- Email: [email protected]
Effect of valproic acid on anxiety-related behaviors in the rat
Bruin Rescwrc~h Bulktin.
Vol. 5, Suppl.
2, pp. 575-577.
Printed
in the U.S.A
Effect of Valproic Acid on Anxiety-Related Behaviors in the Rat HARBANS
Department
of Pharmacology
LAL AND GARY T. SHEARMAN
and Toxicology,
University of Rhode Island, Kingston,
RI 02881
AND STUART
FIELDING,
ROBERT
Hoechst-Roussel
DUNN,
HANSJOERG
Pharmaceuticals,
KRUSE AND KARIN
Inc., Somerville,
THEURER
NJ 08876
LAL, H., G. T. SHEARMAN,
S. FIELDING, R. DUNN, H. KRUSE AND K. THEURER. Effecr of’valproic acid on rat. BRAIN RES. BULL. 5: Suppl. 2, 575-577, 1980.-Valproic acid was tested for anxiolytic activity in two behavioral tests most often used to predict anxiolytic activity in man. In one test, male hooded rats were trained to discriminate the anxiomimetic action of pentylenetetrazol by responding on one of two levers for food reinforcement after pentylenetetrazol injection and on the other lever after saline injection. Pretreatment of these rats with valproic acid (320 mgikg) antagonized the discriminative stimulus produced by pentylenetetrazol. In the other test, male Wistar rats were trained to respond for milk reinforcement in a conflict procedure where some of the reinforced responses resulted in the simultaneous delivery of footshock. Treatment of these rats with valproic acid (320 mgikg) antagonized the suppression of responding induced by the footshock. In both tests, valproic acid showed anxiolytic activity comparable to diazepam. These data suggest that valproic acid may be useful in treating clinical anxiety.
ctnxirty-related
Valproic acid
behaviors
in fk
Diazepam
Anxiety
Drug discrimination
VALPROIC acid was serendipitously discovered as an anticonvulsant drug when it was observed that it protected mice and rabbits from pentylenetetrazol-induced seizures [5]. This finding eventually led to the use of valproic acid in the treatment of epilepsy. Based upon previous findings that anxiolytic drugs protect animals against pentylenetetrazolinduced convulsions [4], we undertook to determine if valproic acid would possess anxiolytic properties. For this purpose we examined the effect of valproic acid in two wellestablished animal tests which detect anxiolytic activity. We now report that valproic acid produces anxiolytic actions and, in this respect, resembles the actions of a known anxiolytic, diazepam.
METHOD
Pentylenetetrazol
Disc~riminution Procedure
Animuls. Male hooded rats of the Long-Evans strain (Charles River Breeding Laboratories, Wilmington, MA) weighing 250-300 g at the beginning of the investigation were used. Animals were housed in single cages in a large colony room thermostatically maintained at 21 2 1°C. Room lights were turned off from 8:00 p.m. to 8:00 a.m. Water was continuously available in the home cages but food was restricted to 20 g a day made available approximately 4 hr following each operant session. Apparatus. The behavioral apparatus consisted of con-
Copyright
‘I 1980 ANKHO
International
Pentylenetetrazol
Conflict behavior
ventional Skinner boxes housed in lightproof, soundattenuated and fan-ventilated chambers. Each Skinner box contained two levers, one on either side of a food cup which was centrally installed equidistant from each lever. Scheduling of contingencies and recording of data was made by a combination of electromechanical and solid-state programming equipment. Discrimination training. The rats were first magazine trained and shaped to lever press for food reinforcement (for detailed procedure see [3]). The subjects were then trained to press one of the levers 15 min following a 20 mg/kg pentylenetetrazol injection and the other lever 15 min following a 1 ml/kg saline injection. Every tenth press (FR 10) on the appropriate lever resulted in the delivery of a 45 mg Noyes food pellet. Responses on the incorrect lever were recorded but did not result in the delivery of food. A possible effect of lever preference was counter balanced by randomly assigning the lever on the right side of the food cup to be the pentylenetetrazol lever for half of the rats and the lever on the left side to be the pentylenetetrazol lever for the remainder of the animals. To avoid the possibility that olfactory cues associated with the correct lever for rats previously tested in the chambers could serve as a cue [l 1], the sequence of pentylenetetrazol-saline injections was irregularly alternated for each group of rats. Training trials were carried out 7 days a week according to an irregularly alternating sequence of injection treatments. For each trial, responses emitted on each lever prior to the first reinforcement were
Inc.-0361-9230/80/080575-03$00.80/O
recorded, as were the total responses emitted on each lever during the entire 10 min session. A~tcrgo~isnr fe.~fi~~. When the animals attained a stable response rate and made not more than four responses on the incorrect lever (i.e., saline lever following pentylenetetrazol injection) prior to the first reinforcement (10 responses on the correct lever) on nine out of ten consecutive trials, antagonism testing was begun. Antagonism tests consisted of 10 min trial sessions separated by at least five practice sessions in which sabne and pentylenetetrazoi were correctly discriminated. Test sessions were always followed by a practice session in which saline was injected. If the rats’ performances on these practice sessions seemed to deteriorate with respect to the number of responses on the incorrect lever prior to the first reinforcement further training sessions were given before testing was reinstated. Animals were injected with the appropriate dose of the test drug or saline to be followed 30 min later by pentylenetetrazol(20 m&kg). Fifteen min after the pentylenetetrazol injection the animals were placed in their assigned Skinner boxes and allowed to respond on the lever of their choice until 10 non-reinforced responses were compieted on one of the levers. The lever on which ten responses were completed first was considered the selected lever and was subsequently fixed to be reinforced (FR 10) for the remainder of the session. Responses emitted on the other lever were recorded but not reinforced.
Ani~?als. The conflict paradigm was as described by Geller and Seifter (21. Male Wistar rats were used. They were housed individualIy and food and water was available ad lib until the animals weighed 300 to 400 g prior to the start of training. Subsequently the rats were food deprived until their body weight was reduced to approximately 80% of original. Body weight was maintained at this level by continuous food restriction. Apparcrtus. The programming and test equipment consisted of Coulboum Instrument solid-state devices, shockers and cages within sound-attenuated environmental enclosures. The data were recorded on both Coulboum Instruments’ solid state print-out counters and (Gerbrand) cumulative recorders. The cages were equipped with a houselight, a single lever, que lights, a liquid dipper, a speaker and a grid floor connected to a shocker. Sweetened condensed milk delivered by the liquid dipper served as the positive reinforcement for all subjects. Conflict training and testing. The animals were trained to lever press for the milk reward in two distinct responsereward segments. In the “anxiety” or “conflict” segment, signalled by onset of both tone and que Lights, a dipper of milk was delivered in response to each lever press (CRF schedule of rei~orcement). Lever presses during this period were also accompanied by a 40 msec pulse of aversive footshock through the grid floor. This created a “conflict” between (1) easy access to milk reward and (2) the simultaneous presentation of a painful footshock. This “conflict” period was 3 min in duration. During the other segment of this paradigm, the lever presses produced a dipper of milk only at variable intervals of time from 60 to 210 set with an average reward of once per 2 min (VI-2 min). No shocks were ever administered during this VI phase of testing which was I5 min in duration. The test procedure consisted of four 15min (non-shock)
VI segments where reinforcement was available on a limited basis. Each VI period was followed by a 3-min “CRFconflict segment when reinforcement was constantly available but always accompanied by an aversive footshock. The shock-level was titrated for each subject to reduce the CRF responding to a total of less than 10 lever presses during the entire test. The rats were tested four days a week. Test drugs were administered on the third day and the performance of the animals was compared to the previous day’s control. The VI responses were used to evaluate any general debilitating drug effects while the CRF responses were used to evaluate any “antianxiety” effect as indicated by increased responding during the “CRF-conflict” period. Du4g.s. Diazepam and valproic acid were generously supplied by Hoffman-LaRoche Inc., Nutley, NJ and Abbott Laboratories, North Chicago, IL, respectively. Diazepam was homogenized in 0.9% saline containing 13% propylene glycol and 1% Tween 80. Valproic acid was dissolved in saline. Drugs were administered intraperitonealiy 45 min before testing for discrimination and 30 min prior to testing in the conflict study. RESU LT.5
All of the rats learned to discriminate pentylenetetrazol from saline to the required criterion. Pretreatment of the animals with diazepam (5 mg/kg) or valproic acid (320 mgikg) significantly antagonized the discriminative stimulus produced by pentylenetetrazol (Table 1). Whereas all of the rats selected the pentylenetetrazoi lever when the pentylenetetrazoi injection was preceded by saline, only 33% of the rats selected the pentylenetetr~oi lever when the pentylenetetr~ol injection was preceded by injection of diazepam or valproic acid. Data summarized in Table 2 show the effect of valproic acid (320 mgikg) and diazepam (4 mg/kg) on conflict behavior in the rat. Both drugs caused a significant increase in the rate of responding suppressed by footshock in the conflict situation. Whereas the aversive footshock resulted in suppressed response rates in all of the rats pretreated with drug vehicle, the shock-induced response suppression was markedly attenuated in the rats pretreated with valproic acid or diazepam. Whereas valproic acid signi~cant~y suppressed non-conflict responding at the 320 mg/kg dose, diazepam at a dose equieffective to valproic acid in increasing conflict responding did not suppress nonconflict responding. DISCUSSION
Valproic acid is well known for its antiepileptic efftcacy (for review see [6,10]. We now report that this drug may also be useful in treating anxiety-related psychiatric disorders. In the present study, valproic acid compared well with diazepam in antagonizing the discriminative stimulus produced by pentylenetet~zol, a property previously reported to be associated with drugs possessing anxiolytic activity [7-91. Similarly, valproic acid increased responding previously suppressed by punishment. This property has also been previously shown to indicate antianxiety activity (for review see [4]. The neurochemical mechanism through which valproic acid exerts its anxiolytic action cannot be delineated at present, Valproic acid has been reported to inhibit both the synthesis and catabolism of brain gamma-amino-butyric acid (GABA) as well as the catabolism of succinic semialdehyde via inhibition of GABA-T and SSADH respectively (for re-
VALPROIC
577
ACID AS AN ANXIOLYTIC TABLE
TABLE 2
1
ANTAGONISM TESTS WITH VALPROIC ACID AND DIAZEPAM RATS TRAINED TO DISCRIMINATE BETWEEN PENTYLENETETRAZOL (20 mgikg) AND SALINE*
Dose Test drug
(mg/kg)
IN
EFFECT OF VALPROIC ACID AND DIAZEPAM BEHAVIOR IN THE RAT
% Change in responding$
5%Selecting drug lever+ Test drug*
Saline Valproic acid Diazepam
320 5
IO0 33; 33+
*30 min following pretreatment with the test drug, the rats were injected with pentylenetetrazol (20 mgikg). 1.5min following the pentylenetetrazol injection, animals were placed in their assigned Skinner boxes and allowed to make a lever selection. The lever with which ten responses were completed first was considered the selected lever. +Percent of rats selecting the pentylenetetrazol lever, out of a total six rats tested for each treatment. 3~<0.05 versus saline treatment; Chi” 2 x R analysis &= 1, x2=6.0.
view see [I]). These actions usually result in the net elevation of brain GABA levels. We found that elevation of brain GABA levels with the GABA-T inhibitors, gammaacetylenic GABA and gamma-vinyl GABA, failed to antagonize the pentylenetetrazol discriminative stimulus [S].
I. Dren, A. T., W. J. Giardina and N. S. Hagen. Valproic acid. In: P1~~irmrrt~nlr~~icrrf crnd BiochcmiaI Properties of Drug SubS(LIR~~S,edited by M. E. Goldberg. Washington, DC: American Pharmaceutical Association of Pharmaceutical Sciences, 1978, pp. s-97. 7. Geller, I. and J. Seifter. The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentallyinduced conflict in the rat. Pspc.hupharmac,oloRicl 1: 482-492, 1960. 3. Lal, H., G. Gianutsos and S. Miksic. Discriminable stimuli produced by narcotic analgesics. In: Djscrimjn~ti~~e Stimulus Pr(~p~~rtje.~ o_f’Drugs, edited by H. Lal. New York: Plenum Press, 1977, pp. 23-47. 4.
Lippa, A. S., P. A. Nash and E. N. Greenblatt. Preciinical
neuropsychopharmacological procedures for anxiolytic drugs. In: Thr Anxio@cs, edited by S. Fielding and H. Lal. New York: Futura Publishing Co., 1979, pp. 41-81. 5. Meunier, H., G. Carraz, Y. Meunier, P. Eymard and M. Aimard. Propertes pharmacodynamiques de I’acide n-dipropylacetique. Therapie 18: 435-438, 1963.
ON CONFLICT
Valproic acid Diazepam
Dose (mdkg)
N*
Non-convict
Conflict
320 4
7 II
-615 -22
+4489 +4868
*30 min following injection of the test drug, the rats were placed in their assigned Skinner boxes and allowed to respond for milk reinforcement. +Number of rats tested. $% decrease (-) or increase (+) from vehicle treatment. $p
While other anxiolytic drugs compete zodiazepine receptors, valproic acid vitro only at very high concentrations. the brain distribution of valproic acid centrated at brain sites where anxiety anism is also not tenable.
for binding with benshows this activity in Unless it is found that is such that it is conoriginates, this mech-
6. Pinder, R. M., R. N. Brogden, T. M. Speight and G. S. Avery. Sodium vafproate: A review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 13: 81-123, 1977. 7. Shearman, G. and H. Lal. Discriminative stimulus properties of pentylenetetrazol and bemegride: Some generalization and antagonism tests. PsychopharmacoloRv 64: 3 15-3 19, 1979. 8. Shearman, G. and H. Lal. Discriminative stimulus (DS) properties of picrotoxin, bemegride and pentylenetetrazol (PTZ): A possible relationship between an anxiogenic action and PTZDS. Fed. Prot. 38: 256, 1979. 9. Shearman, G. and H. Lal. Use of pentyjenetetr~ol (FTZ) as a disc~minative stimulus (DS) for the prediction of anxiolytic activity. P~zarrn~~c~~~~~~ist21: 267, 1979. 10. Simon, D. and J. K. Perry. Sodium di-n-propylacetate (DPA) in the treatment of epilepsy: A review. Epilrpsia 16: 549-573, 1975. 11. Weissman, A. The discriminability of aspirin in arthritic and non-arthritic rat. Pharmac. B&hem. Behav. 5: 583-F-586, 1976.
Vol. 5, Suppl.
2, pp. 575-577.
Printed
in the U.S.A
Effect of Valproic Acid on Anxiety-Related Behaviors in the Rat HARBANS
Department
of Pharmacology
LAL AND GARY T. SHEARMAN
and Toxicology,
University of Rhode Island, Kingston,
RI 02881
AND STUART
FIELDING,
ROBERT
Hoechst-Roussel
DUNN,
HANSJOERG
Pharmaceuticals,
KRUSE AND KARIN
Inc., Somerville,
THEURER
NJ 08876
LAL, H., G. T. SHEARMAN,
S. FIELDING, R. DUNN, H. KRUSE AND K. THEURER. Effecr of’valproic acid on rat. BRAIN RES. BULL. 5: Suppl. 2, 575-577, 1980.-Valproic acid was tested for anxiolytic activity in two behavioral tests most often used to predict anxiolytic activity in man. In one test, male hooded rats were trained to discriminate the anxiomimetic action of pentylenetetrazol by responding on one of two levers for food reinforcement after pentylenetetrazol injection and on the other lever after saline injection. Pretreatment of these rats with valproic acid (320 mgikg) antagonized the discriminative stimulus produced by pentylenetetrazol. In the other test, male Wistar rats were trained to respond for milk reinforcement in a conflict procedure where some of the reinforced responses resulted in the simultaneous delivery of footshock. Treatment of these rats with valproic acid (320 mgikg) antagonized the suppression of responding induced by the footshock. In both tests, valproic acid showed anxiolytic activity comparable to diazepam. These data suggest that valproic acid may be useful in treating clinical anxiety.
ctnxirty-related
Valproic acid
behaviors
in fk
Diazepam
Anxiety
Drug discrimination
VALPROIC acid was serendipitously discovered as an anticonvulsant drug when it was observed that it protected mice and rabbits from pentylenetetrazol-induced seizures [5]. This finding eventually led to the use of valproic acid in the treatment of epilepsy. Based upon previous findings that anxiolytic drugs protect animals against pentylenetetrazolinduced convulsions [4], we undertook to determine if valproic acid would possess anxiolytic properties. For this purpose we examined the effect of valproic acid in two wellestablished animal tests which detect anxiolytic activity. We now report that valproic acid produces anxiolytic actions and, in this respect, resembles the actions of a known anxiolytic, diazepam.
METHOD
Pentylenetetrazol
Disc~riminution Procedure
Animuls. Male hooded rats of the Long-Evans strain (Charles River Breeding Laboratories, Wilmington, MA) weighing 250-300 g at the beginning of the investigation were used. Animals were housed in single cages in a large colony room thermostatically maintained at 21 2 1°C. Room lights were turned off from 8:00 p.m. to 8:00 a.m. Water was continuously available in the home cages but food was restricted to 20 g a day made available approximately 4 hr following each operant session. Apparatus. The behavioral apparatus consisted of con-
Copyright
‘I 1980 ANKHO
International
Pentylenetetrazol
Conflict behavior
ventional Skinner boxes housed in lightproof, soundattenuated and fan-ventilated chambers. Each Skinner box contained two levers, one on either side of a food cup which was centrally installed equidistant from each lever. Scheduling of contingencies and recording of data was made by a combination of electromechanical and solid-state programming equipment. Discrimination training. The rats were first magazine trained and shaped to lever press for food reinforcement (for detailed procedure see [3]). The subjects were then trained to press one of the levers 15 min following a 20 mg/kg pentylenetetrazol injection and the other lever 15 min following a 1 ml/kg saline injection. Every tenth press (FR 10) on the appropriate lever resulted in the delivery of a 45 mg Noyes food pellet. Responses on the incorrect lever were recorded but did not result in the delivery of food. A possible effect of lever preference was counter balanced by randomly assigning the lever on the right side of the food cup to be the pentylenetetrazol lever for half of the rats and the lever on the left side to be the pentylenetetrazol lever for the remainder of the animals. To avoid the possibility that olfactory cues associated with the correct lever for rats previously tested in the chambers could serve as a cue [l 1], the sequence of pentylenetetrazol-saline injections was irregularly alternated for each group of rats. Training trials were carried out 7 days a week according to an irregularly alternating sequence of injection treatments. For each trial, responses emitted on each lever prior to the first reinforcement were
Inc.-0361-9230/80/080575-03$00.80/O
recorded, as were the total responses emitted on each lever during the entire 10 min session. A~tcrgo~isnr fe.~fi~~. When the animals attained a stable response rate and made not more than four responses on the incorrect lever (i.e., saline lever following pentylenetetrazol injection) prior to the first reinforcement (10 responses on the correct lever) on nine out of ten consecutive trials, antagonism testing was begun. Antagonism tests consisted of 10 min trial sessions separated by at least five practice sessions in which sabne and pentylenetetrazoi were correctly discriminated. Test sessions were always followed by a practice session in which saline was injected. If the rats’ performances on these practice sessions seemed to deteriorate with respect to the number of responses on the incorrect lever prior to the first reinforcement further training sessions were given before testing was reinstated. Animals were injected with the appropriate dose of the test drug or saline to be followed 30 min later by pentylenetetrazol(20 m&kg). Fifteen min after the pentylenetetrazol injection the animals were placed in their assigned Skinner boxes and allowed to respond on the lever of their choice until 10 non-reinforced responses were compieted on one of the levers. The lever on which ten responses were completed first was considered the selected lever and was subsequently fixed to be reinforced (FR 10) for the remainder of the session. Responses emitted on the other lever were recorded but not reinforced.
Ani~?als. The conflict paradigm was as described by Geller and Seifter (21. Male Wistar rats were used. They were housed individualIy and food and water was available ad lib until the animals weighed 300 to 400 g prior to the start of training. Subsequently the rats were food deprived until their body weight was reduced to approximately 80% of original. Body weight was maintained at this level by continuous food restriction. Apparcrtus. The programming and test equipment consisted of Coulboum Instrument solid-state devices, shockers and cages within sound-attenuated environmental enclosures. The data were recorded on both Coulboum Instruments’ solid state print-out counters and (Gerbrand) cumulative recorders. The cages were equipped with a houselight, a single lever, que lights, a liquid dipper, a speaker and a grid floor connected to a shocker. Sweetened condensed milk delivered by the liquid dipper served as the positive reinforcement for all subjects. Conflict training and testing. The animals were trained to lever press for the milk reward in two distinct responsereward segments. In the “anxiety” or “conflict” segment, signalled by onset of both tone and que Lights, a dipper of milk was delivered in response to each lever press (CRF schedule of rei~orcement). Lever presses during this period were also accompanied by a 40 msec pulse of aversive footshock through the grid floor. This created a “conflict” between (1) easy access to milk reward and (2) the simultaneous presentation of a painful footshock. This “conflict” period was 3 min in duration. During the other segment of this paradigm, the lever presses produced a dipper of milk only at variable intervals of time from 60 to 210 set with an average reward of once per 2 min (VI-2 min). No shocks were ever administered during this VI phase of testing which was I5 min in duration. The test procedure consisted of four 15min (non-shock)
VI segments where reinforcement was available on a limited basis. Each VI period was followed by a 3-min “CRFconflict segment when reinforcement was constantly available but always accompanied by an aversive footshock. The shock-level was titrated for each subject to reduce the CRF responding to a total of less than 10 lever presses during the entire test. The rats were tested four days a week. Test drugs were administered on the third day and the performance of the animals was compared to the previous day’s control. The VI responses were used to evaluate any general debilitating drug effects while the CRF responses were used to evaluate any “antianxiety” effect as indicated by increased responding during the “CRF-conflict” period. Du4g.s. Diazepam and valproic acid were generously supplied by Hoffman-LaRoche Inc., Nutley, NJ and Abbott Laboratories, North Chicago, IL, respectively. Diazepam was homogenized in 0.9% saline containing 13% propylene glycol and 1% Tween 80. Valproic acid was dissolved in saline. Drugs were administered intraperitonealiy 45 min before testing for discrimination and 30 min prior to testing in the conflict study. RESU LT.5
All of the rats learned to discriminate pentylenetetrazol from saline to the required criterion. Pretreatment of the animals with diazepam (5 mg/kg) or valproic acid (320 mgikg) significantly antagonized the discriminative stimulus produced by pentylenetetrazol (Table 1). Whereas all of the rats selected the pentylenetetrazoi lever when the pentylenetetrazoi injection was preceded by saline, only 33% of the rats selected the pentylenetetr~oi lever when the pentylenetetr~ol injection was preceded by injection of diazepam or valproic acid. Data summarized in Table 2 show the effect of valproic acid (320 mgikg) and diazepam (4 mg/kg) on conflict behavior in the rat. Both drugs caused a significant increase in the rate of responding suppressed by footshock in the conflict situation. Whereas the aversive footshock resulted in suppressed response rates in all of the rats pretreated with drug vehicle, the shock-induced response suppression was markedly attenuated in the rats pretreated with valproic acid or diazepam. Whereas valproic acid signi~cant~y suppressed non-conflict responding at the 320 mg/kg dose, diazepam at a dose equieffective to valproic acid in increasing conflict responding did not suppress nonconflict responding. DISCUSSION
Valproic acid is well known for its antiepileptic efftcacy (for review see [6,10]. We now report that this drug may also be useful in treating anxiety-related psychiatric disorders. In the present study, valproic acid compared well with diazepam in antagonizing the discriminative stimulus produced by pentylenetet~zol, a property previously reported to be associated with drugs possessing anxiolytic activity [7-91. Similarly, valproic acid increased responding previously suppressed by punishment. This property has also been previously shown to indicate antianxiety activity (for review see [4]. The neurochemical mechanism through which valproic acid exerts its anxiolytic action cannot be delineated at present, Valproic acid has been reported to inhibit both the synthesis and catabolism of brain gamma-amino-butyric acid (GABA) as well as the catabolism of succinic semialdehyde via inhibition of GABA-T and SSADH respectively (for re-
VALPROIC
577
ACID AS AN ANXIOLYTIC TABLE
TABLE 2
1
ANTAGONISM TESTS WITH VALPROIC ACID AND DIAZEPAM RATS TRAINED TO DISCRIMINATE BETWEEN PENTYLENETETRAZOL (20 mgikg) AND SALINE*
Dose Test drug
(mg/kg)
IN
EFFECT OF VALPROIC ACID AND DIAZEPAM BEHAVIOR IN THE RAT
% Change in responding$
5%Selecting drug lever+ Test drug*
Saline Valproic acid Diazepam
320 5
IO0 33; 33+
*30 min following pretreatment with the test drug, the rats were injected with pentylenetetrazol (20 mgikg). 1.5min following the pentylenetetrazol injection, animals were placed in their assigned Skinner boxes and allowed to make a lever selection. The lever with which ten responses were completed first was considered the selected lever. +Percent of rats selecting the pentylenetetrazol lever, out of a total six rats tested for each treatment. 3~<0.05 versus saline treatment; Chi” 2 x R analysis &= 1, x2=6.0.
view see [I]). These actions usually result in the net elevation of brain GABA levels. We found that elevation of brain GABA levels with the GABA-T inhibitors, gammaacetylenic GABA and gamma-vinyl GABA, failed to antagonize the pentylenetetrazol discriminative stimulus [S].
I. Dren, A. T., W. J. Giardina and N. S. Hagen. Valproic acid. In: P1~~irmrrt~nlr~~icrrf crnd BiochcmiaI Properties of Drug SubS(LIR~~S,edited by M. E. Goldberg. Washington, DC: American Pharmaceutical Association of Pharmaceutical Sciences, 1978, pp. s-97. 7. Geller, I. and J. Seifter. The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentallyinduced conflict in the rat. Pspc.hupharmac,oloRicl 1: 482-492, 1960. 3. Lal, H., G. Gianutsos and S. Miksic. Discriminable stimuli produced by narcotic analgesics. In: Djscrimjn~ti~~e Stimulus Pr(~p~~rtje.~ o_f’Drugs, edited by H. Lal. New York: Plenum Press, 1977, pp. 23-47. 4.
Lippa, A. S., P. A. Nash and E. N. Greenblatt. Preciinical
neuropsychopharmacological procedures for anxiolytic drugs. In: Thr Anxio@cs, edited by S. Fielding and H. Lal. New York: Futura Publishing Co., 1979, pp. 41-81. 5. Meunier, H., G. Carraz, Y. Meunier, P. Eymard and M. Aimard. Propertes pharmacodynamiques de I’acide n-dipropylacetique. Therapie 18: 435-438, 1963.
ON CONFLICT
Valproic acid Diazepam
Dose (mdkg)
N*
Non-convict
Conflict
320 4
7 II
-615 -22
+4489 +4868
*30 min following injection of the test drug, the rats were placed in their assigned Skinner boxes and allowed to respond for milk reinforcement. +Number of rats tested. $% decrease (-) or increase (+) from vehicle treatment. $p
While other anxiolytic drugs compete zodiazepine receptors, valproic acid vitro only at very high concentrations. the brain distribution of valproic acid centrated at brain sites where anxiety anism is also not tenable.
for binding with benshows this activity in Unless it is found that is such that it is conoriginates, this mech-
6. Pinder, R. M., R. N. Brogden, T. M. Speight and G. S. Avery. Sodium vafproate: A review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 13: 81-123, 1977. 7. Shearman, G. and H. Lal. Discriminative stimulus properties of pentylenetetrazol and bemegride: Some generalization and antagonism tests. PsychopharmacoloRv 64: 3 15-3 19, 1979. 8. Shearman, G. and H. Lal. Discriminative stimulus (DS) properties of picrotoxin, bemegride and pentylenetetrazol (PTZ): A possible relationship between an anxiogenic action and PTZDS. Fed. Prot. 38: 256, 1979. 9. Shearman, G. and H. Lal. Use of pentyjenetetr~ol (FTZ) as a disc~minative stimulus (DS) for the prediction of anxiolytic activity. P~zarrn~~c~~~~~~ist21: 267, 1979. 10. Simon, D. and J. K. Perry. Sodium di-n-propylacetate (DPA) in the treatment of epilepsy: A review. Epilrpsia 16: 549-573, 1975. 11. Weissman, A. The discriminability of aspirin in arthritic and non-arthritic rat. Pharmac. B&hem. Behav. 5: 583-F-586, 1976.