Serotonergic mechanisms of MDMA self-administration. Susan Schenk Victoria University of Wellington School of Psychology

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1 Serotonergic mechanisms of MDMA self-administration Susan Schenk Victoria University of Wellington School of Psychology

2 My lab works in the broad area of Behavioural Pharmacology We test the effects of drugs on behaviour We try to determine the role of various neurochemical systems in the behaviour of interest by measuring effects of selective agonists and antagonists My main interest in substance misuse and we use rat subjects (mainly) Our behavioural assay allows rats to intravenusly self-inject drugs of abuse Our studies examine factors that impact both the acquisition and maintenance of drug-taking

4 Acquisition and maintenance of MDMA self-administration During first 3 days, no preference for active lever.

5 Acquisition and maintenance of MDMA self-administration Last 3 days, there is a marked preference for the active lever

6 Responding maintained by MDMA is dose-dependent when the dose was decreased active lever responding increased in a compensatory manner

7 Cumulated lever pressing Cumulated lever pressing Variability in the acquisition of selfadministration C17 Active lever Inactive lever Some rats acquire self-administration quickly Day 67 Active lever Inactive lever And some rats acquire self-administration slowly Day

8 Acquisition of MDMA self-administration requires an average of 15.9 test sessions Some rats are more susceptible to the initial reinforcing effects of MDMA and meet the criterion of 90 infusions relatively quickly Other rats are less susceptible and require many more test sessions to meet the criterion

9 Why the variability? Maybe it has to do with different pharmacodynamic responses to MDMA-environmental/genetic basis? Need to understand MDMA pharmacology as a start

10 DA (% control) 5-HT (% control) Pharmacology of MDMA MDMA preferentially increases synaptic levels of 5HT with much smaller increases in DA (Baumann 2007) mg/kg mg/kg mg/kg mg/kg Time (min) Time (min)

11 5-HT is generally inhibitory to selfadministration -5HT agonists are not self-administered Götestam and Andersson, 1975; Howell and Byrd, 1995; Wee et al. 2005; Negus et al., HT agonists decrease self-administration of other drugs of abuse Wee and Woolverton, 2006; Czoty et al., 2002; Peltier and Schenk, 1990; Clemens et al., 2006; Leccese and Lyness 1984; Smith et al. 1986; Porrino et al. 1989; Carroll et al. 1990; Richardson and Roberts Relative potency of drug self-administration is inversely related to potency as a 5HT agonist Ritz and Kuhar, 1989; Munzar et al., 1999; Roberts et al., 1999; Kimmel et al., 2009

12 So why is MDMA self-administered? Neuroplastic changes in serotonin as a function of repeated exposure?

13 Many studies have shown that 5HT neurotransmission becomes compromised following repeated exposure to MDMA

14 MDMA self-administration decreases 5HT concentration in various brain sites But there is recovery following 10 weeks of abstinence Do and Schenk 2013

15 5,7 DHT is a selective 5HT neurotoxin that decreases 5HT levels in brain-these lesions facilitated the acquisition of MDMA selfadministration Bradbury et al., 2014

16 Repeated MDMA treatment decreased MDMAproduced synaptic 5HT From Shankaran and Gudelsky, 1999

17 Repeated MDMA treatment facilitated the acquisition of MDMA self-administration the percentage of rats that met the criterion increased the latency to acquisition decreased Van de Wetering and Schenk 2017

18 MDMA self-administration decreases serotonin transporter binding in rat brain Schenk et al., 2007

19 A genetic deletion of the Serotonin Transporter increased MDMA self-administration in rats Oakley A, Schenk A, Ellenbroek BA Molecular Psychiatry (2013) 19, ;

20 The data support the idea that MDMA-produced 5HT initially limits self-administration Decreased 5HT via either MDMA pretreatment, a neurotoxic lesion of 5HT or genetic mutation of the serotonin transporter all facilitated the acquisition of MDMA self-administration Suggests that rats that are initially less responsive to MDMAproduced 5HT might be more likely to self-administer MDMA We have shown this to be true (Colussi-Mas, Wise and Schenk, 2010)

21 What is the role of 5HT in self-administration following the initial acquisition?

22 Reinstatement of extinguished drug-taking behavior- a model of relapse Phase 1 (2 days). Self-administration- rats trained to self-administer MDMA (0.5 mg/kg/infusion) Phase 2. Extinction (at least 2 days- until less that 10 responses produced) Drug solution replaced with saline Phase 3. Reinstatement ( 1 day) Priming injection of drug given at start of session Responding reinforced by saline infusion

23 A priming injection of MDMA reinstated extinguished MDMA -taking behaviour 800 MDMA-produced reinstatement MDMA trained * Phase 1-Rats selfadministered MDMA (FR5) Responses (6 hr) FR5 ext N.a.N MDMA (mg/kg) Phase 2- Drug solution replaced with saline Phase 3- Priming injection of MDMA given at start of session- responding reinforced with saline infusion Schenk et al., 2008

24 5-HT agonists failed to produce drug-seeking Schenk et al., Br J Pharmacol 2011

25 5-HT antagonists failed to alter drug-seeking Schenk et al., 2016

26 5-HT antagonists also failed to alter MDMA self-administration Schenk et al., (2016) Pharmacol Biochem Behav 148:38-45

27 Antagonist doses used were effective in decreasing MDMA-produced hyperactivity Different role in hyperactivity and self-administration

28 Summary MDMA is a preferential 5HT releasing stimulant Following repeated exposure to MDMA, 5HT neurotransmission becomes compromised (decreased tissue levels, decreased transporter binding, decreased release)-all of these effects facilitate MDMA self-administration MDMA self-administration becomes dependent on other pharmacodynamics responses- most likely dopamine (we have lots of data to support this idea)

29 Conclusion 5HT plays an inhibitory role in the acquisition of MDMA selfadministration Following acquisition of self-administration 5HT plays a minimal role in the maintenance of self-administration or in relapse to drug-taking following extinction

30 Of interest.. There is recovery of 5-HT following abstinence from MDMA selfadministration (Do and Schenk, 2013) If, as we have suggested, 5-HT inhibits MDMA self-administration then abstinence would be expected to decrease MDMA selfadministration

31 T o ta l n u m b e r o f in fu s io n s T o ta l n u m b e r o f in fu s io n s And it does! Abstinence decreases MDMA but not cocaine self-administration MDMA Cocaine D a y s (n = 9 ) 1 4 D a y s (n = 1 0 ) D a y s (n = 7 ) 1 4 D a y s (n = 7 ) * * * * P 6 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D a y s o f S A re la tiv e to a b s tin e n c e m a n ip u la tio n 0 P 6 D 1 D 2 D 3 D 4 D 5 D 6 D 7 D a y s o f S A re la tiv e to a b s tin e n c e m a n ip u la tio n Highgate and Schenk, submitted

32 Acknowledgements Many thanks to my lab crew who collected the data presented today Sarah Bradbury, Quenten Highgate, Alex Maan, Ross Van de Wetering Many thanks to the agencies that generously provided funding for these studies Neurological Foundation of New Zealand, Royal Society Marsden Fund, Victoria University of Wellington

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