Residual social, memory and oxytocin-related changes in rats following repeated exposure to γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination.
BACKGROUND
There has been little investigation of the possible lasting adverse effects of γ-hydroxybutyrate (GHB).


OBJECTIVE
This study aims to study whether GHB produces residual adverse effects on memory and social behaviour in rats and lasting changes in brain monoamines and oxytocin-related gene expression.


METHODS
Rats received daily intraperitoneal injections of GHB (500 mg/kg), methylenedioxymethamphetamine (MDMA; 5 mg/kg) or their combination (GHB/MDMA) over ten consecutive days. Locomotor activity and body weight were assessed during the dosing period and withdrawal-related anxiety was assessed 24 h after drug cessation. After a washout of 4 weeks, rats were tested on the emergence, social interaction, and object recognition tasks over a 2-week period. Monoamine levels in cortex and striatum, and hypothalamic oxytocin and oxytocin receptor mRNA, were then assessed.


RESULTS
MDMA and GHB/MDMA caused modest sensitization of locomotor activity over time, while sedative effects of GHB diminished with repeated exposure. GHB-treated rats showed reduced social interaction 24 h after the final dose, indicating GHB withdrawal-induced anxiety. All drug-treated groups displayed residual deficits in social interaction and object recognition. No changes in monoamine levels were detected 8 weeks post-drug. However, MDMA pre-exposure increased hypothalamic oxytocin mRNA while GHB pre-exposure upregulated oxytocin receptor mRNA. GHB/MDMA pre-exposure caused intermediate changes in both of these measures.


CONCLUSIONS
GHB treatment caused residual impairments in memory and social behaviour and increases in anxiety, paralleling the lasting adverse effects of MDMA. Both drugs caused lasting neuroadaptations in brain oxytocin systems and this may be related to the long-term social interaction deficiencies caused by both drugs.
van Nieuwenhuijzen
Petra S
PS
School of Psychology, University of Sydney, Sydney, NSW, 2006, Australia. petra.s.van@gmail.com
Long
Leonora E
LE
Hunt
Glenn E
GE
Arnold
Jonathon C
JC
McGregor
Iain S
IS
D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004644:Emotions / Q000187:drug effects; D005786:Gene Expression Regulation; D007274:Injections, Intraperitoneal; D008297:Male; D008568:Memory / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D010121:Oxytocin / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D012919:Social Behavior; D012978:Sodium Oxybate / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism / Q000523:psychology; D013997:Time Factors
D015306:Biogenic Monoamines; D012333:RNA, Messenger; D018045:Receptors, Oxytocin; D010121:Oxytocin; D012978:Sodium Oxybate; D018817:N-Methyl-3,4-methylenedioxyamphetamine