MDMA AND ITS STEREOISOMERS AS

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MDMA AND ITS STEREOISOMERS AS REINFORCERS IN
RHESUS MONKEYS Serotonergic Involvement
William Fantegrossi, Biopsychology Gail Winger
and James Woods, Pharmacology
Thomas Ullrich and Kenner Rice
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• MDMA exerts preferential effects on central 5-HT
  systems
• blocks reuptake mechanisms
• stimulates 5-HT release

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• Racemic MDMA elicits conditioned place preference
• in rats (Marona-Lewicka et al., 1996)
• Racemic MDMA decreases the threshold for
  rewarding
• electrical stimulation of the brain in rats
• (Hubner et al., 1987)
• Racemic MDMA has twice been shown to act as a
• reinforcer in intravenous self-administration
• paradigms in primates (Beardsley et al., 1986
• Lamb and Griffiths, 1987)
• The reinforcing effects of the stereoisomers
  have
• not been previously assessed.

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• Drug discrimination studies suggest that the
• MDMA stereoisomers may have different
• subjective effects
• the discriminable cue of S()-MDMA may be
• more likely to be reported as dopaminergic
• than serotonergic
• (generalizes to amphetamine, not mescaline)
• the stimulus properties of R(-)-MDMA may be
• more likely to be reported as serotonergic
• than dopaminergic
• (generalizes to mescaline, not amphetamine)
• (Glennon et al., 1988 Baker et al., 1995 Baker
  and Taylor, 1997.)

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• Schedule was FR10 TO 1 min.
• Total session length (including time outs) was 60
  min.
• Two sessions run per day.
• To aggregate data across all four experimental
  animals, data were normalized to percent of
  cocaine control responding, and infusions of 0.01
  mg/kg/inj cocaine were set to 100 of control.

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Racemic MDMA and its stereoisomers are
self-administered by rhesus monkeys
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Racemic MDMA has high affinity for 5-HT
transporters and 5-HT2 serotonin receptors
(Battaglia et al., 1988.) (-)-MDMA has higher
affinity for post-synaptic 5-HT
receptors ()-MDMA has higher affinity for 5-HT
transporters (Battaglia, personal
communication, 2001.)
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Ketanserin is 10- to 30-fold more selective for
5-HT2A than for 5-HT2C
MDL 100907 is 100- to 300-fold more selective
for 5-HT2A than for 5-HT2C
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• 5 MDMA-naïve monkeys were used in these
  antagonism studies.
• The schedule was a multiple-dose procedure
  allowing self-administration of 4 doses of drug
  per session.
• FR30 TO45 sec, for 20 inj or 25min, with a 10 min
  TO between dose components. Session length is
  approximately 130 minutes.
• Pretreatments were administered IM 15-min prior
  to start of session.

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Ketanserin shifts the ascending limb, but not
the descending limb, of the cocaine
self-administration curve
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A large dose of MDL 100907 is required to
suppress cocaine self-administration
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Ketanserin down-shifts the ()-MDMA
self-administration curve
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MDL 100907 right-shifts the ascending limb of the
()-MDMA self-administration curve
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Ketanserin abolishes responding for (-)-MDMA at a
dose that does not affect cocaine-maintained
behavior
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MDL 100907 abolishes responding for (-)-MDMA at a
dose that does not affect cocaine-maintained
behavior
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• DISCUSSION AND CONCLUSIONS
• Drugs with serotonergic mechanisms of action
• rarely maintain self-administration
• Agonists like mescaline and DOM, SSRIs like
• alaproclate, clomipramine, and fluoxetine,
• and releasers like fenfluramine all fail to
• engender significant behavior.

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• DISCUSSION AND CONCLUSIONS
• However, racemic MDMA and both
• stereoisomers are effective reinforcers
• in rhesus monkeys.
• The reinforcing effects of other methylenedioxy
• analogues of amphetamine (MDE, MBDB, etc.)
• therefore deserve further study

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• DISCUSSION AND CONCLUSIONS
• Stimulation of 5-HT2A receptors appears to be
• an integral component to the reinforcing
  effects
• of MDMA, but not to those of cocaine.
• 5-HT2A receptors may be particularly important
• in the reinforcing effects of (-)-MDMA.

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Acknowledgements

• Expert technical assistance was provided by Amy
  Foster, Debbie Huntzinger, Sarah Pilkington, and
  Jolan Terner.
• These studies were supported by USPHS Grants
  DA09161 and DA05923.
• Thanks to ISGIDAR for the travel award!

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Preliminary PET Scan Results
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Antagonist effects are probably not
rate-dependent - 1
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Antagonist effects are probably not
rate-dependent - 2
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Antagonist effects are probably not
rate-dependent - 3