Blockade of the Behavioral Effects of Gamma-hydroxybutyrate by GHB and GABA-B Receptor Antagonists 1 Goodwin , K.M. T. 3 Burlingame , Gamma-hydroxybutyric acid (GHB) is an endogenous substance found in the brain, as well as a drug of abuse. In recent years, GHB has begun to receive more attention due to an increase in reports of nonmedical use and a sharp rise in medical emergencies associated with illicit use of GHB. When administered systemically, GHB produces CNS depressant effects that are similar to those produced by classic sedative-hypnotics such as barbiturates and benzodiazepines. GHB also produces a range of adverse effects including agitation, dizziness, nausea/vomiting, seizures, bradycardia, respiratory depression, and unconsciousness. Although once used as an anesthetic, the only therapeutic and legal use of GHB is currently for the treatment of narcolepsy The neurobiological mechanisms by which GHB produces its behavioral effects are unknown. GHB does not directly modulate GABAA receptors, which are the primary mechanism for the behavioral actions of both barbiturates and benzodiazepines. GHB binds to two receptor sites in the CNS, the GHB receptor and the GABA-B receptor. The current study characterized the behavioral effects of acute GHB administration in baboons and evaluated if the GHB antagonist NCS382 and the GABA-B antagonist CGP36742 would block the behavioral effects of GHB. Figure 1. Effects of GHB on food-maintained behavior 320 GHB 320 GHB 320 GHB + 10 CGP + 32 CGP + 56 CGP Postures 4 0 1 0 Lip droop 3 0 0 0 Ataxia 3 0 1a 0 Defecation with Diarrhea 2 0 0 Vomiting 2 1 3 0 GHB Dose (mg/kg) Four adult male baboons (Papio anubis) with chronic indwelling intragastric (IG) catheters Catheters were protected by a vest/tether system that permitted free movement within the cage 320 GHB + .1 NCS (n=4) 320 GHB 320 GHB + .32 NCS +1 NCS (n=4) (n=3) Figure 6. Effects of NCS-382 pretreatment on the fine motor task Vehicle 320 mg/kg GHB 320 mg/kg GHB+NCS-382 320 GHB +3.2 NCS (n=4) 0 1 1 0 0 1 1 2 0 2 2 1 0 1 1 1 1 0 1b 2 2 1 2 0 0 0 0 0 1 1 0 0 0 0 1 1 0 Vehicle 320 mg/kg GHB 320 mg/kg GHB+NCS-382 Drug Figure 7. Effects of CGP36742 pretreatment on the fine motor task Figure 2. Effects of GHB on fine motor task Bridge Light Sessions were controlled remotely by PCs with MED Associates Software and hardware Experiment 1: Effects Of GHB alone ▪ 150 mls of GHB or water (VEH) administered as a bolus infusion ▪ FR schedule of pellet delivery during daily 20-hr sessions beginning 60- GHB Dose (mg/kg) min after drug administration Frequency and duration of 21 behaviors and 8 postures observed during 60 min periods beginning 60-min after drug or VEH infusion 320 mg/kg GHB 320 mg/kg GHB+CGP36742 Time (sec) ▪ Jewel Lights Levers Vehicle Number of Pellets Pellet Hopper Distilled water (450 mls/day) was infused continuously via a peristaltic pump to maintain catheter patency The home cage served as the experimental cage and was equipped with an intelligence panel containing a Lindsley lever, a speaker, stimulus lights and a food hopper for the experimental control of behavior ▪ and E.M. 1 Weerts Figure 4. Effects of NCS-382pretreatment on foodmaintained behavior ▪ ▪ 320 GHB ALONE Head Lower Posture Tremor Jerk Duration (sec) ▪ Experiment 2: Results Table 2. Number of subjects showing behavioral signs of sedation, muscle relaxation and abdominal discomfort after antagonists + GHB administration Dose (mg/kg) Methods ▪ C. 4 Jakobs , Division of Behavioral Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2 Novartis Pharma AG, Basel Switzerland; 3Oregon Health Science University, Portland, OR, USA; 4Clin. Chem., VU University Medical Center, New Orleans, LA, USA Introduction ▪ E.E.W. 4 Jansen , Time (sec) 1 W. 3 Gibson , Number of Pellets A.K. 2 Froestl , Figure 3. GHB in blood Figure 5. Effects of CGP36742 pretreatment on foodmaintained behavior Vehicle Fine motor task presented immediately before and again after the 60min observation period. 320 mg/kg GHB 320 mg/kg GHB+CGP36742 Summary and Conclusions ▪ Number of Pellets Experiment 1: Results Table 1. Number of subjects showing behavioral signs of sedation, muscle relaxation and abdominal discomfort after GHB administration GHB Dose (mg/kg) 100 (n=4) 180 (n=4) 240 (n=4) 320 (n=4) Resting Postures 1 2 3 4 3 Lip droop 0 1 1 3 2 Ataxia 0 1 1 3 2 Experiment 2: Effects of GABA-B and GHB antagonists on the behavioral effects of GHB Defecation with Diarrhea 0 0 2 2 2* ▪ Vomiting 0 0 1 2 2* 1 0 2 3 2 0 0 0 0 2 Head Lower Posture Tremors Jerks 420 (n=3*) *Baboon KH projectile vomiting and diarrhea within 20 min after dosing-no observation ▪ NCS-382 (0.1-3.2 mg/kg), CGP36742 (10-56 mg/kg), or VEH (sterile water) injected IM immediately prior to IG infusion of 320 mg/kg GHB or VEH All other procedures the same as Experiment 1 ▪ ▪ ▪ GHB dose-dependently reduced food-maintained behavior and disrupted performance on the fine motor task. Pre-treatment with a GABA-B antagonist restored food-maintained behavior to vehicle levels, while pre-treatment with a GHB receptor antagonist produced inconsistent effects. While GHB may share some behavioral effects with classic sedative hypnotics, the behavioral pharmacology of GHB is distinctly different These data are consistent with reports the GABA-B receptor plays an important role in the behavioral effects of acute doses of GHB The role of GHB receptors in mediating the behavioral effects of exogenously administered GHB remain unclear Acknowledgements ▪ ▪ Supported by NIH/NIDA R01-DA14919 (Weerts) GHB and NCS-382 were provided by NIDA drug Supply program; CGP36742 was provided by Novartis Pharma Title, Author(s) Affiliation Abstract – complete as submitted Introduction – include a couple of related studies to build a case Method Inferential Table Results Discussion References – only for sources cited on poster
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