Comparison of the effects of abstinence on MDMA and cocaine self-administration in rats

Highgate, Quenten; Schenk, Susan

doi:10.1007/s00213-018-5026-1

Cited by 7 publications

(12 citation statements)

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“…Amongst those characteristics is an escalation of drug intake as a function of repeated testing and drug-seeking following extinction of self-administration (Ahmed & Koob, 1998;Mandt et al, 2015;Mantsch et al, 2004). Under some conditions, repeated MDMA self-administration led to an escalation of intake (Ball et al, 2007;Highgate & Schenk, 2018;van de Wetering & Schenk, 2020).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

Schenk

Highgate

2021

Journal of Neurochemistry

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“…When daily session lengths are increased (e.g. 6 hours per day), however, a significant escalation in drug intake has been observed over successive test sessions (Ahmed & Koob, 1998;Ahmed, Walker, & Koob, 2000;Highgate & Schenk, 2018;Kitamura, Wee, Specio, Koob, & Pulvirenti, 2006;O'Dell et al, 2007;A. J. Roberts, Heyser, Cole, Griffin, & Koob, 2000).…”

Section: Studying Addictionmentioning

confidence: 99%

“…Response rates for MDMA are initially low, and acquisition of reliable MDMA self-administration (1 mg/kg/infusion) typically requires around 15, 2-hour daily sessions (Schenk et al, 2012). In contrast, the self-administration of cocaine, amphetamine, or methamphetamine is usually reliably acquired within a few days (Carroll & Lac, 1997;Highgate & Schenk, 2018;Maan, Highgate, & Schenk, 2020;Schenk et al, 2007).…”

Section: Mdma Self-administrationmentioning

confidence: 99%

“…Secondly, only about 50% of rats meet acquisition criteria for reliable MDMA selfadministration under these conditions (Schenk et al, 2012) whereas virtually all animals acquire cocaine, amphetamine, or methamphetamine self-administration (Carroll & Lac, 1997;Do & Schenk, 2013;Highgate & Schenk, 2018;Maan et al, 2020). These differences might reflect the unique pharmacology of MDMA compared to other psychostimulants.…”

Section: Mdma Self-administrationmentioning

confidence: 99%

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Effect of repeated MDMA exposure on rat brain and behaviour

Wetering¹

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<p>Rationale. ±3,4-Methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is a popular recreational drug of abuse. Like other drugs of abuse, a proportion of users develop symptoms that are characteristic of a Substance Use Disorder (SUD). The behavioural and neurobiological consequences of repeated misuse of MDMA are not well understood, however. Objectives. The purpose of the present thesis was to investigate behaviourally relevant neuroadaptations that develop with repeated MDMA exposure in laboratory rats. Methods. First, the effect of chronic, long-access (6 hour) self-administration of MDMA on the accumulation of the transcription factor, ΔFosB, in the nucleus accumbens (core, shell), dorsal striatum (dorsomedial, dorsolateral, ventromedial, ventrolateral), prefrontal cortex (anterior cingulate, prelimbic, infralimbic, orbitofrontal), amygdala (central, basolateral), ventral tegmental area (anterior, posterior), and raphe (dorsal, median) was measured using immunohistochemistry. Second, the behavioural relevance of these findings was determined by examining the effect of bi-lateral intra-striatal (nucleus accumbens, dorsomedial striatum, dorsolateral striatum) microinjections of MDMA (200 μg/1 μL/side) on the expression of behavioural sensitisation following two days of withdrawal from a regimen of repeated, systemic MDMA exposure (10 mg/kg/day, i.p., for 5 days). Third, a procedure was developed to examine neurochemical correlates of sensitised MDMA-produced behaviour (0, 5, 10 mg/kg, i.p.) following the same regimen of repeated MDMA exposure. Samples were collected from the medial striatum using in vivo microdialysis and the extracellular concentrations of serotonin, dopamine, MDMA, and their metabolites were quantified using liquid chromatography coupled with quadrupole time-of-flight (Q-TOF) mass spectrometry. Lastly, a unique untargeted metabolomics procedure was developed to further analyse these microdialysis samples and to identify novel or unexpected metabolites that were relevant to the sensitised behavioural response produced by MDMA. Results. MDMA self-administration produced region-dependant increases in ΔFosB. Significant increases in ΔFosB were observed in the nucleus accumbens core, the medial areas of the dorsal striatum, as well as all areas of the prefrontal cortex and amygdala. Small, but significant increases were also observed in the dorsal raphe. Increases were observed in the nucleus accumbens shell and the posterior tail of the ventral tegmental area, but these increases were not significant following statistical correction for multiple comparisons. Acute exposure to MDMA increased locomotor activity only when the drug was infused into the nucleus accumbens. Following repeated systemic exposure, behavioural sensitisation was expressed when MDMA was infused into both the nucleus accumbens or the dorsomedial striatum, but not the dorsolateral striatum. Analysis of microdialysates from the medial striatum indicated that behavioural sensitisation was accompanied by small increases in baseline levels of extracellular serotonin and decreased MDMA-produced increases in serotonin, but these changes were not statistically significant. Behavioural sensitisation was also accompanied by increased extracellular concentrations of dopamine at baseline and following acute MDMA exposure, but these data were not statistically analysed due to small sample sizes. MDMA-produced extracellular concentrations of MDMA did not change with repeated exposure. Untargeted metabolomics revealed potential changes in MDMA and dopamine metabolism that might be relevant to the sensitised behavioural response. Conclusions. The findings of the current research suggest that repeated MDMA exposure results in many of the same neuroadaptations that result from repeated exposure to other drugs of abuse. These included increased ΔFosB expression in many brain regions that are relevant to addiction, such as the nucleus accumbens, dorsal striatum, and prefrontal cortex. Dopaminergic mechanisms also appeared to be influenced and were associated with sensitised MDMA-produced behaviour. Surprisingly, serotonergic mechanisms were not significantly impacted by repeated MDMA exposure under the current conditions. Some of the procedures developed in this thesis are unique and may be of value for future research investigating the neurochemical underpinnings of addictive behaviour or other disease states.</p>

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“…While both are amphetamine analogues, methamphetamine and MDMA have different pharmacological profiles, at least following acute administration (Baumann et al, 2002(Baumann et al, , 2005. However, repeated MDMA exposure produced selective deficits in 5HT neurotransmission and it has been suggested that these deficits might contribute to the acquisition of MDMA self-administration (Aronsen et al, 2016;Bradbury et al, 2014;Highgate and Schenk, 2018;Oakley et al, 2014;Schenk, 2011). Methamphetamine exposure can also produce deficits in 5HT neurotransmission (Volz et al, 2007), but 5HT does not appear to play a prominent role in methamphetamine self-administration.…”

Section: Comparison Of Methamphetamine and Mdmamentioning

confidence: 99%

Comparison of Methamphetamine and MDMA Extended Access Self-administration: Acquisition, Maintenance, and Response Patterns

Maan¹

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<p>Rationale. 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine are two amphetamine derivatives with contrasting pharmacological profiles. Therefore, self- administration profiles might be expected to reflect these differences. Objectives. This study compared the latency and proportion to acquire self-administration, maintenance of self-administration, and within-session response patterns. Methods. Rats were given extended access (8-hour daily sessions) to either methamphetamine, MDMA or vehicle self-administration over a period of 10 consecutive days. A criterion based on the performance of the vehicle control group was used to determine acquisition of reliable MDMA and methamphetamine self-administration. In conjunction, for MDMA self-administration the infusion dose was halved for each rat that achieved a total of 85mg/kg for the remaining sessions. Temporal patterns of responding were assessed using hourly data of the first day of self-administration, the day following acquisition, and the final day of self-administration. Results. A greater proportion of rats in the methamphetamine group acquired self- administration and self-administration was acquired with a shorter latency compared to the MDMA group. Responding maintained by methamphetamine on day one was high. By the third day a pattern developed that was maintained throughout testing. The greatest proportion of responding occurring within the first hour of each daily test session. A progressive escalation of intake was also observed within the methamphetamine group. Responding maintained by MDMA was low on the first day, but by day 5 responding had increased with most of the responding within the session occurring during the first three hours. On day 10 the greatest amount of responding occurred during the first hour. No escalation of intake as a function of test day was observed for MDMA self-administration.</p>

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Comparison of the effects of abstinence on MDMA and cocaine self-administration in rats

Abstract: The selective reduction of MDMA self-administration following abstinence is consistent with the idea that MDMA-stimulated 5-HT release is inhibitory to MDMA self-administration.

Cited by 7 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

Effect of repeated MDMA exposure on rat brain and behaviour

Comparison of Methamphetamine and MDMA Extended Access Self-administration: Acquisition, Maintenance, and Response Patterns

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