1.4 Neurophysiology and Neurochemistry
37
pathway is a central element in the neural representation of
reward, and intense research has been devoted to this area in
recent years. All known drugs of abuse activate the mesoaccum-
bens dopamine pathway, and plastic changes in this pathway are
thought to underlie drug addiction. The mesolimbic projection
is believed to be a major target for the antipsychotic proper-
ties of dopamine receptor antagonist drugs in controlling the
positive symptoms of schizophrenia, such as hallucinations and
delusions.
VTA dopamine neurons also project to cortical structures, such as
the prefrontal cortex, and modulate working memory and attention;
decreased activity in this pathway is proposed to underlie negative
symptoms of schizophrenia. Thus antipsychotic drugs that decrease
positive symptoms by blocking dopamine receptors in the mesolim-
bic pathway may simultaneously worsen these negative symptoms
by blocking similar dopamine receptors in the mesocortical pathway.
The decreased risk of extrapyramidal side effects seen with clozapine
(Clozaril; versus other typical antipsychotic medications) is thought to
be due to its relatively selective effects on this mesocortical projection.
The tuberohypophyseal system consists of dopamine neurons in the
hypothalamic arcuate and paraventricular nuclei that project to the pitu-
itary gland and thereby inhibit prolactin release. Antipsychotic drugs
that block dopamine receptors in the pituitary may thus disinhibit pro-
lactin release and cause galactorrhea.
Norepinephrine and Epinephrine
The postganglionic sympathetic neurons of the autonomic ner-
vous system release norepinephrine, resulting in widespread
peripheral effects including tachycardia and elevated blood
pressure. The adrenal medulla releases epinephrine, which
produces similar effects; epinephrine-secreting pheochromocy-
toma tumors produce bursts of sympathetic activation, central
arousal, and anxiety.
Norepinephrine-producing neurons are found within the brain in the
pons and medulla in two major clusterings: The locus ceruleus (LC) and
the lateral tegmental noradrenergic nuclei (Fig. 1.4-3). Noradrenergic
projections from both of these regions ramify extensively as they proj-
ect throughout the neuraxis. In humans, the LC is found in the dorsal
portion of the caudal pons and contains approximately 12,000 tightly
packed neurons on each side of the brain. These cells provide the major
noradrenergic projections to the neocortex, hippocampus, thalamus, and
midbrain tectum. The activity of LC neurons varies with the animal’s
level of wakefulness. Firing rates are responsive to novel and/or stressful
stimuli, with largest responses to stimuli that disrupt ongoing behav-
ior and reorient attention. Altogether, physiological studies indicate a
role for this structure in the regulation of arousal state, vigilance, and
stress response. The projections from lateral tegmental nucleus neurons,
which are loosely scattered throughout the ventral pons and medulla,
partially overlap those of the LC. Fibers from both cell groups innervate
the amygdala, septum, and spinal cord. Other regions, such as the hypo-
thalamus and lower brainstem, receive adrenergic inputs predominantly
from the lateral tegmental nucleus. The relatively few neurons that uti-
lize epinephrine as a neurotransmitter are located in the caudal pons and
medulla, intermingled with noradrenergic neurons. Projections from
these groups ascend to innervate the hypothalamus, LC, and visceral
efferent and afferent nuclei of the midbrain.
Histamine
Histamine is perhaps best known for its role in allergies. It is
an inflammatory mediator stored in mast cells and released
upon cellular interaction with allergens. Once released, hista-
mine causes vascular leakage and edema and other facial and
topical allergy symptoms. In contrast, central histaminergic
neural pathways have only more recently been characterized by
immunocytochemistry using antibodies to the synthetic enzyme
histidine decarboxylase and to histamine. Histaminergic cell
bodies are located within a region of the posterior hypothala-
mus termed the tuberomammillary nucleus. The activity of
tuberomammillary neurons is characterized by firing that varies
across the sleep–wake cycle, with the highest activity during the
waking state, slowed firing during slow-wave sleep, and absence
of firing during REM sleep. Histaminergic fibers project dif-
fusely throughout the brain and spinal cord (Fig. 1.4-4). Ventral
ascending projections course through the medial forebrain bun-
dle and then innervate the hypothalamus, diagonal band, sep-
tum, and olfactory bulb. Dorsal ascending projections innervate
the thalamus, hippocampus, amygdala, and rostral forebrain.
Figure 1.4-3
Brain noradrenergic pathways (in rats). Projections of noradrener-
gic neurons located in the locus ceruleus (LC) and lateral tegmen-
tal noradrenergic nuclei (LTN). AMG, amygdala; CBM, cerebellum;
cc, corpus callosum; CP, caudate putamen; CTX, neocortex; HI,
hippocampus; HY, hypothalamus; OB, olfactory bulb; TE, tec-
tum; TH, thalamus. (From Sadock BJ, Sadock VA, Ruiz P.
Kaplan &
Sadock’s Comprehensive Textbook of Psychiatry
. 9
th
ed. Philadel-
phia: Lippincott Williams & Wilkins; 2009:66.)
Figure 1.4-4
Brain histaminergic pathways (in rats). Histaminergic neurons are
located in the tuberomammillary nucleus of the caudal hypothala-
mus (TM) and project to the hypothalamus (HY) and more distant
brain regions. CBM, cerebellum; cc, corpus callosum; CP, caudate
putamen; CTX, neocortex; HI, hippocampus; NAc, nucleus accum-
bens; OB, olfactory bulb; TE, tectum; TH, thalamus. (From Sadock
BJ, Sadock VA, Ruiz P.
Kaplan & Sadock’s Comprehensive Textbook
of Psychiatry
. 9
th
ed. Philadelphia: Lippincott Williams & Wilkins;
2009:67.)
