Improvement in γ-hydroxybutyrate-induced contextual fear memory deficit by systemic administration of NCS-382.
Low, nonsedative doses of γ-hydroxybutyric acid (GHB) produce short-term anterograde amnesia in humans and memory impairments in experimental animals. We have previously shown that acute systemic treatment of GHB in adolescent female rats impairs the acquisition, but not the expression, of contextual fear memory while sparing both the acquisition and the expression of auditory cued fear memory. In the brain, GHB binds to specific GHB-binding sites as well as to γ-aminobutyric acid type B (GABAB) receptors. Although many of the behavioral effects of GHB at high doses have been attributed to its effects on the GABAB receptor, it is unclear which receptor mediates its relatively low-dose memory-impairing effects. The present study examined the ability of the putative GHB receptor antagonist NCS-382 to block the disrupting effects of GHB on fear memory in adolescent rat. Groups of rats received either a single dose of NCS-382 (3-10 mg/kg, intraperitoneally) or vehicle, followed by an injection of either GHB (100 mg/kg, intraperitoneally) or saline. All rats were trained in the fear paradigm, and tested for contextual fear memory and auditory cued fear memory. NCS-382 dose-dependently reversed deficits in the acquisition of contextual fear memory induced by GHB in adolescent rats, with 5 mg/kg of NCS-382 maximally increasing freezing to the context compared with the group administered GHB alone. When animals were tested for cued fear memory, treatment groups did not differ in freezing responses to the tone. These results suggest that low-dose amnesic effects of GHB are mediated by GHB receptors.
aDepartment of Psychology, The City College of New York, CUNY bAlbert Einstein College of Medicine, Bronx cFeinstein Institute for Medical Research, Manhasset dResearch Institute on Addictions, University at Buffalo, Buffalo, New York, USA.
Keita
K
Ishiwari
Ratna
R
Sircar
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001567:Benzocycloheptenes / Q000627:therapeutic use*; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects*; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006885:Hydroxybutyrates / Q000633:toxicity*; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000927:Anticonvulsants; D001567:Benzocycloheptenes; D006885:Hydroxybutyrates; C066471:NCS 382; C035142:4-hydroxy-2-butenoic acid