Abstract
Benzodiazepines and neuroactive steroids are positive c-aminobutyric acidA (GABAA) modulators acting at distinct binding sites; during benzodiazepine treatment, tolerance develops to many behavioral effects of benzodiazepines, although cross tolerance typically does not develop to neuroactive steroids. To determine whether differential changes in binding sites contribute to these behavioral differences, interactions between GABAA modulators were studied in two groups of four monkeys: one otherwise untreated group discriminated 0.178 mg/kg of the benzodiazepine midazolam; the other received 5.6 mg/kg/ day of diazepam and discriminated 0.1 mg/kg of flumazenil, which binds to benzodiazepine sites without modulating GABAA receptors. In untreated monkeys, flumazenil antagonized midazolam but not the neuroactive steroid pregnanolone, whereas pentylenetetrazole (a negative modulator acting at a third site) antagonized both positive modulators. In diazepamtreated monkeys, 0.1 mg/kg of flumazenil or 32 mg/kg of pentylenetetrazole produced flumazenil-lever responding, which was reversed by midazolam and pregnanolone. As the flumazenil dose increased, larger doses of midazolam, but not pregnanolone, were needed to reverse flumazenillever responding. When the pentylenetetrazole dose increased, larger doses of both positive modulators were needed. Thus, interactions between GABA A modulators were not different between diazepam-treated and untreated monkeys and do not reveal changes in binding sites that could account for reported differences between benzodiazepines and neuroactive steroids.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 49-57 |
| Number of pages | 9 |
| Journal | Behavioural Pharmacology |
| Volume | 22 |
| Issue number | 1 |
| DOIs | |
| State | Published - Feb 2011 |
Fingerprint
Keywords
- γ-aminobutyric acid modulators
- Diazepam
- Drug discrimination
- Flumazenil
- Monkey
- Neuroactive steroids
- Pentylenetetrazole
- Pregnanolone
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health
Cite this
Chronic benzodiazepine treatment does not alter interactions between positive GABA A modulators and flumazenil or pentylenetetrazole in monkeys. / Gerak, Lisa R; France, Charles P.
In: Behavioural Pharmacology, Vol. 22, No. 1, 02.2011, p. 49-57.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chronic benzodiazepine treatment does not alter interactions between positive GABA A modulators and flumazenil or pentylenetetrazole in monkeys
AU - Gerak, Lisa R
AU - France, Charles P
PY - 2011/2
Y1 - 2011/2
N2 - Benzodiazepines and neuroactive steroids are positive c-aminobutyric acidA (GABAA) modulators acting at distinct binding sites; during benzodiazepine treatment, tolerance develops to many behavioral effects of benzodiazepines, although cross tolerance typically does not develop to neuroactive steroids. To determine whether differential changes in binding sites contribute to these behavioral differences, interactions between GABAA modulators were studied in two groups of four monkeys: one otherwise untreated group discriminated 0.178 mg/kg of the benzodiazepine midazolam; the other received 5.6 mg/kg/ day of diazepam and discriminated 0.1 mg/kg of flumazenil, which binds to benzodiazepine sites without modulating GABAA receptors. In untreated monkeys, flumazenil antagonized midazolam but not the neuroactive steroid pregnanolone, whereas pentylenetetrazole (a negative modulator acting at a third site) antagonized both positive modulators. In diazepamtreated monkeys, 0.1 mg/kg of flumazenil or 32 mg/kg of pentylenetetrazole produced flumazenil-lever responding, which was reversed by midazolam and pregnanolone. As the flumazenil dose increased, larger doses of midazolam, but not pregnanolone, were needed to reverse flumazenillever responding. When the pentylenetetrazole dose increased, larger doses of both positive modulators were needed. Thus, interactions between GABA A modulators were not different between diazepam-treated and untreated monkeys and do not reveal changes in binding sites that could account for reported differences between benzodiazepines and neuroactive steroids.
AB - Benzodiazepines and neuroactive steroids are positive c-aminobutyric acidA (GABAA) modulators acting at distinct binding sites; during benzodiazepine treatment, tolerance develops to many behavioral effects of benzodiazepines, although cross tolerance typically does not develop to neuroactive steroids. To determine whether differential changes in binding sites contribute to these behavioral differences, interactions between GABAA modulators were studied in two groups of four monkeys: one otherwise untreated group discriminated 0.178 mg/kg of the benzodiazepine midazolam; the other received 5.6 mg/kg/ day of diazepam and discriminated 0.1 mg/kg of flumazenil, which binds to benzodiazepine sites without modulating GABAA receptors. In untreated monkeys, flumazenil antagonized midazolam but not the neuroactive steroid pregnanolone, whereas pentylenetetrazole (a negative modulator acting at a third site) antagonized both positive modulators. In diazepamtreated monkeys, 0.1 mg/kg of flumazenil or 32 mg/kg of pentylenetetrazole produced flumazenil-lever responding, which was reversed by midazolam and pregnanolone. As the flumazenil dose increased, larger doses of midazolam, but not pregnanolone, were needed to reverse flumazenillever responding. When the pentylenetetrazole dose increased, larger doses of both positive modulators were needed. Thus, interactions between GABA A modulators were not different between diazepam-treated and untreated monkeys and do not reveal changes in binding sites that could account for reported differences between benzodiazepines and neuroactive steroids.
KW - γ-aminobutyric acid modulators
KW - Diazepam
KW - Drug discrimination
KW - Flumazenil
KW - Monkey
KW - Neuroactive steroids
KW - Pentylenetetrazole
KW - Pregnanolone
UR - http://www.scopus.com/inward/record.url?scp=78651388564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78651388564&partnerID=8YFLogxK
U2 - 10.1097/FBP.0b013e3283425aa0
DO - 10.1097/FBP.0b013e3283425aa0
M3 - Article
VL - 22
SP - 49
EP - 57
JO - Behavioural Pharmacology
JF - Behavioural Pharmacology
SN - 0955-8810
IS - 1
ER -