The effects of kindling and inverse benzodiazepine receptor agonist -carbolines on animal
models of anxiety are briefly reviewed in relation to affective disorder associated with
chemical exposure. Recent experimental results are described. In the present study, cats
were given the inverse benzodiazepine receptor agonist, FG-7142, a powerful anxiogenic
compound in humans and animals. Neural transmission in pathways involved in defensive
behavior in the cat was monitored using evoked potential techniques. Change in these
pathways was related to behavioral changes induced by the drug. It was found that a single
dose offG-7142 lastingly increased defensive response to rodents for at least 40 days
after drug administration. Behavioral change was specific to defensive response, since
approach-attack behavior remained unchanged, replicating previous studies. The
benzodiazepine receptor antagonist, Flumazenil, reversed the increase in defensiveness in
a drug-dependent manner, replicating previous findings. Increased defensiveness was
paralleled by a delayed onset potentiation of neural transmission between the amygdala and
the medial hypothalamus of the left hemisphere. Potentiation in the left hemisphere was
transient, decaying between 6 and 12 days after the drug. There was a longer lasting
potentiation (LTP) of activity evoked in the left and right amygdalo-periacqueductal gray
pathways and in the right amygdalo-medial hypothalamic pathway. Potentiation in these
pathways appeared at the time of behavioral change. Potentiation of the right
amygdalo-periacqueductal gray and right amygdalo-medial hypothalamic pathways persisted
until the end of the experiment. In contrast, potentiation of the left
amygdalo-periacqueductal gray pathway faded by 40 days after the drug. Flumazenil
decreased potentiation only in the right amygdalo-periacqueductal gray pathway. These data
strongly suggest that lasting affective change is mediated by lasting changes in
particular efferents of the amygdala of the right hemisphere. Behavioral and physiological
effects offG-7142 were blocked by the N-methyl-D-Aspartate (NMDA) receptor blocker, AP7.
The data suggest that failure of neural inhibition induced by FG-7142 engages NMDA
receptor processes to produce lasting potentiation of transmission in neural circuits that
mediate defensive response with behavioral consequences. Since FG-7142 interferes with
GABA mediated neural inhibition and is proconvulsant, its action might mimic the action of
other environmental chemicals with similar properties, such as chlorinated hydrocarbon
insecticides. The relationship of the present data to the literature on the neural and
behavioral effects of insecticide exposure is discussed. The significance of these
findings for multiple chemical sensitivity disorder is also briefly discussed.
ABALIS, I.M., ELDEFRAWI, M.E.,
and ELDEFRAWI,
A.T. (1985). High-affinity
stereospecific binding of cyclodiene insecticides and gamma hexachorlorocyclohexane to
gamma-butyric acid receptors of rat brain. Pesticide Biochem.
Physiol.24:
95102.
2.
ABALIS, I.M., ELDEFRAWI, M.E.,
and ELDEFRAWI,
A.T. (1986). Effects of
insecticides on GABA-induced chloride influx into rat brain microsacs.
J. Toxicol. Environ. Health18:
1323.
3.
ADAMEC, R. (1978).
Normal and abnormal limbic system mechanisms of emotive
biasing. In: Limbic Mechanisms (Livingston and
O.
Hornykievicz, ed.). Plenum
Press, New York. pp.
405456.
4.
ADAMEC, R. (1990a).
Does kindling model anything clinically
relevantBiol. Psychiat.27:
249279.
5.
ADAMEC, R. (1990b).
Kindling, anxiety and limbic epilepsy: human and animal
perspectives. In: Kindling 4 (J. Wada, ed.).
Raven Press, New York.
pp. 329341.
6.
ADAMEC, R. (1990c).
Amygdala kindling and anxiety in the rat.
NeuroReport1:
255258.
7.
ADAMEC, R. (1991a).
Acute and lasting effects offG-7142 on defense and approach-attack
behavior in cats: implications for animal model of anxiety which use response
suppression. J.
Psychopharmacol.5(1):
2955.
8.
ADAMEC, R. (1991b).
Partial kindling of the ventral hippocampus: Identification of changes in
limbic physiology which accompany changes in feline aggression and
defense. Physiol.
Behav.49(3):
443453.
9.
ADAMEC, R. (1993a).
Lasting effects offG-7142 on anxiety, aggression and limbic physiology in
the cat. J.
Psychopharmacol.7(3):
232248.
10.
ADAMEC, R. (1993b).
Partial kindling of the ventral hippocampus: The role of the
benzodiazepine receptor in changes in limbic physiology which accompany changes in
feline defense. Physiol. Behav.54:
531545.
11.
ADAMEC, R. and MORGAN, H.
(1994). The effect of kindling of different nuclei in the
left and right amygdala on anxiety in the rat. Physiol.
Behav.55: 112.
12.
ADAMEC, R.E., STARK-ADAMEC, C.,
and LIVINGSTON,
K.E. (1980). The development of
predatory aggression and defense in the domestic cat (Felis Catus) I. Effects of early
experience on adult patterns of aggression and defense. Behav.
Neur. Biol.30:
389409.
13.
ADAMEC, R.E., STARK-ADAMEC, C.,
and LIVINGSTON,
K.E. (1985). Basic science and
clinical aspects of procaine HC1 as a limbic system excitant.
Prog. Neuro-Psychopharmacol. Biol.
Psychiat.9(20):
109120.
14.
ADAMEC, R.E., STARK-ADAMEC, C.
and LIVINGSTON,
K.E. (1987). The effects of
procaine HC1 on population cellular and evoked response activity within the limbic
system of the cat: Evidence for differential excitatory action of procaine in a variety
of limbic circuits. Prog. Neuro-Psychopharmacol. Biol.
Psychiat.11:
345364.
15.
ANDREW, R.J. (1972).
The information potentially available in mammal displays.
In: Non-Verbal Communication (R.A. Hinde, ed.). Cambridge
University Press, London, pp.
204206.
16.
ASHFORD, N.A. and MILLER, C.S.
(1991). Chemical exposures. Low Levels and High Stakes.
Van Nostrand Reinhold, New
York.
17.
BELL, I.R. (1975).
A kinin model of meditation for food and chemical sensitivities:
biobehavioral implications. Ann.
Allergy35:
206215.
18.
BELL, I.R. (1982).
A new medical approach to environmental illness. In:
Clinical Ecology. Common Knowledge
Press, Bolinas, CA.
19.
BELL, I.R. (1987).
Environmental illness and health: the controversy and challenge of
clinical ecology for mind-body health.
Advances4(3):
4555.
20.
BELL, I.R., MILLER, C.S., and
SCHWARTZ,
G.E. (1992). An
olfactory-limbic model of multiple-chemical sensitivity syndrome: possible relationships
to kindling and affective spectrum disorders. Biol.
Psychiat.32(3):
218242.
21.
BLACK, D.W. RATHE, A., and GOLDSTEIN, R.B.
(1990). Environmental illness. A controlled study of 26
subjects with 20th century disease. J. Am. Med.
Assoc.264:
31663170.
22.
BOYLES, J.H. (1985).
Chemical sensitivity. Diagnosis and treatment.
Otolaryngologic Clin. N. Am.18:
787795.
23.
BRODSKY, C.M. (1983).
Allergic to everything': a medical subculture.
Psychosom.24:
731742.
24.
BURCHFIEL, J.L., DUFFY, F.H., and
SIM,
V.M. (1976). Persistent effects
of sarin and dieldrin upon the primate electroencephalogram.
Toxicol. Appl. Pharmacol.35:
365379.
25.
COLE, L.M. and CASSIDA, J.E.
(1986). Polychlorocycloalkane insecticide-induced
convulsions in mice in relation to disruption of GABA regulated chloride
ionophore. Life Sci.39:
18551862.
26.
COLLINGRIDGE, G.L. and BLISS, T.V.P.
(1987). NMDA receptors their role in long-term
potentiation. Trends
Neurosci.10(7):
288293.
27.
COLEMAN, K. and McGAUGH, J.L.
(1993). The right and left amygdalae are differentially
involved in the expression of memory for an aversively motivated task.
Soc. Neurosci. Abstr.19(2):
1226.
28.
CRAWLEY, J.N., NINAN, P.T.,
PICKAR,
D., CHROUSOS, M., LINNOILA, M.,
SKOLNICK,
P., and PAUL, S.M. (1985).
Pharmacological Antagonism of carboline induced anxiety in rhesus
monkeys. J. Neurosci.5:
485497.
29.
DILE, J.R. and SMITH, D.W.
(1964). Central nervous system effects of chronic exposure
to organophosphate insecticides. Aerospace
Med.35: 475478.
30.
DOROW, R., HOROWSKI, R.,
PASCHELKE,
G., AMIN, M., and BRAESTRUP, C.
(1983). Severe anxiety induced by FG-7142, a -carboline
ligand for benzodiazepine receptors.
Lancet2:
9899.
31.
DREIFUSS, J.J., MURPHY, J.T., and
GLOOR,
P. (1968). Contrasting effects
of two identified amygdaloid efferent pathways on single hypothalamic
neurons. J. Neurophysiol.31:
237247.
32.
DREIFUSS, J.J. (1972).
Effects of electrical stimulation of the amygdaloid complex on the
ventromedial hypothalamus. In: The Neurobiology of the Amygdala,
Advances in Neurology (B.E. Eleftheriou, ed.). Vol. 2.
Plenum Press, New York.
pp. 295318.
33.
DRUGAN, R.C., MAIER, S.F.,
SKOLNICK,
P., PAUL, S.M., and CRAWLEY, J.N.
(1985). An anxiogenic benzodiazepine receptor ligand induced
learning helplessness. Eur. J.
Pharmacol.113:
453457.
34.
ELDEFRAWI, M.E., SHERBY, S.M.,
ABALIS,
I.M., and ELDEFRAWI, A.T. (1985).
Interactions of pyrethroid and cyclodiene insecticides with nicotinic
acetylcholine and GABA receptors.
Neurotox.6:
4762.
35.
FILE, S.E. and PELLOW, S.
(1986). The anxiogenic action offG-7142 in the social
interaction test is reversed by chlordiazepoxide and RO-15-1788 but not by CGS
8216. Arch. Int. Pharmacodyn.271:
198208.
36.
GILBERT, M.E. (1992a).
A characterization of chemical kindling with the pesticide
endosulfan. Neurotoxicol. Teratol.14:
151158.
37.
GILBERT, M.E. (1992b).
Neurotoxicants and limbic kindling. In: The
Vulnerable Brain and Environmental Risks, Malnutrition and Hazard Assessment
(R.L.
Isaacson and K.F. Jensen, ed.). Vol. 1.
Plenum Press, New York.
pp. 173192.
38.
GLUSHANKOV, P., VOROBYOV, V., and
SREBITSKY,
V. (1985). Bull. Exp. Biol, and Med.,
Moscow.12:
641768.
39.
GODDARD, G.V., McINTYRE, D.C. and
LEECH,
C.K. (1969). A permanent change
in brain function resulting from daily electrical stimulation.
Exptl. Neurol.25:
295330.
40.
GRANT, E.C. and MacINTOSH, J.H.
(1963). A comparison of the social postures of some common
laboratory rodents. Behavior.21:
246259.
41.
HIYOSHI, T., MATSUDA, M., and
WADA,
J.A. (1991). Centrally induced
feline emotional behavior and limbic kindling.
Epilepsia31:
259269.
42.
HUNKELER, W., MOHLER, H.,
PIERI,
L., POLC, P., BONNETTI, E.P.,
CUMIN,
R., SCHAFFNER, R., and HAEFELY, W.
(1981). Selective antagonists of
benzodiazepines. Nature290:
5152.
43.
JASPER, H.H. and AJMOME-MARSAN, C.A.
(1952). A Stereotaxic Atlas of the Diencephalon of the
Cat. The National Research Council of Canada,
Ottawa.
44.
JEEVANJEE, F., LITTLE, H.J.,
MARTIN,
I.L., NICHOLASS, J.M., and NUTT, D.J.
(1985). Is FG-7142 mediated kindling due to changes in
efficacy at the benzodiazepineGABA receptor complexBr. J.
Pharmacol.84: 186P.
45.
JOY, R.M., STARK, L.G.,
PETERSON,
S.L., BOWYER, J.F., and ALBERTSON, T.E.
(1980). The kindled Scizure: Production of and modification
by dieldrin in rats. Neurobehav.
Toxicol.2:
117124.
46.
JOY, R.M. and ALBERTSON, T.E.
(1987). Interactions of lindane with synaptically mediated
inhibition and facilitation in the dentate gyrus.
Neurotoxicol.8:
529542.
47.
KETTER, T.A., ANDREASON, P.J.,
GEORGE,
M.S., HERCOVITCH, P., and POST, R.M.
(1993). Paralimbic rCBF increases during procaine induced
psychosensory and emotional experience. Abstract Soc. Biol.
Psychiat.
48.
KRAUTH, J. (1988).
DistributionFree Statistics; an ApplicationOriented Approach.
Elsevier, Amsterdam, p.
36.
49.
KRETTEK, J.E. and PRICE, J.L.
(1978). Amygdaloid projections to subcortical structures
within the basal forebrain and brainstem in the rat and cat. J.
Comp. Neurol.178:
225254.
50.
LEYHAUSEN, P. (1956).
Verhaltstudien an Katzen. Z.
Tierpsychol.2:
1120.
51.
LIPSKA, B.K., JASKIW, G.E., and
WEINBERGER,
D.R. (1991). Dorsal hippocampal
lesion abolishes the response to FG-7142 in the rat. Pharmacol.
Biochem. Behav.40:
169172.
52.
LISTER, R.G., GREENBLATT, D.J.,
ABERNETHY,
D.R., and FILE, S.E. (1984).
Pharmacokinetic studies on RO-1788, a benzodiazepine receptor ligand, in
the brain of the rat. Brain Res.290:
183186.
53.
LU, C.L., SHAIKH, M.B., and
SIEGEL,
A. (1992). Role of NMDA
receptors in hypothalamic facilitation offeline defensive rage elicited from the
midbrain periaqueductal gray. Brain
Res.581:
123132.
54.
MAEDA, H. (1976).
Effects of psychotropic drugs upon the hypothalamic rage responses in
cats. Fol. Psychiat. Neurol. Jap.30:
539546.
55.
MAEDA, H. and HIRATA, K.
(1978). Two-stage amygdaloid lesions and hypothalamic range:
A method useful for detecting functional localization. Physiol.
Behav.8(21):
529530.
56.
MAIER-BODE, H. (1968).
Properties, effects, residues and analytic of the insecticide
endosulfan. Residue Rev.22:
144.
57.
MIDTLING, J.E., BARNETT, P.G, and
COYE,
M.C. (1985). Clinical
management offield worker organophosphate poisoning. West J.
Med.142:
514518.
58.
NASHOLD, B.S., Jr., WILSON, N.P., and
SLAUGHTER,
G.S. (1969). Sensations evoked
by stimulation in the midbrain of man. J.
Neurosurg.30:
1424.
59.
NASHOLD, B.S., Jr., WILSON, N.P., and
SLAUGHTER,
G.S. (1974). The midbrain and
pain. In: Advances in Neurology, International Symposium on
Pain (J.J.
Bonica, ed.). Vol. 4. Raven
Press, New York, NY. pp.
191196.
60.
NIEMINEN, S.A., SIRVIOE, J.,
TEITTINEN,
K., PITKAENEN, A., AIRAKSINEN, M.M.,
and RIEKKINEN,
P. (1992). Amygdala kindling
increases fear-response but did not impair spatial memory in rats.
Physiol. Behav.51:
845849.
61.
ONGINI, E. (1983).
Behavioral and EEG effects of benzodiazepines and their antagonists in
the cat. In: Benzodiazepine Recognition Site Ligands:
Biochemistry and Pharmacology (G. Biggio and E. Costa, ed.).
Raven Press, New York.
pp. 211225.
62.
POST, R.M., KENNEDY, C.,
SHINOHARA,
M., SQUILLACE, K., MIYOAKA, M.,
SUDA,
S., INGVAR, D.H., and SOKOLOF F, L.
(1984). Metabolic and behavioral consequences of
lidocaine-kindled seizures. Brain
Res.324:
295303.
63.
RACINE, R.J. (1978).
Kindling: The first decade.
Neurosurg.3(2):
234252.
64.
RAINNIE, D.G., ASPRODINI, E.K.,
and SHINNICK-GALLAGHER,
P. (1991a). Excitatory
transmission in the basolateral amygdala. J.
Neurophysiol.66:
986997.
65.
RAINNIE, D.G., ASPRODINI, E.K.,
and SHINNICK-GALLAGHER,
P. (1991b). Inhibitory
transmission in the basolateral amygdala. J.
Neurophysiol.66:
9991007.
66.
RANDOLF, T.G. (1970).
Domiciliary chemical air pollution in the etiology of ecologic mental
illness. Intl. J. Soc. Psychiat.16:
243265.
67.
RANDOLF, T.G (1974).
The history of ecological mental illness. In:
Annual Review of Allergy, 1973 (C.A. Frazier, ed.).
Medical Exam. Pub. Co., Flushing, New
York.
68.
REA, W.J. (1977).
Environmentally-triggered small vessel vasculitis.
Ann. Allergy38:
245251.
69.
REA, W.J. (1978).
Environmentally-triggered cardiac disease. Ann.
Allergy40:
243251.
70.
ROSENBERG, J.F., FREEDMAN, M.R.,
SCHMALING,
K.B., and ROSE, C. (1990).
Personality styles of patients asserting environmental
illness. J. Occup. Med.32:
678681.
71.
ROSENSTOCK, L., KEIFER, M.,
DANIELL,
W.E., McCONNELL, R., and CLAYPOOLE, K.
(1991). Chronic central nervous systems effects of acute
organophosphate pesticide intoxication.
Lancet338:
223227.
72.
SAVAGE, E.P., KEEFE, T.J., and
MOUNCE,
L.M. (1988). Chronic
neuropsychological sequelae of acute organophosphate pesticide
poisoning. Arch. Environ. Health.43:
3845.
73.
SHAIKH, M.B., STEINBERG, A., and
SIEGEL,
A. (1993a). Evidence that
substance P is utilized in medial amygdaloid facilitation of defensive rage behavior in
the cat. Brain Res.625:
283294.
74.
SHAIKH, M.B., SCHUBERT, K., and
SIEGEL,
A. (1993b). Excitatory amino
acids in basal amygdala facilitate defensive rage in the cat.
Soc. Neurosci. Abstr.19:
754.
75.
SCHUBERT, K., SHAIKH, M.B., and
SIEGEL,
A. (1993). Excitatory amino
acid pathway from the basal amygdala to the midbrain periaqueductal gray defensive rage
sites in the cat. Soc. Neurosci.
Abstr.19: 754.
76.
SKOLNICK, P. (1983).
New concepts in the neurobiology of anxiety. J.
Clin. Psychiat.44:
1219.
77.
STAUDENMAYER, H. and CAMAZINE, M.
(1989). Sensing type personality, projection, and universal
allergic reactivity. J. Psychological
Type18: 5962.
78.
STAUDENMAYER, H. and SELNER, C.
(1990). Neuropsychophysiology during relaxation in
generalized, universal allergic reactivity to the environment: a comparison
study. J. Psychosom. Res.34:
259270.
79.
STARK-ADAMEC, C., ADAMEC, R.E.,
GRAHAM,
J.M., BRUUN-MEYER, S.E., PERRIN, R.G.,
POLLOCK,
D. and LIVINGSTON, K.E. (1982).
Analysis offacial displays and verbal report to access subjective state
in the non-invasive detection of limbic system activation by procaine
hydrochloride. Behav. Brain Res.4:
7794.
80.
STEWART, D.E. and TASKIN, J
(1985). Psychiatric assessment of patients with 20th century
disease (total allergy syndrome). Can. Med. Assoc.
J.133:
10011006.
81.
TERR, A.I. (1986).
Environmental illness. A clinical review of 50 cases.
Arch. Intern. Med.146:
145149.
82.
WIGSTRON, H. and GUSTAFFSON, B.
(1985). Facilitation of hippocampal long-lasting
potentiation by GABA antagonists. Acta Physiol.
Scand.125:
159179.
83.
YEHUDA, R. and ANTELMAN, S.M.
(1993). Criteria for rationally evaluating animal models of
post-traumatic stress disorder. Biol.
Psychiat.33:
479486.
84.
YOUNG, W.S. and KUHAR, M.J.
(1980). Radiohistochemical localization of benzodiazepine
receptors in rat brain. J. Pharm. Exp.
Therap.212(2):
337346.
85.
ZHANG, S.P., BANDLER, R., and
CARRIVE,
P. (1990). Flight and
immobility evoked by excitatory. amino acid microinjection within distinct parts of the
subtentorial midbrain periaqueductal gray of the cat. Brain
Res.520: 7378.
