Research presentation poster

Methods

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

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

Sessions were controlled remotely by PCs with MED Associates Software and hardware

Figure 4. Effects of NCS-382pretreatment on food-maintained behavior

Figure 2. Effects of GHB on fine motor task

Figure 1. Effects of GHB on food-maintained behavior

Blockade of the Behavioral Effects of Gamma-hydroxybutyrate

by GHB and GABA-B Receptor Antagonists

A.K. Goodwin1, W. Froestl2, K.M. Gibson3, T. Burlingame3, E.E.W. Jansen4, C. Jakobs4, and E.M. Weerts1

1 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

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-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

Fine motor task presented immediately before and again after the 60-min observation period.

Table 1. Number of subjects showing behavioral signs of sedation, muscle relaxation and abdominal discomfort after GHB administration

320 mg/kg GHB

Vehicle

320 mg/kg GHB+NCS-382

Number of Pellets

Duration (sec)

Experiment 1: Results

Figure 5. Effects of CGP36742 pretreatment on food-maintained behavior

Figure 6. Effects of NCS-382 pretreatment on the fine motor task

Summary and Conclusions

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

Number of Pellets

Time (sec)

Experiment 2: Results

Table 2. Number of subjects showing behavioral signs of sedation, muscle relaxation and abdominal discomfort after antagonists + GHB administration

Figure 3. GHB in blood

GHB Dose (mg/kg)

GHB Dose (mg/kg)

320 mg/kg GHB

Vehicle

320 mg/kg GHB+CGP36742

Number of Pellets

320 mg/kg GHB

Vehicle

320 mg/kg GHB+NCS-382

Figure 7. Effects of CGP36742 pretreatment on the fine motor task

320 mg/kg GHB

Vehicle

320 mg/kg GHB+CGP36742

Time (sec)

Introduction

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 non-medical 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 GABA-A 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 NCS-382 and the GABA-B antagonist CGP36742 would block the behavioral effects of GHB.

Experiment 2: Effects of GABA-B and GHB antagonists on the behavioral effects of GHB

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

*Baboon KH projectile vomiting and diarrhea within 20 min after dosing-no observation