A. Siegel et al., NEUROCHEMICAL MECHANISMS UNDERLYING AMYGDALOID MODULATION OF AGGRESSIVE-BEHAVIOR IN THE CAT, Aggressive behavior, 21(1), 1995, pp. 49-62
Studies designed to determine the respective roles of substance P, exc
itatory amino acids, and enkephalins in amygdaloid modulation of defen
sive rage behavior in the cat are presented. The basic design of these
studies involved three stages. In stage I, cannula electrodes for sti
mulation and drug infusion were implanted into medial hypothalamic or
midbrain periaqueductal gray (PAG) sites from which defensive rage beh
avior could be elicited. Then, a stimulating electrode was implanted i
nto a site within the medial, basal, or central nuclear complex from w
hich modulation of the defensive rage response could be obtained. Amyg
daloid modulation of defensive rage was determined in the following ma
nner: it employed the paradigm of dual stimulation in which comparison
s were made of response latencies between alternate trials of dual (i.
e., amygdala + medial hypothalamus [or PAG]) and single stimulation of
the hypothalamus or PAG alone. Thus, stage I established the baseline
level of modulation (i.e., facilitation or suppression of defensive r
age) in the predrug stimulation period. In stage II, a selective or no
nselective receptor antagonist for a given transmitter system was admi
nistered either peripherally or intracerebrally at the defensive rage
site, after which time the same dual stimulation paradigm was then rep
eated over the ensuing 180 min postinjection period in order to determ
ine the effects of drug delivery upon amygdaloid modulation of defensi
ve rage. Stage III of the study took place at the completion of the ph
armacological testing phase. The retrograde axonal tracer, Fluoro-Gold
, was microinjected into the defensive rage site within the medial hyp
othalamus or FAG, and following a 6-14 day survival period, animals we
re sacrificed and brains were processed for histological and immunocyt
ochemical analyses for the neurotransmitters noted above. This procedu
re thus permitted identification of cells within the amygdala which we
re labeled retrogradely and which were also immunostained positively f
or substance P, excitatory amino acids, or enkephalin. For studies inv
olving substance P, defensive rage was elicited from the medial hypoth
alamus and for studies examining the roles of excitatory amino acids a
nd enkephalin, defensive rage was elicited from the PAG. In the first
study, facilitation of hypothalamically elicited defensive rage was ob
tained with dual stimulation of the medial nucleus of the amygdala. In
separate experiments, the selective NK1 non-peptide antagonist, CP 96
,345, was administered both peripherally as well as intracerebrally in
to the hypothalamic defensive rage sites in doses of 0.5-4.0 mg/kg (i.
p.) and 0.5-2.5 nmol (i.c.). Following drug delivery, the facilitatory
effects of medial amygdaloid stimulation were blocked in a dose and t
ime-dependent manner in which the effects were noted as early as 5 min
postinjection. The maximum drug dose (4.0 mg/kg) employed for periphe
ral administration resulted in a 42% reduction in the facilitatory eff
ects of the medial amygdala (P < 0.002). This drug, when microinjected
directly into medial hypothalamic defensive rage sites at the maximum
dose level of 2.5 nmol, resulted in an 84% reduction of the suppressi
ve effects of amygdaloid stimulation (P < 0.5) at 5 min postinjection.
In the next study, an N-methyl-D-aspartate (NMDA) antagonist, DL-alph
a-amino-7-phosphonoheptanoic acid (AP-7), was administered either peri
pherally (0.1-1.0 mg/kg) or intracerebrally (0.2 and 2.0 nmol) into FA
G defensive rage sites. Facilitation of defensive rage behavior, which
was observed following dual stimulation of the basal amygdala and FAG
, was significantly reduced by either route of drug administration in
a dose- and time dependent manner At the maximum dose level of periphe
ral administration, AP-7 reduced amygdaloid facilitation of defensive
rage by 63% (P < 0.001) for 60 min, postinjection. A smaller (i.e., 19
%) but still significant (P < 0.05) reduction in facilitation was obta
ined following intracerebral administration of the drug. In a third st
udy, the non-selective opioid receptor antagonist, naloxone (27.5 nmol
), infused directly into FAG defensive rage sites, totally blocked the
suppressive effects of central amygdaloid stimulation for a period of
30 min (P < 0.05) in a dose- and time dependent manner. The anatomica
l phase of this study revealed the following relationships: 1) that la
rge numbers of neurons projecting to the medial hypothalamus from the
medial amygdala immunoreact positively for substance P; 2) that neuron
s projecting to the FAG from the basal complex of amygdala immunoreact
positively for glutamate and aspartate; and 3) that neurons located w
ithin the central nucleus of the amygdala which project to the FAG imm
unoreact positively for met-enkephalin. Collectively, these observatio
ns provide new evidence which characterizes the likely neurotransmitte
rs linked with specific amygdaloid pathways subserving the modulation
of defensive rage behavior in the cat. (C) 1995 Wiley-Liss, Inc.