMA-related increase in cortical perfusion. Conclusions: Cortical 5-HT depletion is associated with increases in perfusion although this mechanism alone does not account for MDMA-related changes. A role for NO, a key regulator of cerebrovascular perfusion, is implicated in MDMA-induced increases in cortical perfusion. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	Rationale: Acute administration of the recreational drug of abuse 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has previously been shown to increase cerebro-cortical perfusion as determined by bolus-tracking arterial spin labelling (btASL) MRI. Objectives: The purpose of the current study was to assess the mechanisms mediating these changes following systemic administration of MDMA to rats. Methods: Pharmacological manipulation of serotonergic, dopaminergic and nitrergic transmission was carried out to determine the mechanism of action of MDMA-induced increases in cortical perfusion using btASL MRI. Results: Fenfluramine (10 mg/kg), like MDMA (20 mg/kg), increased cortical perfusion. Increased cortical perfusion was not obtained with the 5-HT receptor agonist 2,5-dimethoxy-4-iodophenyl-aminopropane hydrochloride (DOI) (1 mg/kg). Depletion of central 5-HT following systemic administration of the tryptophan hydroxylase inhibitor para-chlorophenylalanine ( pCPA) produced effects similar to those observed with MDMA. Pre-treatment with the 5-HT receptor antagonist metergoline (4 mg/kg) or with the 5-HT reuptake inhibitor citalopram (30 mg/kg), however, failed to produce any effect alone or influence the response to MDMA. Pre-treatment with the dopamine D receptor antagonist SCH 23390 (1 mg/kg) failed to influence the changes in cortical perfusion obtained with MDMA. Treatment with the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole (7-NI) (25 mg/kg) provoked no change in cerebral perfusion alone yet attenuated the MDMA-related increase in cortical perfusion. Conclusions: Cortical 5-HT depletion is associated with increases in perfusion although this mechanism alone does not account for MDMA-related changes. A role for NO, a key regulator of cerebrovascular perfusion, is implicated in MDMA-induced increases in cortical perfusion. [ABSTRACT FROM AUTHOR]
ISSN:	00333158
DOI:	10.1007/s00213-014-3790-0