Serotonin antagonists fail to alter MDMA self-administration in rats

Schenk, Susan; Foote, Jason; Aronsen, Dane; Bukholt, Natasha; Highgate, Quenten; Wetering, Ross van de; Webster, Jeremy

doi:10.1016/j.pbb.2016.06.002

Cited by 19 publications

(18 citation statements)

References 64 publications

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“…In a single rat subject, there were minimal effects of the 5HT 1a agonist, 8 OHDPAT (De La Garza et al, 2007). In a larger sample of rats, 5HT 1a, 5HT 1b, or 5HT 2a antagonists failed to alter MDMA self-administration (Schenk et al, 2016). In contrast, the DA D 1 antagonist, SCH 23,390 (Daniela et al, 2004), or the DA D 2 antagonist, eticlopride (Brennan et al, 2009), shifted the dose effect curve for MDMA self-administration to the right.…”

Section: Maintenance Of Self-administrationmentioning

confidence: 78%

“…The cocaine-priming effect has often been attributed to DAergic mechanisms (Anderson & Pierce, 2005). MDMA-seeking was potentiated by DA, but not 5HT, agonists (Schenk et al, 2011) and was attenuated by DA (Schenk et al, 2011) but not 5HT (Schenk et al, 2016) antagonists. All of these data suggest that the behavioral effects of MDMA related to its misuse become controlled by dopaminergic rather than serotonergic mechanisms.…”

Section: Maintenance Of Self-administrationmentioning

confidence: 99%

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Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Schenk

Highgate

2021

Journal of Neurochemistry

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Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug-stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self-administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self-administration and the critical role of DA in the maintenance of MDMA self-administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms.

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Section: Maintenance Of Self-administrationmentioning

confidence: 78%

Section: Maintenance Of Self-administrationmentioning

confidence: 99%

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Schenk

Highgate

2021

Journal of Neurochemistry

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“…Although 5-HT 2A receptor antagonists (e.g., ketanserin, MDL100907), and inverse agonists (e.g., pimavanserin) appear to be more effective at reducing the reinstatement of extinguished responding, than at decreasing the ongoing self-administration of drugs, such as cocaine, MDMA, and nicotine (Lacosta & Roberts, 1993; Howell & Byrd, 1995; Fletcher et al, 2002; 2012; Nic Dhonnchada et al, 2009; Pockros et al, 2011; Murnane et al, 2013; Cousins et al, 2014; Schenk et al, 2016; Banks & Negus, 2017; but see Fantegrossi et al, 2002), 5-HT 2C receptor agonists appear to be effective in both the self-administration and reinstatement models of substance abuse. With regard to the development of 5-HT 2C receptor agonists as pharmacotherapies for substance abuse, the vast majority of preclinical evidence supporting this indication is from studies using Ro 60-0175, an agonist that is ~14-fold selective for 5-HT 2C over 5-HT 2A receptors in vitro (Table 1).…”

Section: Effects Of 5-ht2a and 5-ht2c Receptor Ligands In Preclinimentioning

confidence: 99%

The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders

Collins¹,

Gerak²

2018

Neuropharmacology

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Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT) receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse-related effects of drugs more generally. Lorcaserin is a 5-HT receptor-preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

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“…MDMA self-administration was attenuated by pre-treatment with dopamine antagonists (Brennan, Carati, Lea, Fitzmaurice & Schenk, 2009;Daniela, Brennan, Gittings, Hely & Schenk, 2004;Shin, Qin, Liu & Ikemoto, 2008). Drug-seeking following extensive selfadministration was also modified by pharmacological manipulations of DA (Colussi-Mas, Wise, Howard & Schenk, 2010;Nawata, Kitaichi, Yamamoto, 2016;Schenk et al, 2016;Schenk, Gittings & Colussi-Mas, 2011) and was positively correlated with MDMA-induced DA overflow in the dorsal striatum (Colussi-Mas et al, 2010).…”

Section: Mdma Self-administrationmentioning

confidence: 99%

“…2011;Larson et al, 2010;Perrotti et al, 2008). The caudate putamen has been implicated in mediating drug-seeking behaviours (Epstein, Preston, Stewart & Shaham, 2006;Gabriele & See, 2011;Vanderschuren, Di Ciano & Everitt, 2005), which is controlled similarly by DAergic mechanisms for both MDMA (Colussi-Mas, Wise, Howard & Schenk, 2010;Nawata, Kitaichi, Yamamoto, 2016;Schenk et al, 2016;Schenk, Gittings & Colussi-Mas, 2011) and cocaine (Phillips et al, 2003). Thus, as MDMA and cocaine self-administration behaviours are under control of similar mechanisms within the caudate putamen, it is expected that MDMA will show a similar increased expression of ∆FosB here.…”

Section: Current Studymentioning

confidence: 99%

ΔFosB: A Molecular Mechanism of MDMA Dependence

Foote¹

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<p>Rationale. 3,4-methylenedioxymethamphetamine (MDMA) is a widely used illicit substance and some users show signs of abuse and dependence. It has been suggested that addiction reflects persistent neuroplasticity and one proposed mechanism has been a change in the expression of the transcription factor, ΔFosB. Objectives. This study determined whether ΔFosB expression in reward-relevant brain areas was altered as a function of MDMA self-administration. Methods. Rats were separated into triads. One rat self-administered MDMA (master rat) and the other 2 rats received either MDMA (yoked MDMA) or saline (yoked saline) infusions contingent on the behaviour of the master rat. Testing continued until a total intake of 350 mg/kg of MDMA was delivered. Two days following the final self-administration session, rats were sacrificed and perfused transcardially. Brains were removed, and ΔFosB immunohistochemistry was conducted. ΔFosB expression in striatum and medial prefrontal cortex was compared across groups. Results. Unfortunately the tissue from many of the yoked MDMA rats was compromised and therefore data from this group were not included in any analyses. MDMA self-administration produced a significantly greater expression of ΔFosB in the ventromedial and ventrolateral portions of the caudate putamen when compared to expression produced following yoked saline exposure. Within the infralimbic cortex, accumbens shell and dorsolateral caudate putamen differences approached significance. A significant correlation between ΔFosB expression in the ventromedial caudate putamen and cumulative active lever presses across the final 5 days of self-administration was also found. Conclusions. These findings provide the first evidence of MDMA-induced expression of ΔFosB. Increased expression of ΔFosB was observed in regions associated with the development and maintenance of drug addiction. These data support the idea that induction of ΔFosB may present a mechanism by which MDMA can induce alterations in genetic transcription, which may underlie the development of MDMA dependence. Future studies should utilise antagonism of ΔFosB via region-selective administration of Δc-jun in order to further elucidate the role of these transcriptional changes in the development and maintenance of self-administration.</p>

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Serotonin antagonists fail to alter MDMA self-administration in rats

Cited by 19 publications

References 64 publications

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders

ΔFosB: A Molecular Mechanism of MDMA Dependence

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