Gamma hydroxybutyrate (GHB) occurs naturally in the brain. Exogenously it is used recreationally for its euphoric and anabolic effects, and therapeutically in the treatment of narcolepsy and as an anesthetic agent. GHB belongs to the class of substances referred to as """"""""club drugs"""""""", and, like them, has been reorted to be a """"""""date rape drug"""""""". Illicit use of GHB has been associated with significant adverse effects such as amnesia, dizziness, confusion, agitation, hallucination, and at very high doses respiratory depression, unconsciousness, coma and death. Compromised cognitive function, particularly memory lapses, is a major concern with GHB use, as with all date rape drugs. Yet in animals, effect of GHB on memory has never been studied. GHB use and abuse is most prevalent among adolescents and young adults, but neurobehavioral and pharmacological effects of GHB in adolescent animals remains unknown. This is a major caveat in GHB animal literature, since adolescents are known to differ from adults in their response to other drugs of abuse. Compared to adult rats, adolescent rats have been shown to be less sensitive to the sedative and motor impairing effects of ethanol. Also, following ethanol exposure adolescent rats show greater memory impairments than adults. In a preliminary study, we have shown that GHB exposure in adolescent rats cause significant deficits in spatial learning and memory (SL&M). The present study will systematically investigate the immediate and persistent effects of adolescent GHB exposure on SL&M. Hypotheses to be tested are: (1) effects of adolescent GHB exposure on learning and memory are long-term and gender dependent, (2) behavioral effects of GHB exposure in adolescent rats differ from those in adult rats, (3) adolescent GHB exposure do not impair non-mnemonic functions such as anxiety, (4) adolescent GHB-induced deficits in SL&M are associated with alterations in neurotransmitter functions, (5) adolescent GHB-induced deficits in SL&M can be reversed by pharmacologic interventions. Male and female rats will be exposed to low doses of GHB or saline during the adolescent period and tested as adolescents, and as adults, for impairments in spatial learning and memory and anxiety. The metabolism and clearance rates of GHB in blood and brain of adolescent and adult rats are not known, and will be measured in this study to look for ontogenic differences in GHB pharmacokinetics at the two ages. We have some evidence indicating that adolescent GHB treatment is associated with altered regulation of the N-methyl-D-aspartate (NMDA) receptor. In this proposal, adolescent GHB on neuroadaptations in the glutamatergic system will be investigated. The proposed studies will be the first study where an animal model using adolescent rats will be used to explore the neurochemical and psychopharmacological effects of GHB. Data obtained from these studies will further define plasticity of the central nervous system during the adolescent period in rats. Such information will be relevant to GHB exposure in human adolescents, and help in the development of novel prevention and/or treatment strategies.
| Ishiwari, Keita; Sircar, Ratna (2016) Improvement in ?-hydroxybutyrate-induced contextual fear memory deficit by systemic administration of NCS-382. Neuroreport 27:627-31 |
| Sircar, Ratna; Basak, Ashim; Sircar, Debashish et al. (2010) Effects of gamma-hydroxybutyric acid on spatial learning and memory in adolescent and adult female rats. Pharmacol Biochem Behav 96:187-93 |
| Sircar, Ratna; Basak, Ashim; Sircar, Debashish (2008) Gamma-hydroxybutyric acid-induced cognitive deficits in the female adolescent rat. Ann N Y Acad Sci 1139:386-9 |
