Grant Number:
|
5R01DA014919-05
$354,138 |
Project Title:
|
Behavioral
Pharmacology and GHB Physical Dependence |
PI
Information: |
Name |
Email |
Title |
|
WEERTS, ELISE M. |
[email protected]
|
ASSOCIATE
PROFESSOR |
Abstract: DESCRIPTION (provided by applicant): Gamma-hydroxybutyrate
(GHB) is a drug of abuse with potent CMS depressant effects. Chronic
administration of GHB can produce physical dependence and the withdrawal
syndrome reportedly resembles withdrawal from classic sedative-hypnotics
(benzodiazepines and alcohol). The mechanisms underlying the
pharmacological actions of GHB appear to involve multiple systems
including GHB, Gamma-aminobutyric acid CGABA), and opioid. Three
specific aims are proposed to further characterize the behavioral
pharmacology and physical dependence potential of GHB. Aim 1 will
evaluate the effects of dose and duration of GHB administration on
development of physical dependence. A range of GHB doses will each be
administered for the same duration and then a GABA-B antagonist will be
administered. Signs of withdrawal and effects on food-maintained
behavior will be characterized. Second, GHB dose will be held constant
and the length of exposure will be varied. The severity of
antagonist-precipitated withdrawal behaviors as a function of the length
of GHB administration will be determined. Aim 2 will examine the
behavioral effects GHB, benzodiazepine GABA-A and GABA-B receptor
agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn
subjects. The ability of each drug to potentiate GHB effects,
precipitate withdrawal and/or alleviate GHB withdrawal will be
determined. These studies will determine if chronic GHB administration
produces functional changes in GHB, GABA-A and/or GABA-B receptors as
evidenced by shifts in the drug dose effect functions. Aim 3 will
characterize the reinforcing effects and pattern of self- administration
of GHB, and pro-drugs gamma-butyrolactone (GBL) and 1,4-butendiol
(1,4-BD) using a 24-hr self-injection procedure. The relative
reinforcing efficacy of each drug will be compared, as measured by the
maximum work output or "breaking point" completed for each injection
under a progressive ratio procedure. Physical dependence in the context
of self-injection of GHB, GBL and 1,4-BD will also be evaluated. These
studies will provide critical information on the behavioral pharmacology
and dependence-producing effects of GHB.
Public Health Relevance:
This Public Health Relevance is not available.
Thesaurus Terms:
baboon, behavior, psychopharmacology, receptor
acid, alcohol, ataxia, barbiturate, benzodiazepine, benzodiazepine
receptor, binding site, brain, butyrolactone, central nervous system
depressant, cocaine, conditioning, drug abuse, drug screening
/evaluation, enzyme, food, food processing /preparation, human, model,
muscle relaxation, narcolepsy, opioid receptor, pharmacology, quality of
life, rape, receptor expression, sedative /hypnotic, sensory depression,
syndrome, triazolam
Institution:
|
JOHNS HOPKINS
UNIVERSITY |
|
W400 Wyman Park
Building |
|
BALTIMORE, MD
212182680 |
Fiscal Year:
|
2007 |
Department:
|
PSYCHIATRY AND
BEHAVIORAL SCIENCES |
Project Start:
|
30-SEP-2001 |
Project End:
|
31-MAR-2011 |
ICD:
|
NATIONAL
INSTITUTE ON DRUG ABUSE |
IRG:
|
BRLE |
Chronic intragastric administration of gamma-butyrolactone
produces physical dependence in baboons.
Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, Gibson KM,
Weerts EM.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine, Baltimore, MD, USA.
Psychopharmacology (Berl). 2006 Nov;189(1):71-82. Epub 2006 Sep 20
RATIONALE: Abuse of gamma-hydroxybutyrate (GHB) and its
precursors is a public health concern. Gamma-butyrolactone (GBL) is
found in commercially available products and, when ingested, is
metabolized to GHB. OBJECTIVE: The goal was to evaluate the physical
dependence potential and behavioral effects of GBL. METHODS: Vehicle and
then GBL were administered continuously (24 h per da y) in baboons (Papio
anubis, n=5) via intragastric catheters. GBL dosing was initiated at 100
mg/kg/day and then progressively increased stepwise by increments of 100
mg/kg to a final dose of 600 mg/kg. The number of food pellets earned,
fine-motor task performance, and observed behaviors were used as
dependent measures. Precipitated withdrawal was evaluated after
administration of GABA-B and benzodiazepine receptor antagonists during
chronic GBL dosing (400-600 mg/kg). Spontaneous withdrawal was evaluated
after discontinuation of chronic GBL 600 mg/kg. Blood GHB levels were
determined during chronic dosing of each GBL dose by isotope dilution
assay.
RESULTS: Chronic GBL dose-dependently decreased
food-maintained behavior, disrupted performance on the fine-motor task,
and produced signs of sedation and muscle relaxation. The GABA-B
antagonist SGS742 [56 mg/kg, intramuscular (IM)] precipitated a
withdrawal syndrome, whereas the benzodiazepine antagonist flumazenil (5
mg/kg, IM) produced little or no effect. Signs of physical dependence
were also demonstrated when chronic GBL dosing was discontinued.
Analysis of plasma indicated GBL was metabolized to GHB; levels were 825
to 1,690 micromol l(-1) GHB and 2,430 to 3,785 micromol l(-1) GHB after
week 1 of 400 and 600 mg/kg/day, respectively.
CONCLUSIONS: These data
indicate that, like GHB, chronic GBL dosing produced physical dependence
that likely involved the GABA-B receptor.
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