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Introduction to the structure and
function of the amygdala
The region of the human brain
commonly referred to as the amygdala comprises an area of
approximately 3 cm3 [1,2]. At the dorsal base of the
brain, the elevation of the para-hippocampus at the uncus is in part
a result of the amygdala, which resides dorsal to it. Although neuro-anatomists
often make reference to this portion as a single unitary structure,
the amygdala is actually three distinct collections of nuclei. The
largest portion of the amygdaloid complex is the basolateral nuclear
group, consisting of the lateral nucleus, the irregular basal
nucleus, and the accessory basal nucleus. The other major portion
consists of the centro-medial group, which comprises the central
nucleus and the medial nucleus. The centromedial group communicates
via fibers of the stria terminalis to the bed nucleus of the stria
terminalis (BST)[2] (Figure 1). Cell types in the BST are
identical to those in the centromedial, causing the BST to be
included in the classification of amygdalar tissue. The BST lies in
the basal forebrain, which also contains the basal nucleus of
Meynert, the nucleus accumbens, and the ventral portions of the
putamen and globus pallidus. Anatomically, the smallest portion of
the amygdaloid complex is the cortical nucleus; with primary input
originating from the olfactory bulb and olfactory cortex,
undoubtedly this plays a role in emotion-associated olfaction[2].
Nitric oxide correlates amygdalar
function When we examine nitric oxide (NO) signaling, we notice
two constitutive enzymatic components, the constitutive NO synthase
(cNOS), including endothelial (eNOS) and neuronal (nNOS) isoforms.
cNOS, as the name implies, is always expressed. When cNOS is
stimulated, NO release occurs for a short period of time, but this
level of NO can exert profound physiological actions for a long
period of time[3]. NO not only is an immune, vascular,
and neural autoregulatory signaling molecule, but also performs
vital physiological activities via its constitutive expression[4,5].
Both the amygdala and the
hippocampus contain numerous receptors for varying
neurotransmitters. The central nucleus of the amygdala is most
strongly modulated by dopamine, norepinephrine (NE), epinephrine,
and serotonin[6,7]. The basal nuclei receive moderately
high inputs of dopamine, NE, and serotonin[6,7], each of
which has been demonstrated to exert their desired effect via NO[4].
Taken together, we surmise that NE initially promotes a slight
vasoconstriction of the artery during the amygdalar compensatory
response, which is defined as the limbic system's inherent mechanism
to maintain homeostasis and lower stress levels. This mechanism is
indicated by a slight enhancement of sympathetic activity on
stimulation (ie, emotional), and is immediately followed by the
release of NO from the peripheral nitroxi-dergic nerve, which
mediates a concentration-dependent vasodilation[5]. In
primates, the cerebral arterial diameter, under resting conditions,
is maintained by tonic release of NO from the nerve (10%-20%), or
from the nerve and endothelium (30%)[8]. This observation
is supported by other data from our laboratory because of the fact
that basal NO is cNOS-derived and keeps particular types of cells in
a state of inhibition[5]. Endogenous superoxide dismutase
in the cerebral artery appears to protect the relaxation induced by
NO from perivascular nerves from the NO scavenger action of
superoxide anions[9]. This NO then produces the
longer-lived phenomenon of smooth muscle relaxation. In another
report, it was found that NE vascular hyperresponsiveness in
hypertension was dependent on an impairment of NO activity that was
realized through NE-induced oxygen free radical production[10],
providing an important contribution to the understanding of this
regulatory process.
Amygdalar NO release and its
relationship to sexual behavior
In addition to NO and the amygdala,
new knowledge has emerged concerning the role of hypothalamic,
limbic, and brainstem structures, neuropeptides, and brain
monoamines in the control of partner preference, sexual desire,
erection, copulation, ejaculation, orgasm, and sexual satiety - the
details of which are discussed below. At least one important
sex difference exists between the male and female amygdala of many
species. Owing to the interplay of the differing sex hormones, males
and females will experience pleasure from differing experiences (eg,
it has been shown that males are more visually stimulated than
females[7,11]). In addition, modulating the concentration
of testosterone may cause a male to partake in stereotypical "male
behavior." Likewise, modifying the concentration of estrogen may
cause the female to partake in specified, stereotypical "female
behavior"[7,11]. The amygdala is intimately involved in
sex and sexuality. It is important to note that the male amygdala is
slightly bigger than that of the female. The medial part of the
female amygdala plays an important role in pregnancy and appropriate
coordination of the endocrine system. Stimulation of the amygdala
will produce penile erection, sexual sensation,
representations/memories of intercourse, and orgasm[7,12,13].
Furthermore, precortical region epilepsy has been shown to elicit
spontaneous sexual arousal and orgasm, thus clearly demonstrating
the role of the amygdala in sexual pleasure[12,13].
Stimulation of the corticomedial
amygdala has been shown to induce ovulation in the female, and
cutting the stria terminalis abolishes this effect. The introduction
of tract lesions to the rat amygdala, including the medial nucleus,
eliminates male libido, but not female libido[2,7,11,14].
In humans, temporal lobe epilepsy has been associated with sexual
arousal in women to the point of orgasm; however, evidence of this
in men is unsubstantiated[12,13].
Nitric oxide release has been
demonstrated as the critical link between corticomedial stimulation
and its relationship with the densely packed estrogen/androgen
regions within the amygdala[15-19]. NO has been shown to
be crucial for the occurrence of basal luteinizing hormone (LH)
release in males[15], and for the LH surge in
ovariectomized females treated with estradiol plus progesterone[16-18].
Furthermore, NO donors induce an LH surge in estradiol-treated
ovariectomized females[16-20], and thus, have a
progesterone-like effect. Concomitant findings show that estradiol
stimulates nNOS expression in the preoptic area and exerts a helping
influence on NO-producing neurons[17]. The released NO
appears to be able to modulate the activity of gonadotrophic
releasing hormone neurons (GnRH)[17]. These observations
implicate neuronal NO in the regulation of GnRH cell activity in the
preoptic area[20-23]. It is important to note that some
studies suggest that at the median eminence (ME) level, the NO
implicated in the modulation of GnRH release is endothelial in
origin, rather than neuronal[23]. This is consistent with
the fact that, unlike in the preoptic area where GnRH perikarya are
surrounded by nNOS-containing cells, nNOS fibers and GnRH fibers in
the ME are distributed separately in the internal and external
zones, respectively[19]. Furthermore, in the ME, eNOS
immunoreactivity is observed in endothelial cells of the pituitary
portal blood vessels[20], located in immediate proximity
to the GnRH terminals[21]. The endothelial origin of NO
secreted from ME fragments is further substantiated by the results
of prior reports that show that central administration of eNOS
antisense is more efficacious than nNOS antisense administration in
suppressing an estradiol-/progesterone-induced LH surge in
ovariectomized females[21]. These findings are directly
related to amygdalar function by way of neuronal projections
extending from the amygdala precortical region to the ME
(interestingly, this relationship can be made without regard to
whether ME signaling occurs via neuronal or endothelial NO). Thus,
we can hypothesize a more robust signaling system involving both NO
from amygdalar origins, as well as hypothalamic hormonal
relationships.
Emotional stressors mediated via
amygdalar NO release
Morphine and related compounds
mediating NO release within the amygdala
The endocannabinoids, anandamide, and
2-arachidonyl glycerol, are naturally occurring, constitutively
expressed, NO-stimulating signaling molecules[24].
Anandamide and morphine can also cause NO release from human immune
cells, neural tissues, and human vascular endothelial cells[25].
Moreover, both anandamide and morphine can initiate invertebrate
immune cell cNOS-derived NO[26]. Additionally, estrogen
can stimulate cNOS-derived NO in human immune and vascular cells[27,28].
Anandamide, as part of the ubiquitous arachidonate and eicosanoid
signaling cascade, serves to maintain and augment tonal NO in
vascular tissues[24].
Both the hippocampus and the
amygdala (particularly the lateral nucleus) contain high
concentrations of receptors for the endocannabinoids[29,30].
In fact, reports have found endogenous morphine within the structure
of the hippocampus[29,30]. In addition, this morphine
activates pleasure pathways via NO and has been shown to do so in
the rat brain hippocampus and amygdala[31-34]. Studies
from our laboratory confirm the mediated release of NO via real-time
amperometric measurement from the rat brain hippocampus[34]
and amygdala[31]. This information can further be
used to understand some of the pleasurable aspects of sexual
activity that, indeed, are often found to have morphine-like
properties and, perhaps, are mediated via these endocannabinoid and
morphine laden amygdalar pathways[31,35]. Further
credence to these findings stems from lesional data. Humans with
amygdala lesions show a decrease in emotional tension and related
sexual dysfunction[6,7]. It has been postulated that
endocannabinoids and endogenous morphine may act on the lateral
nucleus to prevent the linkage of sexual significance to sensory
stimuli prior to conscious processing, thus interfering with the
perception of sexually and emotionally charged stimuli[36].
Estrogen mediates NO release
within the amygdala Estro-gen, through NO release, provides an
additional pathway by which the system can downregulate immunocyte
and vascular function in women[37]. This may be because
of both the immune and vascular trauma associated with cyclic
reproductive activities, such as endometrial buildup, when a high
degree of vascular and immune activities occur. Given the extent of
proliferative growth capacity during peak estrogen levels in this
cycle, NO may function to enhance down regulation of the immune
system to allow for these changes. Therefore, enhanced cNOS activity
would be a beneficial effect within the concept and time framework
of amygdalar compensation (as defined earlier) and the subsequent
sense of calm it induces. Thus, these signal molecules, especially
endocannabinoid and opiate alkaloids, have the potential to make you
"feel" good and relax[38] by releasing NO, which may once
again be part of the sexual resolution (post coitus) phase of the
sexual cycle.
Emotionally charged events
mediating NO release within the amygdala Within this context of
varying stimuli evoking NO release, emotional stresses such as fear
and anxiety can induce cardiovascular alterations, such as cardiac
dysrhyth-mias. These are some of the same events that occur when one
is exposed to sexually charged stimulus, or engaged in a sexual act[39-42].
These cardiovascular events are initiated at the level of the
cingulated, amygdalar, and hypothalamic processes, as well as their
projection into the higher level cerebral cortex, further altering
the heart rate under stressful or sexually aroused conditions[43].
Neurons in the insular cortex, the central nucleus of the amygdala,
and the lateral hypothalamus, owing to their role in the integration
of emotional and ambient sensory input, may be involved in the
emotional link to the cardiovascular phenomenon[44].
These include changes in cardiac autonomic tone with a shift from
the cardioprotective effects of parasympathetic predominance to
massive cardiac sympathetic activation[45]. This
autonomic component, carried out with parasympathetic and
sympathetic preganglionic cells via subcortical nuclei from which
descending central autonomic pathways arise, may therefore be a
major pathway in how emotional state may affect cardiovascular
function. The importance of an elicited emotional response (and
therefore limbic activation) was further demonstrated in ischemic
heart disease when patients with frequent and severe ventricular
ectopic rhythms were subjected to psychological stress[46].
The frequency and severity of ventricular ectopic beats increased
dramatically during emotional activation of sympathetic mechanisms,
but not during reflexively induced increased sympathetic tone.
Perhaps we can even relate this mechanism to sexual orgasm, a
process dominated by increased sympathetic tone.
The hard-wiring of emotional and
sexual sensations coupled to cardiovascular neural processes
probably involves many subcortical descending projections from the
forebrain, midbrain, and, specifically, the amygdala[47-50].
Cardiovascular changes were observed in experiments where the motor
cortex surface was stimulated, eliciting tachycardia accompanied by
and independent of changes in arterial blood pressure[51].
The "sigmoid" cortex[52] and frontal lobe[53-55],
and, in particular, the medial agranular region[56],
subcallosal gyrus[57], septal area[58],
temporal lobe[59], and cingulate gyrus[60-62]
appear to be involved. The insular cortex in cardiac regulation is
important because of its high connectivity with the limbic system,
suggesting that the insula is involved in cardiac rate and rhythm
regulation under emotional stress[53,54]. This form of
regulation is mediated via a parasympathetic response, and is
probably active in the resolution phase following orgasm[2,6,12,13].
The amygdala, with respect to
autonomic-emotional integration[63,64], is composed of
numerous subnuclei, which play a major role in the elaboration of
autonomic responses[65]. There are profuse inputs to this
region from the insular and orbitofrontal cortices, the parabrachial
nucleus, and the nucleus tractus solitarius[66].
Amygdalo-tegmental projections are viewed as a critical link in
cerebral cortical control of autonomic function[8,67].
This level of input allows for cerebral control of sexual behavior,
such as showing sexual restraint and the ability to pass on sexual
gratification. Indeed, a great deal of research center on
sex-offenders' inability for, or lack of, the above-mentioned
amygdalo-tegmental projections[68,69].
Mechanisms of amygdala-induced
emotional compensation
As noted above, once individuals are
exposed to sexually explicit or emotionally charged information,
they experience peripheral vasodilation: warming of the skin, an
increase in heart rate, and an ensuing sense of agitation[5,70].
This experience is remarkably similar to the physiological state
that exists throughout the sexual cycle, from initial arousal
through to resolution. It is the function of the amygdala to aid in
the relief of these altered states, through the amygdalar
primary compensatory response as defined above[2,6,7,53].
In examining a potential mechanism for this relief, besides the
overriding central nervous system output via the autonomic nervous
system, peripheral neuro-vascular processes would appear to be
important. We surmise that NO is of fundamental importance in this
response because of the increase in peripheral temperature (ie,
vasodilation[5]). For a complete review of possible
related mechanisms as well as the related mechanisms outlined above,
see the studies by Toda et al[8], Lembo et al[10],
Okamura et al[66], and Toda[67].
We also surmise, based on current
studies, that endothelial-derived NO, released through normal
pulsations as a result of vascular dynamics responding to heart beat[38],
as well as acetylcholine-stimulated endothelial NO release, may
contribute to the effect of NO in inducing smooth muscle relaxation[5,70].
Furthermore, vascular pulsations may be of sufficient strength to
also stimulate nNOS-derived NO release, limiting any basal NE
actions[5,70]. Interestingly, nitrosative stress,
mediated by involvement of the reactive nitrogen oxide species, N2O3,
does inhibit dopamine hydroxylase, which, in turn, inhibits NE
synthesis and contributes to the regulation of neurotransmission and
vasodilation[5,70]. This system may provide an
autoregulatory mechanism involved in the neuronal control of
peripheral vasomotor responses and may, once again, aid in the
resolution phase of sexual intercourse (Figure 2).
Conclusion
Our conclusion is two-fold. We
demonstrate that amygdalar regulation of the male and female sexual
cycle is medicated by estrogen-/androgen-related signaling
molecules, both of which exert their respective influences on
ovulation and sexual behavior via coupled NO release. Furthermore,
we propose that amygdalar-induced homeostatic control mechanisms
acting in response to emotionally charged stimuli, including
sexually stimulating sensations, appear to be mediated by a system
of regulation involving NO as a neurotransmitter and as a locally
acting hormone. Hence, these two principal roles of the amygdala
exert their respective behaviors via NO.
In final summary, we have
demonstrated numerous mechanisms and neurochemical pathways with
regard to both emotion and sexual behavior (ovulation, arousal,
etc), and we have shown a link between each of these complex
pathways systems, as well as the use of NO as a major biochemical
messenger. Moreover, throughout each of the aforementioned pathways,
we have attempted to offer a possible relationship to sex, either as
a mediator of direct sexual activity, or as a mediator of an
individual aspect of the sexual cycle.
Acknowledgment
We thank John R Hesselink, Professor
of Radiology and Neurosciences at University of California San Diego
Medical Center, San Diego, CA, for permission to use his figure of
the limbic system (Figure 1).
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