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agonists and antagonists in non-dependent, GHB- dependent and GHB-withdrawn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 |
Comparison of the behavioral effects of bretazenil and
flumazenil in triazolam-dependent and non-dependent baboons.
Weerts EM, Ator NA, Kaminski BJ, Griffiths RR.
Johns Hopkins University School of Medicine, Department of Psychiatry
and Behavioral Sciences, MD 21224, USA.
[email protected]
Eur J Pharmacol. 2005 Sep 5;519(1-2):103-13
Behavioral effects of the benzodiazepine receptor partial agonist
bretazenil were compared with those of the benzodiazepine receptor
antagonist flumazenil under conditions in which three baboons received
continuous intragastric (i.g.) infusion of vehicle and then continuous
i.g. infusion of triazolam (1.0 mg/kg/day). In each condition, acute
doses of flumazenil (0.01-3.2 mg/kg) and bretazenil (0.01-10.0 mg/kg)
were administered every 2 weeks (beginning after 30 days of treatment in
the triazolam-dependent condition). Food pellets were available during
daily 20-h sessions. Following test injections, 60-min behavioral
observations were conducted followed by a fine motor assessment. During
chronic vehicle administration, neither drug produced changes in
observed behaviors. Bretazenil increased pellets earned and time to
complete the fine-motor task (10.0 mg/kg dose). During chronic triazolam
dosing, both bretazenil and flumazenil precipitated benzodiazepine
withdrawal syndromes, characterized by vomiting, tremors/jerks, and a
decrease in pellets earned. Thus, bretazenil can function as an
antagonist under conditions of benzodiazepine physical dependence.
|