Ganglionic Transmission
Whether sympathetic or parasympa-
thetic, all efferent visceromotor nerves
are made up of two serially connected
neurons. The point of contact (synapse)
between the first and second neurons
occurs mainly in ganglia; therefore, the
first neuron is referred to as pregan-
glionic and efferents of the second as
postganglionic.
Electrical excitation (action poten-
tial) of the first neuron causes the re-
lease of acetylcholine (ACh) within the
ganglia. ACh stimulates receptors locat-
ed on the subsynaptic membrane of the
second neuron. Activation of these re-
ceptors causes the nonspecific cation
channel to open. The resulting influx of
Na
+
leads to a membrane depolariza-
tion. If a sufficient number of receptors
is activated simultaneously, a threshold
potential is reached at which the mem-
brane undergoes rapid depolarization in
the form of a propagated action poten-
tial. Normally, not all preganglionic im-
pulses elicit a propagated response in
the second neuron. The ganglionic syn-
apse acts like a frequency filter (A). The
effect of ACh elicited at receptors on the

appropriate high-frequency ganglionic
activation. The concentration of nico-
tine in the synaptic cleft can neither
build up as rapidly as that of ACh re-
leased from nerve terminals nor can
nicotine be eliminated from the synap-
tic cleft as quickly as ACh.
The ganglionic effects of ACh can be
blocked by tetraethylammonium, hexa-
methonium, and other substances (gan-
glionic blockers). None of these has in-
trinsic activity, that is, they fail to stim-
ulate ganglia even at low concentration;
some of them (e.g., hexamethonium)
actually block the cholinoceptor-linked
ion channel, but others (mecamyla-
mine, trimethaphan) are typical recep-
tor antagonists.
Certain sympathetic preganglionic
neurons project without interruption to
the chromaffin cells of the adrenal me-
dulla. The latter are embryologic homo-
logues of ganglionic sympathocytes. Ex-
citation of preganglionic fibers leads to
release of ACh in the adrenal medulla,
whose chromaffin cells then respond
with a release of epinephrine into the
blood (D). Small doses of nicotine, by in-
ducing a partial depolarization of adre-
nomedullary cells, are effective in liber-

Effects of Nicotine on Body Functions
At a low concentration, the tobacco al-
kaloid nicotine acts as a ganglionic stim-
ulant by causing a partial depolarization
via activation of ganglionic cholinocep-
tors (p. 108). A similar action is evident
at diverse other neural sites, considered
below in more detail.
Autonomic ganglia. Ganglionic
stimulation occurs in both the sympa-
thetic and parasympathetic divisions of
the autonomic nervous system. Para-
sympathetic activation results in in-
creased production of gastric juice
(smoking ban in peptic ulcer) and en-
hanced bowel motility (“laxative” effect
of the first morning cigarette: defeca-
tion; diarrhea in the novice).
Although stimulation of parasym-
pathetic cardioinhibitory neurons
would tend to lower heart rate, this re-
sponse is overridden by the simultane-
ous stimulation of sympathetic cardio-
accelerant neurons and the adrenal me-
dulla. Stimulation of sympathetic
nerves resulting in release of norepi-
nephrine gives rise to vasoconstriction;
peripheral resistance rises.
Adrenal medulla. On the one hand,
release of epinephrine elicits cardiovas-

chemoceptors leads to excitation of the
medullary emetic center.
At low concentration, nicotine is al-
so able to augment the excitability of
the motor endplate. This effect can be
manifested in heavy smokers in the
form of muscle cramps (calf muscula-
ture) and soreness.
The central nervous actions of nico-
tine are thought to be mediated largely
by presynaptic receptors that facilitate
transmitter release from excitatory
aminoacidergic (glutamatergic) nerve
terminals in the cerebral cortex. Nico-
tine increases vigilance and the ability
to concentrate. The effect reflects an en-
hanced readiness to perceive external
stimuli (attentiveness) and to respond
to them.
The multiplicity of its effects makes
nicotine ill-suited for therapeutic use.
110 Nicotine
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Nicotine 111
A.Effects of nicotine in the body
Antidiuretic
effect
Vigilance
Respiratory rate Sensitivity

Vasoconstriction
Blood pressure
Defecation,
diarrhea
Blood glucose
and
free fatty acids
Glycogenolysis,
lipolysis,
“silent stress”
Bowel motilityVasoconstriction
Nicotine
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Consequences of Tobacco Smoking
The dried and cured leaves of the night-
shade plant Nicotiana tabacum are
known as tobacco. Tobacco is mostly
smoked, less frequently chewed or tak-
en as dry snuff. Combustion of tobacco
generates approx. 4000 chemical com-
pounds in detectable quantities. The
xenobiotic burden on the smoker de-
pends on a range of parameters, includ-
ing tobacco quality, presence of a filter,
rate and temperature of combustion,
depth of inhalation, and duration of
breath holding.
Tobacco contains 0.2–5 % nicotine.
In tobacco smoke, nicotine is present as

ic activity of blood, and enhances coag-
ulability.
The health risks of tobacco smoking
are, however, attributable not only to
nicotine, but also to various other ingre-
dients of tobacco smoke, some of which
possess demonstrable carcinogenic
properties.
Dust particles inhaled in tobacco
smoke, together with bronchial mucus,
must be removed from the airways by
the ciliated epithelium. Ciliary activity,
however, is depressed by tobacco
smoke; mucociliary transport is impair-
ed. This depression favors bacterial in-
fection and contributes to the chronic
bronchitis associated with regular
smoking. Chronic injury to the bronchi-
al mucosa could be an important causa-
tive factor in increasing the risk in
smokers of death from bronchial carci-
noma.
Statistical surveys provide an im-
pressive correlation between the num-
ber of cigarettes smoked a day and the
risk of death from coronary disease or
lung cancer. Statistics also show that, on
cessation of smoking, the increased risk
of death from coronary infarction or
other cardiovascular disease declines

4
3
2
Platelet
aggregation
Epinephrine
Coronary disease
Annual deaths/1000 people
Bronchial carcinoma
Annual cases/1000 people
Inhibition of
mucociliary
transport
Years Months
Chronic
bronchitis
BronchitisFree
fatty acids
Fibrinolytic
activity
–40–20–100 >40 >4015-401–140
Ex-smoker
Duration of
exposure
Damage to
bronchial
epithelium
Damage to
vascular
endothelium

, and D
4
). The aforemen-
tioned actions are mediated mainly by
D
2
receptors. When given by infusion,
dopamine causes dilation of renal and
splanchnic arteries. This effect is mediat-
ed by D
1
receptors and is utilized in the
treatment of cardiovascular shock and
hypertensive emergencies by infusion of
dopamine and fenoldopam, respective-
ly. At higher doses, !
1
-adrenoceptors
and, finally, "-receptors are activated, as
evidenced by cardiac stimulation and
vasoconstriction, respectively.
Dopamine is not to be confused with do-
butamine which stimulates "- and !-ad-
renoceptors but not dopamine receptors
(p. 62).
Dopamine-mimetics. Administra-
tion of the precursor L-dopa promotes
endogenous synthesis of dopamine (in-
dication: parkinsonian syndrome,
p. 188). The ergolides, bromocriptine,

in basophils and tissue mast cells. It
plays a role in inflammatory and allergic
reactions (p. 72, 326) and produces
bronchoconstriction, increased intesti-
nal peristalsis, and dilation and in-
creased permeability of small blood ves-
sels. In the gastric mucosa, it is released
from enterochromaffin-like cells and
stimulates acid secretion by the parietal
cells. In the CNS, it acts as a neuromod-
ulator. Two receptor subtypes (G-pro-
tein-coupled), H
1
and H
2
, are of thera-
peutic importance; both mediate vascu-
lar responses. Prejunctional H
3
recep-
tors exist in brain and the periphery.
Antagonists. Most of the so-called
H
1
-antihistamines also block other re-
ceptors, including M-cholinoceptors and
D-receptors. H
1
-antihistamines are used
for the symptomatic relief of allergies

-Antihistamines”
ChlorpromazineDiphenhydramine
DopamineAcetylcholine
mACh-Receptor Dopamine receptors
Sedation,
hypnotic,
antiemetic
action
H
2
-ReceptorsH
1
-Receptors
H
2
-Antagonists
e.g., ranitidine
H
1
-Antagonists
e.g., fexofenadine
Histamine
D
2
-Agonists
e.g., bromocriptine
Dopamin
Receptors
Dopamine
Dopaminergic neuron

-Agonists
e.g., fenoldopam
Blood
flow
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Inhibitors of histamine release: One
of the effects of the so-called mast cell
stabilizers cromoglycate (cromolyn)
and nedocromil is to decrease the re-
lease of histamine from mast cells (p.
72, 326). Both agents are applied topi-
cally. Release of mast cell mediators can
also be inhibited by some H
1
antihista-
mines, e.g., oxatomide and ketotifen,
which are used systemically.
Serotonin
Occurrence. Serotonin (5-hydroxytrypt-
amine, 5-HT) is synthesized from L-
tryptophan in enterochromaffin cells of
the intestinal mucosa. 5-HT-synthesiz-
ing neurons occur in the enteric nerve
plexus and the CNS, where the amine
fulfills a neuromediator function. Blood
platelets are unable to synthesize 5HT,
but are capable of taking up, storing,
and releasing it.
Serotonin receptors. Based on bio-

cur by several indirect mechanisms: 5-
HT
1A
receptors mediate sympathoinhi-
bition (Ǟ decrease in neurogenic vaso-
constrictor tonus) both centrally and
peripherally; 5-HT
2B
receptors on vas-
cular endothelium promote release of
vasorelaxant mediators (NO, p. 120;
prostacyclin, p. 196) 5-HT released from
platelets plays a role in thrombogenesis,
hemostasis, and the pathogenesis of
preeclamptic hypertension.
Ketanserin is an antagonist at 5-
HT
2A
receptors and produces antihyper-
tensive effects, as well as inhibition of
thrombocyte aggregation. Whether 5-
HT antagonism accounts for its antihy-
pertensive effect remains questionable,
because ketanserin also blocks !-adren-
oceptors.
Sumatriptan and other triptans are
antimigraine drugs that possess agonist
activity at 5-HT
1
receptors of the B, D

anxiolytic properties thought to be me-
diated by central presynaptic 5-HT
1A
re-
ceptors. Ondansetron, an antagonist at
the 5-HT
3
receptor, possesses striking
effectiveness against cytotoxic drug-in-
duced emesis, evident both at the start
of and during cytostatic therapy. Trop-
isetron and granisetron produce analo-
gous effects.
Psychedelics (LSD) and other psy-
chotomimetics such as mescaline and
psilocybin can induce states of altered
awareness, or induce hallucinations and
anxiety, probably mediated by 5-HT
2A
receptors. Overactivity of these recep-
tors may also play a role in the genesis
of negative symptoms in schizophrenia
(p. 238) and sleep disturbances.
116 Biogenic Amines
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Biogenic Amines 117
A. Serotonin receptors and actions
LSD
Lysergic acid diethylamide

Platelets
Constriction
Endothelium-
mediated Dilation
5-HT
2
5-HT
4
Hallucination
Emesis
Blood vessel Intestine
5-Hydroxy-tryptamine
Serotonin
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