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CHRONIC BENZODIAZEPINE TREATMENT INCREASES THE EFFECTS OF THE INVERSE AGONIST FG7142

MSCs: Angelo Bruschi, MD

[H.J.LITTLE, R.GALE,N.SELLARS, D.J.NUTT, S.C.TAYLOR. Neuropsychopharmacology 27(4): 383-389 (1988)]

WEDNESDAY FEBRUARY 2012

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Benzodiazepines act by binding to specific receptor sites through which they potentiate GABA transmission.

INTRODUCTION (I)

Consistent changes in the binding to BZDs receptors after chronic treatment have not been found.

BDZs are know clinically to cause abstinence signs on withdrawal, including excess anxiety.

(Haefely, Pieri, Pole and Schaffner, 1981)

(Petursson and Lader, 1984)

(Mohler, Okada and Enna,1978; Sharf and Feil, 1983)

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There are compounds that act through BDZs with an opposite effect: INVERSE AGONIST

These INVERSE AGONIST decrease the effects of GABA and are been blocked(as well as AGONIST) by an ANTAGONIST

INVERSE AGONIST (II)

(File, Lister and Nutt, 1982)

AGONIST

PARTIALFULL

INVERSE AGONIST

PARTIAL FULL

ANTAGONIST

ANTICONVULSIVE

SEDATIVE

ANXIOLYTIC

NEUTRAL

ANXIOGENIC PROCONVULSIVE

STIMULATORY

(Nutt, Cowen and Green, 1980)

(Adapted from: Nutt & Malizia, 2001)

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FG-7142 (ZK-31906) is a drug which acts as a PARTIAL INVERSE AGONIST of the benzodiazepine receptor. It lowers convulsion threshold (pro-convulsant) and has anorectic and anxiogenic effects in human studies. It also lowers body temperature and improves memory retention in animal studies.

It does not cause full convulsions when given alone.

FG-7142 (III)

FG-7142 - (CID 4375)Also known as: N-Methyl-beta-carboline-3-carboxamide, ZK-39106

(Taylor et al. , 1985; File et al.,1985; Dorow et al.,1983)

(Little, Nutt & Taylor, 1984)

(Little et al., 1984)

Chronic treatment with FG7142 decreases GABA receptor function. (This resemble chemical kindling in that the change appears to last for the lifetime of the animal.)

When FG-7142 is given chronically occurs an increase in his convulsive action.

(Little, Nutt & Taylor, 1986)

+STUDY DESIGN (IV)

MAIN QUESTION IS:

Which is the effect of INVERSE AGONIST after a chronic treatment with BDZ AGONIST ?

Male CDI mice30-35 g, groups of 8-10

MATERIALS and METHODS:

Intraperitoneal FG-7142

Intraperitoneal FLURAZEPAM

Intraperitoneal FLUMAZENIL

Intraper. and drinkable MIDAZOLAM

Intravenous PTZ (Convulsant)

FLURAZEPAM was given once a day, 40mg kg-1 for 7 days

FLUMAZENIL (Ro 15-1788) was given in two doses of 20 mg kg-1 before and after flurazepam (Used to exclude an action of flurazepam at BDZ receptors)

MIDAZOLAM was administered with several schedules because of its short duration of action

(Not linked to any excitatory effects even at large doses) FG-7142 was given, at different doses, 24hr

after the last administration of AGONIST

PTZ (Pentylenetretazol) was used to test the threshold for convulsions (threshold = amount injected)

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Full convulsions were seen with FG-7142, over a rage of doses, after repeated administration of Flurazepam. This effects continued for almost a week after the cessation of the treatment.

RESULTS(V)

EFFECTS OF FG-7142 AFTER FLURAZEPAM

The effects followed a U-shaped dose-response curve, with a maximal effect at 40 mg kg-1

EFFECTS OF FLUMAZENIL (Ro 15-1788)

When Flumazenil was given with the treatment with Flurazepam, the incidence of convulsions with FG-7142 was decreased, but the difference was not significant (p<0.07). Instead, it antagonised the hypothermic effect of the first dose of Flurazepam. (Dose bias?)

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After every schedule of treatment FG7142 caused convulsions but it reached significance only when midazolam was given in the drinking water for 3 weeks followed by an intraperitoneal injection. (p<0.05)

RESULTS(VI)

EFFECTS OF FG-7142 AFTER MIDAZOLAM

EFFECTS OF FG-7142 AFTER A SINGLE DOSE OF BDZ

The most effective dose of FG-7142 (40 mg kg-1) was tested 24hr after on injection of each BDZ. The incidence was not significantly different from controls (p>0.05).

p<0.05

+RESULTS(VII)

DEVELOPMENT OF TOLERANCE TO THE BDZ

At 24 hr. after the last injection of Flurazepam, partial tolerance was found to its anticonvulsant action. At 48 hr. after the last dose of Flurazepam the tolerance had disappeared.

Significant tolerance (to the hypodermic action) was seen only after Midazolam was administered in the drinking water for 3 weeks.

p<0.05

p<0.01

+DISCUSSIONS (VIII)

Repeated administration of BDZs (Flurazepam and Midazolam) caused a prolonged increase in the convulsant effect of the partial inverse agonist FG-7142. (Well known as not full convulsant alone)

The duration of the convulsant effect of FG-7142 was longer than that of the tolerance to the anticonvulsant effect of Flurazepam (6 days vs. 48 hr.).

It was excluded that the excitatory actions of Flurazepam could result in a type of “kindling”, because the convulsions occur even with Midazolam, which does not possess such actions.

+CONCLUSIONS (IX)

A. PRECIPITATION OF WITHDRAWAL(Can only occur if BDZ agonist remain in the brain)

THE CONVULSIONS SEEN WITH FG-7142 COULD HAVE BEEN DUE TO:

FLURAZEPAM LASTS LESS THAN 24 HR.

EXCLUDE

DB. ALTERATIONS IN INTRINSIC ACTIVITYTHE RIGHT ANSWER

CONCLUSIONS:

Repeated administration of BDZ AGONIST in mice produced not only tolerance to the effect of the AGONIST but an increase in the effect of INVERSE AGONIST.

+THANKS FOR THE ATTENTION