A comparison of MDMA and d-amphetamine in the drug discrimination paradigm.

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Magnus Wells
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1 A comparison of MDMA and d-amphetamine in the drug discrimination paradigm. D.N. Harper, A. Crowther, S. Schenk School of Psychology Victoria University of Wellington, New Zealand

2 AIM To compare the subjective experience of two commonly used stimulants that share overlapping neurochemical and behavioural properties: Amphetamine (AMPH) & 3,4-Methylenedioxymethamphetamine (MDMA)

3 BACKGROUND I Acute MDMA acts as a 5-HT agonist across a variety of brain regions (even at doses as low as 1.0mg/kg) MDMA also acts as a dopamine (DA) agonist (altho' comparatively higher doses may be needed, >2.5mg/kg, to produce significant increases in extracellular DA levels)

4 e.g. Baumann et al (2008) NAC Striatum PFC

5 Therefore, at higher doses MDMA becomes a 'little more AMPH-like' (which even at relatively low doses acts primarily as a DA agonist). Effect of 2.0 mg/kg AMPH on extracellular DA from Shoblock et al (2002)

6 BACKGROUND II In terms of impact on cognition and memory, we have shown that MDMA and AMPH produce very similar profiles of effect (distinct from many other amnetic drugs, e.g. scopolamine) - Harper et al (2005,06); Kay et al (2010). These effects can be ameliorated somewhat by dopamine antagonists. Mean Percent Correct SCH23390 only SALINE MDMA + SCH 0.02 mg/kg MDMA + SCH 0.01 mg/kg MDMA 2.5 mg/kg DELAY (seconds) SCH MDMA

7 So do users (of the human or rat kind) also experience a subjective overlap in terms of the behavioural effects of MDMA and AMPH (possibly driven by DA-agonist actions)? human users of MDMA show a mix of generalisation to AMPH and 5-HT agonist m-cpp (Tancer &Johanson, 2003), with more experienced users perceiving MDMA as more AMPH-like (Johanson et al., 2006). a little more tricky to ask rats about this

The Drug Discrimination paradigm assesses the relative subjective experience of acutely administered drugs by requiring rats to respond on one lever if

8 The Drug Discrimination paradigm assesses the relative subjective experience of acutely administered drugs by requiring rats to respond on one lever if they have been given a specific drug (AMPH or MDMA in the current study) vs. an alternate lever if they have been administered saline prior to a session.

9 EXPERIMENT 1 'Do rats trained to discriminate MDMA from saline generalise to AMPH and vice versa?' EXPERIMENT 2 'Does the concurrent administration of a D1 antagonist (SCH23390) block the ability of rats to discriminate MDMA from saline or AMPH from saline?'

10 METHOD - Experiment 1 & 2 Subjects 16 Sprague Dawley rats. 8 trained to discriminate between AMPH and saline 8 trained to discriminate between MDMA & saline Training Rats administered a training dose of AMPH (0.5mg/kg ) or MDMA (1.5mg/kg) or saline and placed in an operant chamber. Two retractable levers were inserted into the chamber. Responding on the appropriate lever resulted in availability of a reinforcer on an FR10 schedule. Responding on the unpaired lever reset the FR for the correct lever.

11 EXPERIMENT 1 - Generalisation Testing Across a number of probe sessions all animals were administered a range of doses of MDMA (0, 0.75, 0.375, or 1.5 mg/kg) or AMPH (0, 0.375, 0.25, or 0.5mg/kg). Sessions ended at completion of the first 10 consecutive responses on either lever. (no reinforcers delivered). EXPERIMENT 2 - Discrimination following concurrent administration of D1 antagonist SCH23390 ( mg/kg) was administered concurrently with the appropriate training dose of AMPH or MDMA.

12 % Drug Appropriate Responses % Drug Appropriate Responses RESULTS - Experiment 1 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Rats trained on MDMA AMPH MDMA 0(0) 0.25(0.375) 0.375(0.75) 0.5(1.5) Dose of AMPH (MDMA) mg/kg Rats trained on MDMA did NOT generalise to AMPH 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Rats trained on AMPHETAMINE AMPH MDMA 0(0) 0.25(0.375) 0.375(0.75) 0.5(1.5) Dose of AMPH (MDMA) mg/kg Rats trained on AMPH showed partial generalisation to MDMA (at the highest dose)

13 % Drug Appropriate Responses RESULTS - Experiment 2 Impact of SCH on AMPH or MDMA trained rats AMPH grp given training dose MDMA grp given training dose Dose of SCH23390 Dose of SCH23390 (D2 antagonist) Partial blocking of stimulus control by MDMA Full blocking of stimulus control by AMPH

14 But wait... there might be a problem here (i.e. I'm going to point this out before someone else does)... The doses of MDMA used here and previous drug discrimination studies dont produce strong DA agonist actions (relative to the effects of AMPH on DA at the training dose used).

15 EXPERIMENT 3 - Three-lever drug discrimination task Two main differences: 1) 3-lever task (all within subject comparisons) 2) Generalisation testing at higher doses of MDMA than used in baseline (>1.5mg/kg). These higher doses of MDMA in the range shown to produce significant DA agonist effects. Prediction - Alto' MDMA can be discriminated from AMPH at doses of, or lower than, 1.5mg/kg MDMA, at probe doses higher than 1.5mg/kg MDMA will be confused with AMPH.

16 % Responses RESULTS - Experiment 3 Probe Session Baseline Trained Doses 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% saline lever MDMA lever AMPH lever saline AMPH 0.5 MDMA 1.5 Probe Session Drug & Dose (mg/kg)

17 % Responses RESULTS - Experiment 3 Probe Session Generalisation Higher MDMA Doses 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% saline lever MDMA lever AMPH lever MDMA 1.5 MDMA 3.0 MDMA 4.5 Probe Session Drug & Dose (mg/kg)

18 CONCLUSIONS Overall Experiments 1 & 2 indicated that MDMA induces some of the subjective experiences elicited by AMPH, but that the primary subjective experience of MDMA is still markedly different from that of AMPH (possibly because of the relative dominance of the 5-HT vs. DA agonist action with MDMA relative to AMPH) HOWEVER Experiment 3 suggests this may only be the case at relatively low doses of MDMA.

19 ... turning the subjective experience of MDMA from this to something more like this Thanks also to: Richard Moore & Anna-Lena Langen, 2009 Summer Scholarship Scheme & VUW Faculty of Science Summer Research Grant

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

Serotonergic mechanisms of MDMA self-administration Susan Schenk Victoria University of Wellington School of Psychology My lab works in the broad area of Behavioural Pharmacology We test the effects of