Repeated administration of the 5-HT1B/1A agonist, RU 24969, facilitates the acquisition of MDMA self-administration: role of 5-HT1A and 5-HT1B receptor mechanisms

Aronsen, Dane; Bukholt, Natasha; Schenk, Susan

doi:10.1007/s00213-016-4225-x

Cited by 12 publications

(3 citation statements)

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“…Mice lacking 5-HT 1B Rs show enhanced cocaine intake in the self-administration (SA) model and enhanced cocaine-induced locomotion (Rocha et al, 1998), suggesting that 5-HT 1B R signaling normally inhibits these behaviors. In male rats, however, 5-HT 1B R agonists enhance acquisition of 3,4-methylenedioxy-methamphetamine (MDMA) SA and produce a leftward shift in the cocaine SA dose–response function on low effort schedules of cocaine reinforcement, suggesting that 5-HT 1B R signaling enhances psychostimulant reinforcing value (Aronsen et al, 2016; Parsons et al, 1998; Pentkowski et al, 2009). Similarly, viral-mediated overexpression of 5-HT 1B Rs in the nucleus accumbens and ventral tegmental area (VTA) of male rats increases the breakpoint on a progressive ratio schedule of cocaine reinforcement and shifts the cocaine dose–response function upward and to the left (Pentkowski et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

5-HT_1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

et al. 2021

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Background: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. Aims: We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. Methods: Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21–60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions). Results: Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion. Conclusions: CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT1BR agonists may have clinical efficacy as anti-relapse medications for cocaine use disorders.

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Section: Introductionmentioning

confidence: 99%

5-HT_1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

et al. 2021

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“…Tests continued until a total of 90 infusions (90 mg/kg) had been self-administered by the master rat or 25 days, whichever came first. A total of 15 master rats, and the associated triads, failed to meet this criterion and were not included for further testing (Aronsen, Bukholt, & Schenk, 2016;Bradbury et al, 2014;Schenk et al, 2012). For the remaining 36 rats (12 triads) the dose was reduced to 0.5mg/kg until an additional 150 infusions were administered.…”

Section: Methodsmentioning

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 decrease in stimulated 5-HT release, for example, has been demonstrated following repeated self-administered MDMA (Reveron et al, 2010) and would be expected to facilitate the acquisition of MDMA self-administration. Changes in postsynaptic 5-HT receptor mechanisms may also have been a contributing factor since a downregulation of 5-HT1a receptors induced by pre-treatment with the 5-HT1a/1b agonist, RU-24969, facilitated the acquisition of self-administration (Aronsen, Bukholt, & Schenk, 2016).…”

Section: Experiments 2: Acquisition Of Mdma Self-administrationmentioning

confidence: 99%

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

Wetering¹

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<p>Rationale. ±3, 4-methelynedioxymethamphetamine (MDMA) is the primary psychoactive ingredient of the increasingly popular recreational street drug, ecstasy. As with other drugs of abuse, repeated intermitted exposure to MDMA can lead to an increase in the subsequent behavioural effects of the drug. This phenomenon, termed behavioural sensitisation, has been attributed to sensitisation of central DAergic mechanisms considered to underlie several aspects of addiction. Objectives. The purpose of the present research was to investigate the role of DA D₂ receptor mechanisms in the development of MDMA sensitisation and the acquisition of MDMA self-administration in rats. Methods. Rats received daily i.p. injections of the selective D₂ antagonist, eticlopride (0.0, 0.05, 0.3 mg/kg), prior to injections of MDMA (0.0, 10.0 mg/kg) for five days. Two days following the final pre-treatment session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) were determined. Another group of rats were surgically implanted with i.v. jugular catheters before undergoing the same pre-treatment regimen. Two days following the final pre-treatment session, these rats were subsequently tested for acquisition of MDMA self-administration. The locomotor activating effects of MDMA (5 mg/kg i.p.) were determined two days following the last self-administration session. Results. Pre-treatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration, as evidenced by an increased likelihood to meet an acquisition criterion. Co-administration of eticlopride during pre-treatment completely blocked the development of sensitisation to MDMA-produced hyperactivity but failed to significantly attenuate the facilitation of MDMA self-administration. Interestingly, pre-treatment with eticlopride alone also facilitated the acquisition of self-administration. MDMA self-administration failed to alter MDMA-produced locomotor hyperactivity. Conclusions. These findings suggest that repeated activation of DA D₂ receptors is required for the development of sensitisation to MDMA-produced hyperactivity but not for the development of sensitisation to MDMA-produced reinforcement. D₂ receptor mechanisms evidently play some role, however, because repeated exposure to eticlopride also facilitated MDMA self-administration. It is suggested that both sensitised DAergic mechanisms and desensitised 5-HTergic mechanisms contribute to the acquisition of MDMA self-administration.</p>

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Repeated administration of the 5-HT1B/1A agonist, RU 24969, facilitates the acquisition of MDMA self-administration: role of 5-HT1A and 5-HT1B receptor mechanisms

Cited by 12 publications

References 67 publications

5-HT_1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

5-HT_1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

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

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

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Repeated administration of the 5-HT1B/1A agonist, RU 24969, facilitates the acquisition of MDMA self-administration: role of 5-HT1A and 5-HT1B receptor mechanisms

Cited by 12 publications

References 67 publications

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

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

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

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Product

Resources

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5-HT_1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

5-HT_1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats