Is behavioral sensitization to 3,4-methylenedioxymethamphetamine (MDMA) mediated in part by cholinergic receptors?

Lettfuss, Nadine Y.; Seeger-Armbruster, Sonja; Ameln-Mayerhofer, Andreas von

doi:10.1016/j.bbr.2013.01.033

Cited by 10 publications

(8 citation statements)

References 28 publications

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“…It is noteworthy that the failure to observe a concomitant increase in the number of forward locomotor counts contrasts with previously reported increases in forward locomotion, as measured by locomotor activity counts, that became sensitised following repeated intermittent exposure to ± MDMA (Ball et al, 2006;Lettfuss et al, 2013;Spanos and Yamamoto, 1989;Kalivas et al, 1998) including data from our laboratory (Bradbury et al, 2012). We previously reported that repeated daily injections of racemic MDMA (10.0 mg/kg, IP × 5 days) increased the number of ambulatory counts in response to 10.0 mg/kg MDMA and shifted the dose-effect curve for this response to the left when measured 2 days following the last experimenter-administered exposure to MDMA (Bradbury et al, 2012).…”

Section: Discussioncontrasting

confidence: 79%

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Persistent sensitisation to the locomotor activating effects of MDMA following MDMA self-administration in rats

Schenk

Bradbury

2015

Pharmacology Biochemistry and Behavior

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Section: Discussioncontrasting

confidence: 79%

“…Effects of ±MDMA on vertical activity are equivocal. Some studies have failed to consistently observe this behaviour (O'Loinsigh et al, 2001) whereas others have reported MDMA-produced rearing (Lettfuss et al, 2013).…”

Section: Introductionmentioning

confidence: 97%

Persistent sensitisation to the locomotor activating effects of MDMA following MDMA self-administration in rats

Schenk

Bradbury

2015

Pharmacology Biochemistry and Behavior

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“…An increase in vertical locomotor activity was, however, evident in both groups that received MDMA exposure. This finding is consistent with findings from previous studies that also found an increase in vertical locomotor activity following repeated experimenter-administered (Lettfuss et al, 2013), or self-administered (Schenk & Bradbury, 2015) MDMA. Because increased vertical locomotor activity has been attributed to increased DA release (Thiel et al, 1999), an increase in vertical locomotor activity following repeated MDMA exposure may reflect the increase in MDMA-produced DA release produced following pre-exposure (Colussi-Mas et al, 2010;Kalivas et al, 1998).…”

Section: Discussionsupporting

confidence: 92%

“…There are a number of studies that report a sensitised locomotor response following repeated exposure to various stimulants including cocaine (Kalivas & Stewart, 1991;Post & Contel, 1983), and amphetamine (Kuczenski & Segal, 1988;Robinson & Becker, 1986). Repeated administration of MDMA also produced sensitisation of MDMA-produced forward locomotor activity (Ball, Wellman, Fortenberry, & Rebec, 2009;Bradbury, Gittings, & Schenk, 2012;Colussi-Mas & Schenk, 2008;Kalivas, Duffy, & White, 1998;Spanos & Yamamoto, 1989) and vertical locomotor activity (Lettfuss, Seeger-Armbruster, & von Ameln-Mayerhofer, 2013;Schenk & Bradbury, 2015).…”

Section: Behavioural Correlates Of Sensitisationmentioning

confidence: 99%

The effect of MDMA self-administration on MDMA-produced hyperactivity and c-fos expression

Bukholt¹

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<p>Background: MDMA preferentially releases serotonin (5HT) but following repeated exposure there is a decrease in this MDMA-produced effect. At the same time, some studies suggest an increase in MDMA-produced dopamine (DA) release following repeated exposure. The sensitised DA response is often accompanied by sensitisation of MDMA-produced locomotor activity. Because DAergic mechanisms have been implicated in the positively reinforcing properties of MDMA, these neuroadaptations might be relevant to MDMA self-administration. Objectives: The main objective of this study was to determine whether MDMA self-administration and non-contingent MDMA exposure differentially affected the development of sensitisation to MDMA-produced hyperactivity. Additionally, the relationship between MDMA-produced hyperactivity and changes in c-fos expression in DA terminal regions was determined. Methods: Triads of rats were designated ‘master’, ‘yoked MDMA’, or ‘yoked saline’. Lever press responding by the master rat resulted in an intravenous infusion of MDMA for both the master rat and the yoked MDMA rat, as well as an equal infusion of vehicle for the yoked control rat. Daily tests continued until a total of 350 mg/kg MDMA had been self-administered. Three days following the last self-administration session, forward and vertical locomotion produced by MDMA (5.0 mg/kg, i.p) were measured during a 2 hr test. Rats were sacrificed immediately following the behavioural test, and c-fos immunohistochemistry was measured. Results: Repeated MDMA exposure resulted in sensitised forward and vertical locomotor activity. Sensitisation of the increase in forward locomotion was produced only in rats that self-administered MDMA; non-contingent MDMA administration failed to sensitise this behavioural response. In contrast, sensitisation to MDMA-produced vertical activity was produced following both contingent and non-contingent MDMA exposure. C-fos expression was reduced in ventrolateral, and ventromedial areas of the dorsal striatum, as well as the infralimbic cortex, after MDMA exposure, regardless of whether the exposure was via self-administration or yoked administration. A selective decrease in c-fos expression in the nucleus accumbens (NAc) core and the cingulate cortex was produced by MDMA self-administration. There was a negative correlation between MDMA-produced forward locomotor activity and MDMA-produced c-fos expression in the NAc core, cingulate cortex and infralimbic cortex. A negative correlation between rearing activity and MDMA-produced c-fos expression in the NAc core, NAc shell, cingulate cortex, and infralimbic cortex was also found. Conclusions: These data provide evidence of behavioural sensitisation as a result of repeated MDMA exposure. Furthermore, MDMA-produced behavioural sensitisation was associated with a decrease in c-fos expression that was evident in the NAc and prefrontal cortex. Finally, region-specific changes in c-fos expression suggest an important role of neuroadaptations in the NAc core and the infralimbic cortex as a consequence of MDMA self-administration.</p>

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“…A wealth of data has subsequently shown similar effects following administration of DA agonists, and these effects are blocked by neurotoxic 6-OHDA lesions in the mesolimbic DA system (for example, Kelly & Iversen, 1976) and by DA antagonists (Pijnenburg et al, 1976;Pijnenburg, Honig, & Van Rossum, 1975). Repeated exposure to MDMA (Ball, Budreau, & Rebec, 2006;Ball, Klein, Plocinski, & Slack, 2011;Ball, Wellman, Fortenberry, & Rebec, 2009;Ball, Wellman, Miller, & Rebec, 2010;Bradbury, Gittings, & Schenk, 2012;Colussi-Mas & Schenk, 2008;Kalivas et al, 1998;Lettfuss, Seeger-Armbruster, & von Ameln-Mayerhofer, 2013;Ludwig, Mihov, & Schwarting, 2008;McCreary, Bankson, & Cunningham, 1999;Modi, Yang, Swann, & Dafny, 2006), produced an augmented horizontal activity response following some dosing regimens, corresponding with an enhanced DA response (Kalivas et al, 1993;Kalivas & Stewart, 1991;Sorg & Kalivas, 1991). Enhanced synaptic DA also underlies increased vertical activity (rearing), although relatively fewer investigations of the neurochemical underpinnings of this behaviour have been conducted.…”

Section: Introductionmentioning

confidence: 99%

The Role of Serotonin in MDMA Self-administration in Rats

Bradbury¹

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<p>Rationale: The profile of acquisition for MDMA self-administration differs from that of amphetamine and cocaine self-administration in that fewer rats meet an acquisition criterion and the latency to acquisition is longer. These characteristics of MDMA self-administration may be because it preferentially stimulates serotonin (5HT) release whereas self-administration has generally been attributed to enhanced dopamine (DA) neurotransmission. Because 5HTergic agonists are not self-administered and increased synaptic 5HT decreased self-administration of other drugs, MDMA self-administration may be initially inhibited by the pronounced 5HT response. Accordingly, the acquisition of MDMA self-administration might proceed as a result of deficits in 5HT neurotransmission and a corresponding disinhibition of DA neurotransmission. Objective: The primary objective was to determine the role of 5HT in the acquisition and maintenance of MDMA self-administration. Methods: MDMA-induced increases of extracellular 5HT and DA and their primary metabolites were measured in the DA terminal regions of the nucleus accumbens (NAc) using in vivo microdialysis, prior to the commencement of MDMA self-administration. The relationship between MDMA-induced increases of neurotransmitter levels and the acquisition of MDMA self-administration was assessed. A subsequent study depleted brain 5HT by administering the neurotoxin, 5,7 – DHT, or vehicle into the lateral ventricle of the left hemisphere, prior to the commencement of MDMA self-administration. The proportion of subjects that acquired MDMA self-administration and the latency to acquire MDMA self-administration was compared for the two groups. In order to determine effects of MDMA self-administration on 5HT and DA responses, behaviours that reflect 5HT and/or DA neurotransmission were measured 5 or 14 days after self-administration of 165 mg/kg MDMA, or 14 days after vehicle self-administration. These time periods were chosen because they reflect a period of 5HT deficits (5 days) and recovery (14 days). Finally, the effect of abstinence on MDMA self-administration was measured. Results: The MDMA-induced increase of extracellular 5HT was significantly lower for the group that subsequently acquired MDMA self-administration but the MDMA-induced increase in DA was not different from the group that failed to acquire self-administration. 5, 7-DHT administration significantly decreased tissue levels of 5HT, but not DA. MDMA self-administration was facilitated by the lesion; 100% of the lesion group acquired MDMA self-administration, whereas only 50% of the control group acquired self-administration. Five days following the last MDMA self-administration session, DAergic behaviours were enhanced and 5HTergic behaviours were reduced relative to the control group. These differences in 5HTergic mediated behaviours were not apparent 14 days after self-administration but the DAergic behaviours remained elevated. The pattern of self-administration did not differ as a function of the length of the abstinence period. Conclusions: The variability in acquisition of MDMA self-administration was related to the magnitude of the 5HT response evoked by initial exposure to MDMA. These findings suggested that predisposing differences in the 5HT response might explain differences in the variability in acquisition of MDMA self-administration. The negative impact of 5HT on the acquisition of MDMA self-administration was clearly demonstrated following a 5, 7-DHT lesion. Thus, 5HT limits the development of MDMA self-administration. With repeated exposure to self-administered MDMA, behavioural responses indicative of 5HT activation were reduced whereas behavioural indices of DA activation were increased. The maintenance of MDMA self-administration was comparable regardless of whether there was a forced abstinence period or not. These data are consistent with the hypotheses that 5HT is inhibitory to the acquisition, but not the maintenance, of MDMA self-administration. Rather, the maintenance of self-administration might reflect sensitised DA responses that became apparent following repeated exposure.</p>

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Is behavioral sensitization to 3,4-methylenedioxymethamphetamine (MDMA) mediated in part by cholinergic receptors?

Cited by 10 publications

References 28 publications

Persistent sensitisation to the locomotor activating effects of MDMA following MDMA self-administration in rats

Persistent sensitisation to the locomotor activating effects of MDMA following MDMA self-administration in rats

The effect of MDMA self-administration on MDMA-produced hyperactivity and c-fos expression

The Role of Serotonin in MDMA Self-administration in Rats

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