The Anxiolytic Activity of Gabapentin in Mice
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
05Sethi-vol5no3 1/26/70 6:29 PM Page 415
The Anxiolytic Activity of
Gabapentin in Mice
A. Sethi, MD*
B. P. Das, MD*
B. K. Bajaj, DM, MD†
*Department of Pharmacology (Clinical Pharmacology), BP Koirala Institute of Health Sciences,
Dharan, Nepal
†
Department of Medicine (Neurology), BP Koirala Institute of Health Sciences, Dharan, Nepal
KEY WORDS: gabapentin, anxiolysis, The lack of effect of gabapentin on mem-
experimental model ory, exhibiting anxiolytic activity at a low
dose, the lack of cognition deficits, lack of
drug interaction, alleviating the require-
ABSTRACT ment for plasma monitoring, and its free-
Gabapentin is a new gamma aminobu- dom from dependence or abuse liability
tyric acid (GABA) analogue that has suggest the potential advantage of
anticonvulsant activity. Preliminary gabapentin over the exiting anxiolytics.
results are promising with gabapentin
for the treatment of refractory anxiety INTRODUCTION
disorders. In a supplementary role in Anxiety disorders are the highly preva-
several behavioral disorders, especially lent psychiatric disorders, affecting an
in acute mania, it has produced signifi- estimated 25% of the adult population
cant beneficial results. In this study, the at some point during their lifetime.1
anxiolytic activity of gabapentin was These psychiatric disorders can be diffi-
examined in mice. There was a signifi- cult to diagnose in a primary care prac-
cant decrease in time spent in the cen- tice. A large survey found that less that
tral square, an increase in the crossings, 14% of people with psychiatric disor-
and an increase in rearing in the open ders receive treatment.2 Anxiety disor-
field with the low-dose gabapentin (10 ders are highly comorbid, occurring in
and 30 mg/kg), implying anxiolysis. about 58% of patients with major
Furthermore, potentiation of diazepam depressive disorder and 93% of patients
with gabapentin was also reported. On with bipolar disorder.3 Remission is the
screening the gabapentin for learning minimum goal in the treatment of anxi-
and memory with passive avoidance ety disorder, which is often chronic. It
response, there was significant prolonga- may take several years before the anxi-
tion of step-down latency, decrease in ety disorder is diagnosed. The burden of
step-down error, and decrease in the anxiety disorders is substantial, includ-
total time spent by the mice in the shock ing not only direct costs of treatment
zone at 10 and 100 mg/kg of gabapentin. but also the indirect costs of impaired
Gabapentin was not associated with any functioning in all aspects of the patient’s
adverse effect on the memory of mice. life.
The Journal of Applied Research • Vol. 5, No. 3, 2005 41505Sethi-vol5no3 1/26/70 6:29 PM Page 416
Table 1. The Study Groups With the ment of several behavioral disorders.4
Respective Drugs* Gabapentin as an adjuvant therapy in
treatment of bipolar disorders yielded
Groups Drugs Received significant beneficial results.5-8
Control Normal saline . In posttraumatic stress disorder
Standard Diazepam (1mg/kg) (PTSD), there are reports in which the
G-10 Gabapentin (10 mg/kg) addition of gabapentin reduced irritabil-
G-30 Gabapentin (30 mg/kg) ity and increased sleep with reduction in
G-100 Gabapentin (100 mg/kg) nightmares and flashbacks.9 The
D+G(10) Diazepam (1 mg/kg) + accompanying depression of the patient
Gabapentin (10 mg/kg) improved, and there was a reduction in
panic attack frequency. One patient with
*All drugs were administered intraperitoneal uncontrolled generalized anxiety disor-
20 animals per groups were used.
der who was being treated with high
doses of diazepam experienced marked
improvement in generalized symptoms
In the management of anxiety disor- of worry when the dosage was tapered
ders, medication is used to prevent or from diazepam to gabapentin.10
reduce the frequency and severity of Moreover, the improvement was sus-
anxiety attacks and to decrease the tained at 3 months and the dosage of
anticipatory anxiety precipitated on the diazepam was reduced to 10 mg/day.
withdrawal of the antianxiety drugs. Gabapentin has also decreased anxi-
Many anxiety disorders may respond to ety associated with withdrawal of alco-
the treatment but are not treated to hol.11 A double-blind, randomized,
remission. The groups of medications placebo-controlled trial established the
commonly used are tricyclic antidepres- efficacy and safety of gabapentin in
sants (TCAs), benzodiazepines, and relieving the symptoms of social phobia.
monoamine oxidase inhibitors A significant reduction in the symptoms
(MAOIs). was observed with gabapentin.12
Antidepression therapies have pro- Gabapentin was used to treat 15
duced beneficial affects in the manage- alcoholic outpatients who had persistent
ment of anxiety, especially in social insomnia after 4 weeks of alcohol absti-
anxiety disorder. A large proportion of nence. The dose of gabapentin was
patients do not tolerate TCAs and titrated to the sleep response of the
MAOIs, whereas benzodiazepines are patients. All patients showed improve-
well tolerated. ment in the quality of sleep and reduc-
These drugs provide only sympto- tion in the daytime anxiety at dosages of
matic relief in certain types of anxiety 600 to 1500 mg/day of gabapentin.13 All
disorders, and they are usually not effec- studies showed that gabapentin was well
tive in preventing relapse and other tolerated.9-15
existing conditions or symptoms with Several experimental studies have
anxiety. Thus, the ultimate goal of thera- examined the anxiolytic activity and
py full symptom resolution and the confirmed that it does not impair memo-
patient’s return to normal functioning is ry but this needs to be investigated fur-
unmet with the existing drugs. ther.16-19
Gabapentin is a gamma aminobu- Gabapentin may exert its effects
tyric acid GABA analogue possessing through its structural relationship to
anticonvulsant activity. A recent study GABA, playing an important role in
shows its secondary role in the treat- decreasing excitatory input (glutamae)
416 Vol. 5, No. 3, 2005 • The Journal of Applied Research05Sethi-vol5no3 1/26/70 6:29 PM Page 417
Table 2. Observation in Open-Field Model
Groups Time in Central Square (sec) Squares Crossed (n)
Control 2.05 ± 1.46 103.25 ± 18.90
Standard
(diazepam 1 mg/kg) 4.45 ± 9.83 133.25 ± 39.95
Test Groups
1st G-10 095 ± 0.39*† 134.34 ± 34.11*
nd
2 G-30 1.10 ± 1.04* 119.71 ± 26.85*
3rd G-100 2.9 ± 8.59 104.9 ± 32.12†
th †
4 D+G (10 mg/kg) 1.05 ± 0.67* 129.8 ± 32.64*
G-10, G-30, and G-100 indicate the test groups at doses of 10 mg /kg, 30 mg/kg, and 100 mg/kg, respectively.
D+G (10 mg/kg) indicates the test group receiving diazepam and low-dose gabapentin.
*Significant, P05Sethi-vol5no3 1/26/70 6:29 PM Page 418
Table 3. Observations in Open-Field Model
Groups Freezing (sec) Rearing
Control 0.85 ± 3 30.95 ± 9.5
Standard 2.4 ± 7.06 39.6 ± 12.09
Test groups
1st G-10 0.3 ± 1.13 49.9 ± 14.37*
2nd G-30 1.86 ± 2.03* 33.47 ± 9.26
rd
3 G-100 8.05 ± 14.97* 27.2 ± 9.40†
th
4 D+G (10 mg/kg) 4.35 ± 11.25 47.25 ± 17.04*
G-10, G-30, and G-100 indicate the test groups at doses of 10 mg /kg, 30 mg/kg, and 100 mg/kg, respectively.
D+G (10 mg/kg) indicates the test group receiving diazepam and low-dose gabapentin.
*Significant, P05Sethi-vol5no3 1/26/70 6:29 PM Page 419
Table 4. Observations in Passive Avoidance Test
Groups Step-Down Latency(s) Step-Down Error Time in Shock Zone
Control 107 ± 89.56 11.9 ± 8.5 9.9 ± 11.47
Standard 188.25 ± 111.83 12.95 ± 6.28 37.85 ± 81.20
Test groups
1st G-10 186.8 ± 123.9* 5.4 ± 4.53*† 8 ± 8.93
2nd G-30 125.4 ± 120.5 9.1 ± 9.87 13.25 ± 39.08
rd †
3 G-100 228.3 ± 115.77* 4.7 ± 7.15* 1.4 ± 3.80*†
th † †
4 D+G 259.25 ± 81.55* 2.3 ± 1.72* 1.1 ± 2.31*†
(10 mg/kg)
G-10, G-30, and G-100 indicate the test groups at doses of 10 mg /kg, 30 mg/kg, and 100 mg/kg, respectively.
D+G (10 mg/kg) indicated the test group receiving diazepam and low-dose gabapentin.
*Significant, P05Sethi-vol5no3 1/26/70 6:29 PM Page 420
Passive Avoidance Response periodic freeze or immobility, a prefer-
The following observations were made ence for peripheral areas near the
from the passive avoidance test (Table 4 ). boundary, and a reduction in normal
behavioral patterns such as rearing and
Step-down Latency. A significant pro- grooming, which are studied in an open-
longation of the step-down latency was field test. Anxiety is also associated with
observed in the gabapentin 10 mg/kg, augmented autonomic activity resulting
gabapentin 100 mg/kg, and low-dose in increased defecation and urination.
gabapentin + diazepam groups com- Increase of the time spent in the central
pared with the control group. The com- area as well as the ratio of central/total
bination group receiving low-dose locomotion or decreases of latency to
gabapentin + diazepam, only demon- enter the central part are indications of
strated a significant prolongation of step anxiolysis in an open field.21 In the pas-
down latency as compared with sive avoidance test, the animal avoids
diazepam. punishment by refraining from making a
specified response, ie, by staying in the
Step-down error. There was a significant SFZ. A decrease in step-down latency
decrease in step-down errors in and an increase in step-down errors
gabapentin 10 mg/kg, gabapentin 100 indicate reduction of normal anxiety
mg/kg, and low-dose gabapentin + associated with exposure to a novel
diazepam groups compared with stan- environment. All these effects are accen-
dard and control groups. tuated by anxiogenic drugs and attenu-
ated by anxiolytic ones.22 An open-field
Time spent in shock zone. A decrease in test and passive avoidance behavior are
the time spent in shock zone was some of the standard procedures used to
observed in the gabapentin 100 mg/kg screen the anxiolytic effects of drugs in
and the low-dose gabapentin + comparison with a standard such as
diazepam test groups compared with diazepam. The open-field test and pas-
both the standard and control groups. sive avoidance test are simple, sensitive,
With diazepam, there was an insignifi- and reproducible, and they are effective
cant increase in the time spent by the in screening different classes of anxio-
animals in shock zone as compared to genic and anxiolytic agents. However,
the control group (Table 4). extreme caution should be exercised in
that the handling of animals, sound
On the basis of these findings from pas- proofing the system, and the doses
sive avoidance, anxiolytic activity was adopted do not adversely affect motor
observed at 10 mg/kg and 100 mg/kg of activity, thereby making the test results
gabapentin. There was a potentiation of unreliable.
the response of the low-dose gabapentin This study establishes the anxiolytic
+ diazepam. No significant effect was effect of gabapentin in animal models of
demonstrated at 30 mg/kg of gabapentin anxiety. However, these effects were
alone and diazepam in the passive pronounced at doses of 10 mg/kg and 30
avoidance task. mg/kg but not at high doses of 100
mg/kg of gabapentin in the open field.
DISCUSSION This finding is contrary to De-Paris et
Exposure to a novel environment is al17 reporting maximum anxiolysis at 100
associated with emotional disturbance mg/kg of gabapentin. These results are
and anxiety. An anxious animal shows in agreement with Singh and colleagues19
reduced locomotion associated with who reported effective anxiolytic-like
420 Vol. 5, No. 3, 2005 • The Journal of Applied Research05Sethi-vol5no3 1/26/70 6:29 PM Page 421
behavior of gabapentin at 30 mg/kg, anxiolytics, which show amnesia at doses
indicated by an increase in the rearing, used for the treatment of anxiety
number of crossings, and a decrease in disorders.
the time spent by the mice in central
square. In contrast, gabapentin 100 ACKNOWLEDGMENTS
mg/kg did cause a nonsignificant trend We would like to thank Mr. Surya
to decrease rearing in the open-field Niraula for the statistical guidance, Mr.
training session. This tendency could be Gokarna Bhandari for technical assis-
attributed to the sedative effect of this tance, Mr. Om Prakash Chaudhary for
drug at this dose. the handling of animals, and Mrs. Rusha
On screening the drugs for learning Tamrakar for secretarial support. We
and memory with passive avoidance appreciate Sun Pharmaceuticals for pro-
response, it was observed that viding the drug gabapentin.
gabapentin has no effect on memory at
all doses used. There was significant pro- REFERENCES
longation of step-down latency, decrease 1. Kjernised KD, Bleau P. Long-term goals in
in step-down error, and time spent by the management of acute and chronic anxiety
disorders. Can J Psychiatry. 2004;49(suppl
the animal in the shock zone at 10
1):51S-65S.
mg/kg alone and in combination with
2. Leon A, Portera L, Weissman M. The social
diazepam and 100 mg/kg of gabapentin. costs of anxiety disorders. Br J Psychiatry
However, with diazepam there was Suppl. 1997:170:205-208.
increased in the time spent in shock 3. Kessler R. Comorbidity of unipolar and bipo-
zone by the mice but this was not signifi- lar depression with other psychiatric disor-
cant. An early report exhibited a mixed ders in a general population survey. In: Tohen
M, ed. Comorbidity in Affective Disorder.
response of diazepam in PAR, with sig- New York: Marcel Dekker Inc; 1999:1-25.
nificant decrease in step-down error,
4. Ashton H, Young AH. Gaba-ergic drugs: exit
locomotor activity, and an increase in stage left, enter stage right. J
the time in shock zone.21 The effect of Psychopharmacol. 2003;17:174-178.
gabapentin at 100 mg/kg and low-dose 5. Erfurth A, Kammerer C, Grunze H, et al. An
gabapentin (10 mg/kg) in combination open label study of gabapentin in the treat-
ment of acute mania. J Psychiatr Res.
with diazepam was superior to diazepam 1998;32:261-264.
alone.
6. Schaffer B, Schaffer LC. Gabapentin in the
In this study we used a simple open- treatment of bipolar disorder. Am J
field model that is more sensitive to anx- Psychiatry. 1997;154:291-291.
iolytic effect produced by classical 7. Letterman L, Markowitz JS. Gabapentin: a
benzodiazepines, but it has produced review of published experience in the treat-
ment of bipolar disorder and other psychi-
inconsistent results with serotonergic
atric conditions. Pharmacotherapy.
drugs.23 However, the efficacy of 5-HT1A 1999;19:565-572.
receptor serotonergic agonist in general 8. Hatzimanolis J, Lykouras L, Oulis P,
anxiety disorder is well established,23,24 Christodoulou GH. Gabapentin as monother-
and clinical trials suggest antianxiety apy in the treatment of acute mania. Eur
Neuropsychopharmacol. 1999;9:257-258.
action of these agents. A modified open
field that can observe drug-induced 9. Berigan TR. Gabapentin in the treatment of
postraumatic stress disorder: a letter to the
changes in feeding behavior and loco- editor. Prim Care Companion J Clin
motor activity would be more appropri- Psychiatry. 2000;2:105.
ate.25 10. Pollack MH, Matthews J, Scott EL.
The lack of adverse effect of Gabapentin as a potential treatment for anxi-
ety disorders. Am J Psychiatry. 1998;155:992-
gabapentin on memory suggests its
993.
potential advantage over the existing
The Journal of Applied Research • Vol. 5, No. 3, 2005 42105Sethi-vol5no3 1/26/70 6:29 PM Page 422
11. Myrick H, Malcolm R, Brady KT. Gabapentin 18. Watson WP, Robinson E, Little HJ. The novel
treatment of alcohol withdrawal. Am J anticonvulsant, gabapentin, protects against
Psychiatry. 1998;155:1632. both convulsant and anxiogenic aspects of the
ethanol withdrawal syndrome.
12. Chouinard G, Beauclair L, Belanger MC.
Neuropharmacology. 1997;36:1369-1375.
Gabapentin: long-term antianxiety and hyp-
notic effects in psychiatric patients with 19. Singh L, Field MJ, Ferris P, et al. The
comorbid anxiety-related disorders. Can J antiepileptic agent gabapentin (Neurontin)
Psychiatr. 1998;43:305. possesses anxiolytic-like and antinociceptive
actions that are reversed by D-serine.
13. Karam-Hage M, Brower KJ. Gabapentin
Psychopharmacology (Berl). 1996;127:1-9.
treatment of insomnia associated with alcohol
dependence. Am J Psychiatry. 2000;157:151. 20. Morris GL. Gabapentin. Epilepsia.
1999;40(suppl 5):S63-S70.
14. Herrmann N, Lanctol K, Myszak M.
Effectiveness of gabapentin for the treatment 21 Prut L, Belzung C. The open field as a para-
of behavioral disorders in dementia. J Clin digm to measure the effects of drugs on anxi-
Psychopharmacol. 2000;20:90-93. ety-like behaviors: a review. Eur J
Pharmacology. 2003;463:3-33.
15. Pande AC, Davidson JR, Jefferson JW, et al.
Treatment of social phobia with gabapentin: a 22. Vohora D, Pal SN, Pillai KK. Effect of locomo-
placebo-controlled study. Clin tor activity on the passive avoidance test for
Psychopharmacol. 1999;19:341-348. the evaluation of cognitive function. Indian J
Pharmacology. 2000;32:242-245.
16. Weizman R, Raz L, Peter Y, et al. Behavioral
effects of agents active at the gamma- 23. DeVry J. 5-HT1A receptor antagonist: recent
aminobutyric acid receptor complex in the developments and controversial issues.
staircase paradigm. Brain Res. 2001;901:137- Psychopharmacology (Berl). 1995;121:1-26.
142.
24. Straughan JL, Conradie EA. Buspirone-
17. De-Paris F, Busnello JV, Vianna MR, et al. Frontrunner of a new genre of anxiolytics. S
The anticonvulsant compound gabapentin Afr Med J. 1998;74:441-444.
possesses anxiolytic but not amnesic effects in
rats. Behav Pharmacol. 2000;11:169-173. 25. Rex A, Voigt JP, Voits M, Fink H.
Pharmacological evaluation of a modified
open field test sensitive to anxiolytic drugs.
Pharmacol Biochem Behav. 1998;59:677-683.
422 Vol. 5, No. 3, 2005 • The Journal of Applied ResearchYou can also read
