Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention: differential antagonism by flumazenil and beta-CCt.
BACKGROUND
The pharmacological approach, using subtype selective ligands, complements genetic studies on the specific contribution of individual receptor subtypes to the various effects of benzodiazepines.


OBJECTIVE
The aim of this study was to examine the relative significance of alpha1-containing GABA(A) receptors in the effects of modulators at the benzodiazepine site on anxiety and memory processes.


METHODS
We tested the effects of the nonselective antagonist flumazenil, the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt), the nonselective agonist midazolam, the preferential alpha1-subunit selective agonist zolpidem, and the nonselective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in a two-way active avoidance task in rats. The influence of flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg) on the effects of the two agonists were also examined. In the schedule 2 x 30 trials, drugs were administered i.p. 20 min before the training session. Avoidance responses in the training session are an anxiety-mediated behavior, whereas performance in the retention session relates to the effects on memory.


RESULTS
Flumazenil and beta-CCt did not affect behavior. Midazolam (2.0 mg/kg) facilitated acquisition performance, while DMCM (1.0 and 2.0 mg/kg) induced the opposite effect. Flumazenil antagonized both effects. Beta-CCt potentiated the effect of midazolam, and partly antagonized the effect of DMCM. Midazolam (0.5 and 1.0 mg/kg) and zolpidem (1.0-3.0 mg/kg) impaired, while DMCM (0.1 mg/kg) facilitated the subjects' performance in the retention test. The amnesic effects were attenuated but not fully reversed, while the effect of DMCM was counteracted by both antagonists.


CONCLUSIONS
The results indicate the alpha1-subunit interferes with the anxiolytic effect of a benzodiazepine site agonist and may contribute to the DMCM-induced anxiogenic effect. It is also substantially involved in the bidirectional memory processing in the active avoidance paradigm.
Savić
Miroslav M
MM
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Serbia and Montenegro. miroslav@pharmacy.bg.ac.yu
Obradović
Dragan I
DI
Ugresić
Nenad D
ND
Cook
James M
JM
Sarma
P V V S
PV
Bokonjić
Dubravko R
DR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001665:Binding Sites; D002243:Carbolines / Q000008:administration & dosage / Q000494:pharmacology*; D003292:Convulsants / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology*; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000502:physiology; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology; D012153:Retention, Psychology / Q000187:drug effects* / Q000502:physiology; D000077334:Zolpidem
D014151:Anti-Anxiety Agents; D002243:Carbolines; D003292:Convulsants; D018755:GABA Agonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D008024:Ligands; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005442:Flumazenil; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate; D008874:Midazolam
Neurosci Biobehav Rev. 1998 Sep;22(5):623-33
9662724
Neurobiol Learn Mem. 1997 Jan;67(1):1-13
9013495
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8980-5
12084936
Behav Neurosci. 1989 Feb;103(1):202-5
2923673
Neurosci Biobehav Rev. 1986 Fall;10(3):265-72
2877426
FASEB J. 1988 Aug;2(11):2707-11
3135223
Mol Pharmacol. 1993 Aug;44(2):437-42
8102787
Behav Pharmacol. 2000 Nov;11(7-8):517-34
11198125
J Pharmacol Exp Ther. 2002 Jan;300(1):2-8
11752090
Pharmacol Rev. 1998 Jun;50(2):291-313
9647870
Pharmacol Biochem Behav. 1990 Feb;35(2):281-4
2108447
Eur Neuropsychopharmacol. 1999 Jan;9(1-2):45-50
10082227
Neuropharmacology. 1991 Dec;30(12A):1263-7
1787880
Behav Brain Res. 1988 Sep 1;30(1):31-6
2844205
Brain Res Bull. 1987 Sep;19(3):365-70
3676859
Brain Res Bull. 1987 Sep;19(3):359-64
3676858
Brain Res Brain Res Rev. 2003 Mar;41(2-3):268-87
12663083
Eur J Pharmacol. 1990 Oct 23;187(3):487-94
1981555
Psychopharmacology (Berl). 1986;88(1):1-11
3003778
J Med Chem. 2000 Apr 20;43(8):1427-47
10780899
Pharmacol Res. 1991 Oct;24(3):273-82
1956872
Trends Pharmacol Sci. 1991 Jul;12(7):260-5
1658996
Psychopharmacology (Berl). 2000 Apr;149(2):176-80
10805613
Psychopharmacology (Berl). 1988;94(3):402-4
3128818
Science. 2000 Oct 6;290(5489):131-4
11021797
J Psychopharmacol. 1998;12 (4):356-65
10065909
Life Sci. 1984 Oct 1;35(14):1445-51
6434890
Psychopharmacology (Berl). 1991;103(4):519-23
1676530
Mol Pharmacol. 1991 Jun;39(6):691-6
1646944
Nature. 1999 Oct 21;401(6755):796-800
10548105
Pharmacol Biochem Behav. 2001 Feb;68(2):235-44
11267628
Neurobiol Learn Mem. 1999 Sep;72(2):78-94
10438649
J Pharmacol Exp Ther. 1997 Jul;282(1):420-9
9223583
Pharmacol Res. 1993 Jul-Aug;28(1):53-8
8234145
Prog Neurobiol. 2003 Jun;70(2):83-244
12927745
Psychopharmacology (Berl). 1999 Sep;146(2):205-13
10525757
Neurosci Biobehav Rev. 1983 Summer;7(2):119-88
6348604
Psychol Rev. 1992 Apr;99(2):195-231
1594723
Behav Pharmacol. 2000 Apr;11(2):125-31
10877117
Mol Pharmacol. 2001 Mar;59(3):442-5
11179437
Br J Pharmacol. 1985 Oct;86(2):357-66
3931731
Brain Res Bull. 1991 Jan;26(1):173-6
1673080
Brain Res. 1991 May 10;548(1-2):74-80
1651148
Life Sci. 1984 Nov 26;35(22):2227-36
6094935
J Psychopharmacol. 1990 Jan;4(1):29-34
22282924
Psychopharmacology (Berl). 1992;107(2-3):347-51
1352055
Psychopharmacology (Berl). 1986;90(2):207-10
2878460
Behav Neural Biol. 1990 Jul;54(1):27-41
1974134
Physiol Behav. 1995 Jul;58(1):111-8
7667407
Psychopharmacology (Berl). 1997 Jun;131(4):354-60
9226737
Behav Pharmacol. 1996 Nov;7(6):560-572
11224453
Curr Top Med Chem. 2002 Aug;2(8):841-51
12171575
Behav Res Ther. 1990;28(6):455-68
2076083
J Psychopharmacol. 1995 Jan;9(2):103-11
22298735
Pharmacol Biochem Behav. 2004 Oct;79(2):279-90
15501303
Eur J Pharmacol. 1983 Mar 18;88(1):111-6
6406240
Trends Pharmacol Sci. 2000 Jun;21(6):208-10
10838606
Neurobiol Learn Mem. 1997 Nov;68(3):285-316
9398590
J Pharmacol Exp Ther. 1986 May;237(2):649-58
2871178
Br J Anaesth. 1990 Aug;65(2):190-6
2223335
Behav Neural Biol. 1992 Jul;58(1):16-26
1358054
Pharmacol Biochem Behav. 1988 Nov;31(3):541-6
3251238
Neuroscience. 2000;101(4):815-50
11113332
J Physiol Pharmacol. 1997 Jun;48(2):253-61
9223029
Neuropharmacology. 1996;35(8):1081-91
9121611
Pharmacol Biochem Behav. 1997 Dec;58(4):887-91
9408191
Psychopharmacology (Berl). 1996 Apr;124(3):245-54
8740046
Neurobiol Learn Mem. 1996 Nov;66(3):341-52
8946426
Psychopharmacology (Berl). 1986;89(3):317-22
2873608
J Pharmacol Exp Ther. 1990 Nov;255(2):789-94
2173758
J Neurosci. 1996 Jan;16(1):283-97
8613794
Annu Rev Neurosci. 2004;27:1-28
15217324
Neuropharmacology. 2002 Sep;43(4):685-94
12367614
Psychopharmacology (Berl). 1987;93(4):507-14
2893417
Psychopharmacology (Berl). 1991;105(1):1-8
1684055
Trends Pharmacol Sci. 2001 Aug;22(8):402-3
11515499
J Pharmacol Exp Ther. 1995 Nov;275(2):761-7
7473164
Psychopharmacology (Berl). 1989;97(2):222-7
2498931
Psychopharmacology (Berl). 1993;112(4):455-60
7871057
Anesthesiology. 1989 Jun;70(6):899-904
2499223
Prog Neurobiol. 2002 Jun;67(2):113-59
12126658
J Neurosci. 2002 Jul 1;22(13):5572-80
12097508
Behav Neural Biol. 1992 May;57(3):233-43
1319705
Neurosci Biobehav Rev. 1994 Fall;18(3):355-72
7984354
Life Sci. 1991;48(7):685-92
1846660
Nature. 1986 Jun 26-Jul 2;321(6073):864-6
3724846
Funct Neurol. 1992 Sep-Oct;7(5):401-5
1338052
Alcohol. 2004 Feb;32(2):101-11
15163561
Nat Neurosci. 2000 Jun;3(6):587-92
10816315
J Neural Transm (Vienna). 1997;104(6-7):733-46
9444572