Grant Number:
|
5R01DA004133-21
$348,813 |
Project Title:
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Functional
Analysis of GABAerglc Sedative/Anxiolytics |
Abstract:
DESCRIPTION (provided by applicant): Anxiolytics and sedative-hypnotics
are among the most widely prescribed of all psychoactive medications.
Misuse, abuse, and physiological dependence associated with their use
are of continuing concern. Over the past 20 years, drug discrimination
analysis has provided an animal model for classification of the
subjective effects of psychoactive drugs relevant to preclinical drug
abuse liability assessments. It also has proven uniquely sensitive and
selective as a behavioral assay for examining functional in vivo
relevance of novel chemical structures, novel receptor binding profiles,
and novel cellular activity for centrally acting drugs. The aims of the
present application are predicated on the evidence from our previous
work that drug discrimination analysis is uniquely powerful for
analyzing the relationship between the biochemical and behavioral
effects of psychoactive drugs. Specific Aim 1 is to characterize the
relation between in vitro profiles for GABAA modulators that bind the
benzodiazepine (Bz) site and their in vivo profiles of discriminative
stimulus effects. Advances in understanding the structure of the GABAA-receptor
complex have led to development of novel compounds that preferentially
bind GABAA receptor subtypes, have lower efficacy in modulating GABA, or
both. The hope is that such compounds will be better treatments for
anxiety and sleep disorders, produce less tolerance with chronic use,
and have less abuse liability and dependence potential. The in vitro
work on these compounds provides a platform for making predictions about
specific behavioral effects, which we will test. Specific Aim 2 is to
test predictions about the relation between chronic Bz administration
and the effects of glutamatergic ligands administered during and after
the chronic Bz. In vitro data and data from studies of convulsant
thresholds in mice strongly suggest that the withdrawal syndrome that
emerges after discontinuation of chronic Bz use may be due less to
reduced GABAergic functioning as to overfunctioning of the ionotropic
glutamatergic system. The proposed studies will exploit the sensitivity
of drug discrimination training for neuronal substrates of drug action
to explore the predictions of the glutamate hypothesis of the Bz
withdrawal syndrome. These data will be critical to our understanding of
mechanisms of Bz dependence and their relation to Bz tolerance. One of
the studies under Specific Aim 2 will extend our work on physiological
dependence on Bz ligands to provide a direct test of the use of
non-competitive antagonists for the N-methyl-D-aspartate receptor to
ameliorate Bz withdrawal.
Public Health Relevance:
This Public Health Relevance is not available.
Thesaurus Terms:
GABA receptor, benzodiazepine, benzodiazepine receptor, drug addiction,
glutamate, pentobarbital, psychopharmacology, sedative /hypnotic,
tranquilizer
NMDA receptor, diazepam, discrimination learning, drug withdrawal,
ketamine, lorazepam, neuropharmacology, operant conditioning,
psychological reinforcement, receptor binding, substance abuse related
behavior
baboon, behavior test, behavioral /social science research tag,
laboratory rat
Institution:
|
JOHNS HOPKINS
UNIVERSITY |
|
W400 Wyman Park
Building |
|
BALTIMORE, MD
212182680 |
Fiscal Year:
|
2007 |
Department:
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PSYCHIATRY AND
BEHAVIORAL SCIENCES |
Project Start:
|
01-MAY-1992 |
Project End:
|
30-JUN-2009 |
ICD:
|
NATIONAL
INSTITUTE ON DRUG ABUSE |
IRG:
|
IFCN |
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.
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