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MDMA stimulus generalization to the 5-HT(1A) serotonin agonist 8-hydroxy-2- (di-n-propylamino)tetralin
1Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
Abstract:
The abused substance N-methyl-1-(3, 4-methylenedioxyphenyl)-2-aminopropane, or MDMA, serves as a training drug in animals. Because the 5-HT(1A) receptor antagonist NAN-190 has been shown to partially antagonize the MDMA stimulus, and because NAN-190 binds at several different types of receptors, in the present study we examined other agents (e.g., adrenergic, dopaminergic, sigma) in tests of stimulus generalization and stimulus antagonism to determine their influence on the MDMA stimulus. Each of these agents (i.e., clenbuterol, S(-)propranolol, R(+)SCH-23390, amantadine, NANM) was without effect on MDMA-appropriate responding. The finding that NAN-190 behaves as a 5-HT(1A) partial agonist in some studies prompted examination of the 5-HT(1A) receptor agonist 8-OH DPAT and its optical isomers. MDMA-stimulus generalization occurred to racemic 8-OH DPAT (ED(50) = 0.3 mg/kg), R(+)8-OH DPAT (ED(50) = 0.2 mg/kg), and to the 5-HT(1A) receptor partial agonist S(-)8-OH DPAT (ED(50) = 0.4 mg/kg). The results suggest that the MDMA stimulus might possess a 5-HT(1A) component of action. Furthermore, because 8-OH DPAT is known to enhance the stimulus effects of hallucinogens as discriminative stimuli, and because MDMA reportedly enhances the effects of hallucinogenic agents in humans ("flipping," "candy flipping"), this latter MDMA-induced phenomenon might involve a 5-HT(1A) mechanism.
Insights
The abused substance MDMA (N-methyl-1-(3, 4-methylenedioxyphenyl)-2-aminopropane) may act via the 5-HT(1A) receptor. This study found that 8-OH DPAT, a 5-HT(1A) agonist, generalized the MDMA stimulus in animals.
Area of Science:
- Neuroscience
- Pharmacology
- Psychopharmacology
Background:
- The abused substance N-methyl-1-(3, 4-methylenedioxyphenyl)-2-aminopropane (MDMA) is used as a training drug in animal models.
- The 5-HT(1A) receptor antagonist NAN-190 partially antagonizes the MDMA stimulus, but also binds to other receptors, necessitating further investigation into the MDMA stimulus's receptor interactions.
Purpose of the Study:
- To investigate the influence of various receptor agents (adrenergic, dopaminergic, sigma, and 5-HT(1A)) on the MDMA stimulus.
- To determine if the 5-HT(1A) receptor plays a role in the discriminative stimulus properties of MDMA.
Main Methods:
- Tested stimulus generalization and antagonism using agents like clenbuterol, S(-)propranolol, R(+)SCH-23390, amantadine, NANM, and 8-OH DPAT (racemic and optical isomers).
- Administered agents to animals trained to discriminate MDMA stimulus and assessed responding.
Main Results:
- Clenbuterol, S(-)propranolol, R(+)SCH-23390, amantadine, and NANM did not affect MDMA-appropriate responding.
- MDMA-stimulus generalization occurred with racemic 8-OH DPAT (ED(50) = 0.3 mg/kg), R(+)8-OH DPAT (ED(50) = 0.2 mg/kg), and S(-)8-OH DPAT (ED(50) = 0.4 mg/kg).
Conclusions:
- The results suggest that the MDMA stimulus may involve a 5-HT(1A) receptor component.
- The 5-HT(1A) mechanism might be involved in MDMA's potentiation of hallucinogenic effects in humans, such as "candy flipping".