Reduced efficacy of fluoxetine following MDMA (“Ecstasy”)-induced serotonin loss in rats

Durkin, Sarah; Prendergast, Alison; Harkin, Andrew

doi:10.1016/j.pnpbp.2008.09.008

Cited by 18 publications

(13 citation statements)

References 44 publications

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“…In adult rodents, repeated exposure to SSRIs decreases serotonin turnover in the hippocampus and prefrontal cortex (Baldessarini et al 1992; Frankfurt et al 1994; Harkin et al 2003; Thompson et al 2004; Miura et al 2007; Durkin et al 2008). This action is believed to be a consequence of SSRIs inhibiting serotonin reuptake and metabolism (Baldessarini et al 1992; Frankfurt et al 1994; Leonardi and Azmitia 1994; Harkin et al 2003; Thompson et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we found that both paroxetine (10 mg/kg) and fluoxetine reduced serotonin levels in the prefrontal cortex, while only paroxetine decreased serotonin content in the hippocampus. Repeated SSRI treatment has occasionally been shown to reduce serotonin content in various brain regions of adult rodents (Caccia et al 1992; Trouvin et al 1993; Thompson et al 2004), although nonsignificant effects are more typically reported (Harkin et al 2003; Durkin et al 2008; Karanges et al 2011; Shishkina et al 2012). SSRI-induced reductions in serotonin content are usually observed after extended drug exposure (i.e., 3 or more weeks) or when high doses of SSRI are administered.…”

Section: Discussionmentioning

confidence: 99%

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Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats

et al. 2015

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Rationale The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depression in adolescent humans. In contrast, the SSRI paroxetine has limited efficacy and is more at risk for inducing suicidal behavior. Objective The purpose of the present study was to more fully characterize the differential actions of paroxetine and fluoxetine. Methods In Experiment 1, male and female rats were injected with paroxetine (2.5 or 10 mg/kg), fluoxetine (10 mg/kg), or vehicle for 10 days starting on postnatal day (PD) 35, and affective behaviors were assessed using sucrose preference and elevated plus maze tasks. A separate set of rats were used to examine monoamine levels. In Experiment 2, rats were injected with paroxetine (2.5, 5 or 10 mg/kg), fluoxetine (5, 10 or 20 mg/kg), or vehicle during the same time frame as Experiment 1 and anxiety-like behaviors were measured using elevated plus maze, light/dark box, and acoustic startle. Results Repeated SSRI treatment failed to alter sucrose preference, although both paroxetine and fluoxetine reduced time spent in the open arms of the elevated plus maze and light compartment of the light/dark box. Paroxetine, but not fluoxetine, enhanced acoustic startle and interfered with habituation. Serotonin turnover was decreased by both acute and repeated fluoxetine treatment but unaltered by paroxetine administration. Discussion These results show that repeated treatment with paroxetine and fluoxetine has dissociable actions in adolescent rats. In particular, paroxetine, but not fluoxetine, increases acoustic startle at low doses and may increase sensitivity to environmental stressors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats

et al. 2015

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“…Frontal cortex and striatum were harvested for determination of neurotransmitter concentration. 5‐HT and 5‐HIAA concentrations were determined by high‐performance LC coupled to electrochemical detection as previously described (Durkin et al ., ).…”

Section: Methodsmentioning

confidence: 97%

“…Subsequently, a higher dose of MDMA as reported was used. The treatment regimen and recovery period has been employed previously to assess long‐term effects of MDMA associated with sustained 5‐HT loss (Durkin et al ., ). Perfusion parameters were measured 8 weeks following MDMA administration to allow time for sustained 5‐HT loss to be established.…”

Section: Methodsmentioning

confidence: 97%

MDMA‘ecstasy’ increases cerebral cortical perfusion determined by bolus‐tracking arterial spin labelling (btASL)MRI

Rouine

Gobbo

Campbell

et al. 2013

British J Pharmacology

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Background and Purpose The purpose of this study was to assess cerebral perfusion changes following systemic administration of the recreational drug 3,4‐methylendioxymethamphetamine (MDMA ‘ecstasy’) to rats. Experimental Approach Cerebral perfusion was quantified using bolus‐tracking arterial spin labelling (btASL) MRI. Rats received MDMA (20 mg·kg−1; i.p.) and were assessed 1, 3 or 24 h later. Rats received MDMA (5 or 20 mg·kg−1; i.p.) and were assessed 3 h later. In addition, rats received MDMA (5 or 10 mg·kg−1; i.p.) or saline four times daily over 2 consecutive days and were assessed 8 weeks later. Perfusion‐weighted images were generated in a 7 tesla (7T) MRI scanner and experimental data was fitted to a quantitative model of cerebral perfusion to generate mean transit time (MTT), capillary transit time (CTT) and signal amplitude. Key Results MDMA reduces MTT and CTT and increases amplitude in somatosensory and motor cortex 1 and 3 h following administration, indicative of an increase in perfusion. Prior exposure to MDMA provoked a long‐term reduction in cortical 5‐HT concentration, but did not produce a sustained effect on cerebral cortical perfusion. The response to acute MDMA challenge (20 mg·kg−1; i.p.) was attenuated in these animals indicating adaptation in response to prior MDMA exposure. Conclusions and Implications MDMA provokes changes in cortical perfusion, which are quantifiable by btASL MRI, a neuroimaging tool with translational potential. Future studies are directed towards elucidation of the mechanisms involved and correlating changes in cerebrovascular function with potential behavioural deficits associated with drug use.

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“…MDMA abuse is associated with serious adverse effects such as cardiac arrhythmias, hyperthermia, renal failure, hepatotoxicity, rhabdomyolysis, seizures and intracranial hemorrhage (Hegadoren et al ., 1999; Green et al ., 2003; Hall and Henry, 2006). In addition to these acute toxic effects, there is substantial evidence that MDMA can result in long‐term neurotoxic effects on central serotonergic neurons (Stone et al ., 1987; Capela et al ., 2009), and that this may represent a predisposing factor to psychological disturbances/psychiatric disease (Montoya et al ., 2002; Durkin et al ., 2008). While the incidence and severity of acute or long‐term adverse effects of MDMA are generally positively correlated with the extent of use, there is also evidence of idiosyncratic reactions to MDMA (Cole and Sumnall, 2003).…”

Section: Introductionmentioning

confidence: 99%

Methylenedioxymethamphetamine (‘Ecstasy’)‐induced immunosuppression: a cause for concern?

Boyle

Connor

2010

British J Pharmacology

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Methylenedioxymethamphetamine (MDMA; ‘Ecstasy’) is a ring‐substituted amphetamine and a popular drug of abuse. In addition to ability to induce euphoria, MDMA abuse is associated with a range of acute and long‐term hazardous effects. This paper is focused on once such adverse effect: its ability to negatively impact on functioning of the immune system. Research demonstrates that MDMA has immunosuppressive properties, with both innate and adaptive arms of the immune system being affected. The ability of MDMA to suppress innate immunity is indicated by impaired neutrophil phagocytosis and reduced production of dendritic cell/macrophage‐derived pro‐inflammatory cytokines including tumour necrosis factor‐alpha, interleukin (IL)‐1β, IL‐12 and IL‐15. MDMA also suppresses innate IFN‐γ production, and considering the role of IFN‐γ in priming antigen‐presenting cells, it is not surprising that MDMA reduces MHC class II expression on dendritic cells and macrophages, and inhibits co‐stimulatory molecule expression. Paradoxically, studies demonstrate that MDMA elicits pro‐inflammatory actions in the CNS by activating microglia, the resident innate immune cells in the brain. In terms of adaptive immunity, MDMA reduces circulating lymphocyte numbers, particularly CD4+ T‐cells; suppresses T‐cell proliferation; and skews cytokine production in a Th2 direction. For the most part, the immunosuppressive effects of MDMA cannot be attributed to a direct action of the drug on immune cells, but rather due to the release of endogenous immunomodulatory substances. In this regard, peripheral β‐adrenoceptors and cholinergic receptors have been shown to mediate some immunosuppressive effects of MDMA. Finally, we discuss emerging evidence indicating that MDMA‐induced immunosuppression can translate into significant health risks for abusers.

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Reduced efficacy of fluoxetine following MDMA (“Ecstasy”)-induced serotonin loss in rats

Cited by 18 publications

References 44 publications

Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats

Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats

MDMA‘ecstasy’ increases cerebral cortical perfusion determined by bolus‐tracking arterial spin labelling (btASL)MRI

Methylenedioxymethamphetamine (‘Ecstasy’)‐induced immunosuppression: a cause for concern?

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