PMID- 16253319
OWN - NLM
STAT- MEDLINE
DCOM- 20060302
LR  - 20191210
IS  - 0091-3057 (Print)
IS  - 0091-3057 (Linking)
VI  - 82
IP  - 2
DP  - 2005 Oct
TI  - Pizotyline effectively attenuates the stimulus effects of 
      N-methyl-3,4-methylenedioxyamphetamine (MDMA).
PG  - 404-10
AB  - MDMA (N-methyl-3,4-methylenedioxyamphetamine) produces a discriminative stimulus 
      (DS) effect in animals, but attempts to completely block this action with 
      selective neurotransmitter antagonists have not been very successful. 
      Biochemically, MDMA can increase synaptic levels of serotonin, dopamine, and 
      norepinephrine that, conceivably, might interact with multiple populations or 
      subpopulations of neurotransmitter receptors. The present study attempted to 
      antagonize the DS effects of MDMA using the nonselective agents clozapine, 
      cyproheptadine, and pizotyline. An extensive and comparative radioligand binding 
      profile was also obtained for the latter two agents. The purported antagonists 
      were administered in combination with the training dose of MDMA to groups of 
      Sprague-Dawley rats trained to discriminate 1.5 mg/kg of MDMA from saline vehicle 
      in a standard two-lever operant paradigm using a VI-15s schedule of 
      reinforcement. Clozapine was without effect at the doses evaluated, and 
      cyproheptadine only partially attenuated MDMA-appropriate responding. In 
      contrast, pizotyline (AD50=2.5 mg/kg), in combination with the MDMA training 
      dose, resulted in a dose related decrease in percent drug-appropriate responding 
      to saline levels. In a separate group of animals trained to discriminate the 
      structurally-related agent N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) 
      from vehicle, pretreatment with pizotyline also resulted in a substantial 
      decrease in drug-appropriate responding. The results with cyproheptadine and 
      pizotyline in the binding assays confirmed that these agents display high 
      affinity for multiple subpopulations of serotonergic, dopaminergic, adrenergic, 
      histaminergic, and cholinergic receptors. The overall results of the present 
      investigation indicate that pizotyline, which is clinically available in some 
      countries, might be of clinical utility in the treatment of MDMA overdose.
FAU - Young, Richard
AU  - Young R
AD  - Department of Medicinal Chemistry, School of Pharmacy, Medical College of 
      Virginia Campus, Virginia Commonwealth University, Box 980540 Richmond, Virginia 
      23298-0540, United States.
FAU - Khorana, Nantaka
AU  - Khorana N
FAU - Bondareva, Tatiana
AU  - Bondareva T
FAU - Glennon, Richard A
AU  - Glennon RA
LA  - eng
GR  - R01 DA001642/DA/NIDA NIH HHS/United States
GR  - DA 01642/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20051025
PL  - United States
TA  - Pharmacol Biochem Behav
JT  - Pharmacology, biochemistry, and behavior
JID - 0367050
RN  - 0 (Central Nervous System Stimulants)
RN  - 0 (Hallucinogens)
RN  - 0 (Receptors, Neurotransmitter)
RN  - 0 (Receptors, Serotonin)
RN  - 0 (Serotonin Antagonists)
RN  - 0 (paramethoxymethamphetamine)
RN  - 0BY8440V3N (Pizotyline)
RN  - 2YHB6175DO (Cyproheptadine)
RN  - 44RAL3456C (Methamphetamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Central Nervous System Stimulants/*antagonists & inhibitors/pharmacology
MH  - Cyproheptadine/pharmacology
MH  - Discrimination, Psychological/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Generalization, Psychological
MH  - Hallucinogens/*antagonists & inhibitors/pharmacokinetics/pharmacology
MH  - Male
MH  - Methamphetamine/analogs & derivatives/pharmacokinetics/pharmacology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*antagonists & 
      inhibitors/pharmacokinetics/pharmacology
MH  - Pizotyline/pharmacokinetics/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Neurotransmitter/drug effects/metabolism
MH  - Receptors, Serotonin/drug effects/metabolism
MH  - Serotonin Antagonists/pharmacokinetics/*pharmacology
EDAT- 2005/10/29 09:00
MHDA- 2006/03/03 09:00
CRDT- 2005/10/29 09:00
PHST- 2005/03/25 00:00 [received]
PHST- 2005/08/18 00:00 [revised]
PHST- 2005/09/02 00:00 [accepted]
PHST- 2005/10/29 09:00 [pubmed]
PHST- 2006/03/03 09:00 [medline]
PHST- 2005/10/29 09:00 [entrez]
AID - S0091-3057(05)00312-6 [pii]
AID - 10.1016/j.pbb.2005.09.010 [doi]
PST - ppublish
SO  - Pharmacol Biochem Behav. 2005 Oct;82(2):404-10. doi: 10.1016/j.pbb.2005.09.010. 
      Epub 2005 Oct 25.