TY - JOUR
T1 - Cognitive performance of MDMA-Treated rhesus monkeys
T2 - Sensitivity to serotonergic challenge
AU - Taffe, Michael A.
AU - Davis, Sophia A.
AU - Yuan, Jie
AU - Schroeder, Richard
AU - Hatzidimitriou, George
AU - Parsons, Loren H.
AU - Ricaurte, George A.
AU - Gold, Lisa H.
N1 - Funding Information:
We are grateful for the expert technical assistance of Ilham Polis, Tannia Gutierrez, and Bob Lintz. Supported by USPHS grants: DA13390 (MAT), DA11004 (LHP), DA05707 (GAR) and DA09111 (LHG). This is publication #14556-NP from The Scripps Research Institute.
PY - 2002/12/1
Y1 - 2002/12/1
N2 - Recreational users of (±)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") exhibit poor performance on a number of neurocognitive measures, with tests of memory and attention most commonly affected. Cognitive impairments can be persistent or possibly permanent, since users who have been abstinent from MDMA for many months are also impaired. Repeated treatment of rats or nonhuman primates with MDMA has consistently been demonstrated to produce specific, lasting depletions of brain serotonin (5-HT) markers, a potential source of such cognitive symptoms. We have shown, however, that monkeys treated with a regimen of MDMA (4 days, 10 mg/kg i.m., b.i.d.), sufficient to produce a 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid in cerebrospinal fluid, do not exhibit lasting deficits in a range of cognitive domains. Acute drug challenges are often effective at unmasking consequences of amphetamine toxicity. Here, the performance of MDMA-treated and control monkeys on tests of spatial working memory (self-ordered spatial search), vigilance and reaction time (5-choice reaction time), reinforcer efficacy and sustained attention (progressive ratio responding) and fine motor control (bimanual motor skill task) was challenged with ketanserin (0.1-1.7 mg/kg, i.m.), 1-(3-Chlorophenyl)piperazine dihydrochloride (mCPP, 0.03-0.5 mg/kg, i.m.) and (±)8-hydroxy-DPAT hydrobromide (8-OH-DPAT, 0.032-0.1 mg/kg, i.m.). MDMA-exposed animals exhibited increased sensitivity to challenge with mCPP on the reaction time and progressive ratio tasks but otherwise were equivalently sensitive to drug challenge. Post-mortem analysis demonstrated that 76-93% reductions of 5-HT in neocortex persist 17-20 months post-MDMA. These observations suggest that large depletions of brain 5-HT produced by MDMA can persistently alter behavioral sensitivity to the disrupting effects of serotonergic agents.
AB - Recreational users of (±)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") exhibit poor performance on a number of neurocognitive measures, with tests of memory and attention most commonly affected. Cognitive impairments can be persistent or possibly permanent, since users who have been abstinent from MDMA for many months are also impaired. Repeated treatment of rats or nonhuman primates with MDMA has consistently been demonstrated to produce specific, lasting depletions of brain serotonin (5-HT) markers, a potential source of such cognitive symptoms. We have shown, however, that monkeys treated with a regimen of MDMA (4 days, 10 mg/kg i.m., b.i.d.), sufficient to produce a 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid in cerebrospinal fluid, do not exhibit lasting deficits in a range of cognitive domains. Acute drug challenges are often effective at unmasking consequences of amphetamine toxicity. Here, the performance of MDMA-treated and control monkeys on tests of spatial working memory (self-ordered spatial search), vigilance and reaction time (5-choice reaction time), reinforcer efficacy and sustained attention (progressive ratio responding) and fine motor control (bimanual motor skill task) was challenged with ketanserin (0.1-1.7 mg/kg, i.m.), 1-(3-Chlorophenyl)piperazine dihydrochloride (mCPP, 0.03-0.5 mg/kg, i.m.) and (±)8-hydroxy-DPAT hydrobromide (8-OH-DPAT, 0.032-0.1 mg/kg, i.m.). MDMA-exposed animals exhibited increased sensitivity to challenge with mCPP on the reaction time and progressive ratio tasks but otherwise were equivalently sensitive to drug challenge. Post-mortem analysis demonstrated that 76-93% reductions of 5-HT in neocortex persist 17-20 months post-MDMA. These observations suggest that large depletions of brain 5-HT produced by MDMA can persistently alter behavioral sensitivity to the disrupting effects of serotonergic agents.
KW - 8-OH-DPAT
KW - Attention
KW - Ketanserin
KW - MDMA
KW - Memory
KW - mCPP
UR - http://www.scopus.com/inward/record.url?scp=0036898951&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036898951&partnerID=8YFLogxK
U2 - 10.1016/S0893-133X(02)00380-9
DO - 10.1016/S0893-133X(02)00380-9
M3 - Article
C2 - 12464456
AN - SCOPUS:0036898951
SN - 0893-133X
VL - 27
SP - 993
EP - 1005
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 6
ER -