GABA A receptors and therapeutics: beyond benzodiazepines
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1 GABA A receptors and therapeutics: beyond benzodiazepines Lisa R. Gerak Department of Pharmacology and Behavioral Pharmacology Group University of Texas Health Science Center at San Antonio, TX
2 Clinical uses of benzodiazepines Anxiolytic effects Sedative/hypnotic effects Anticonvulsant effects Muscle relaxation Conscious sedation/induction of anesthesia Alcohol withdrawal
3 Clinical uses of benzodiazepines Anxiolytic effects Sedative/hypnotic effects Anticonvulsant effects Muscle relaxation Conscious sedation/induction of anesthesia Alcohol withdrawal Adverse effects of benzodiazepines Sedative/hypnotic effects Ataxia Impairment of cognitive function Abuse Tolerance Physical dependence
4
5 Neuroactive steroids
6 Drug discrimination
7 Drug discrimination training Midazolam (.178 mg/kg) saline REINFORCER REINFORCER
8 Drug discrimination testing Test compound % Midazolam lever responding REINFORCER REINFORCER
9 % Midazolamlever responding Rate (resp/sec) S Dose (mg/kg) Midazolam
10 % Midazolamlever responding Midazolam Rate (resp/sec) V Dose (mg/kg)
11 % Midazolamlever responding Midazolam Flunitrazepam 3 Rate (resp/sec) 2 1 V Dose (mg/kg)
12 % Midazolamlever responding Midazolam Flunitrazepam Pregnanolone 3 Rate (resp/sec) 2 1 V Dose (mg/kg)
13 % Midazolamlever responding Midazolam Flunitrazepam Pregnanolone Pentobarbital 3 Rate (resp/sec) 2 1 V Dose (mg/kg)
14 % Midazolamlever responding Midazolam Flunitrazepam Pregnanolone Pentobarbital Ketamine Rate (resp/sec) V Dose (mg/kg) V.1 1.
15 Neuroactive steroids /Flumazenil
16 Flumazenil dose (mg/kg):.1 % Midazolamlever responding Flu.1 1 Dose (mg/kg) Midazolam
17 % Midazolamlever responding Flumazenil dose (mg/kg): Flu.1 1 Dose (mg/kg) Midazolam
18 Neuroactive steroids /Flumazenil
19 % Midazolamlever responding Flumazenil dose (mg/kg): Flu.1 1 Dose (mg/kg) Midazolam
20 Flumazenil dose (mg/kg): % Midazolam lever responding Flu.1 1 Midazolam Flu 1 1 Pregnanolone Dose (mg/kg)
21 Chronic treatment Tolerance Cross tolerance Dependence Withdrawal
22 % Midazolamlever responding Midazolam +32 mg/kg Chlordiazepoxide V.1 1 Dose (mg/kg)
23 % Midazolam lever responding Midazolam +32 mg/kg Chlordiazepoxide V mg/kg Chlordiazepoxide Pregnanolone V 1 1 Dose (mg/kg)
24 Neuroactive steroids /Flumazenil
25 Midazolam % Midazolamlever responding Flunitrazepam S Dose (mg/kg)
26 % Midaz lever resp ED 5 Flumazenil Dose (mg/kg) Midazolam/Flunitrazepam
27 % Midazolamlever responding Flumazenil Dose (mg/kg) Midazolam+Flunitrazepam
28 % Midazolamlever responding Flumazenil dose (mg/kg): Flumazenil Dose (mg/kg) Midazolam+Flunitrazepam
29 Flumazenil dose (mg/kg): % Midazolam lever responding Flumazenil Midazolam+Flunitrazepam Flumazenil Midazolam+Pregnanolone Dose (mg/kg)
30 Flumazenil dose (mg/kg): % Midazolam lever responding Flumazenil Midazolam+Flunitrazepam Flumazenil Midazolam+Pregnanolone Dose (mg/kg)
31 Benzodiazepines and neuroactive steroids Similar acute effects Differential effects during chronic treatment Combinations might provide clinical benefit
32 Differences between benzodiazepines and neuroactive steroids Distinct modulatory sites Modulatory sites located on different populations of GABA A receptors Direct activation of GABA A receptors Uncoupling of modulatory sites
33 Acknowledgements Behavioral Pharmacology Group Charles France Rick Lamb Wouter Koek Brett Ginsburg Lance McMahon Jun Xu Li Victoria Hill Toni Andrews Navya Kondapalli Armando Hernandez Brandi Blaylock Blake Harrington Victoria Le These studies were supported by NIDA (DA9157).
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