1.4 Neurophysiology and Neurochemistry
41
of activation of monoaminergic receptors. Reuptake is also a
primary mechanism for replenishing terminal monoamine neu-
rotransmitter stores. Moreover, transporters serve as molecular
targets for a number of antidepressant drugs, psychostimulants,
and monoaminergic neurotoxins. Whereas transporter mol-
ecules for serotonin (SERT), dopamine (DAT), and norepineph-
rine (NET) have been well characterized, transporters selective
for histamine and epinephrine have not been demonstrated.
Among drugs of abuse, cocaine binds with high affinity to all three
known monoamine transporters, although the stimulant properties of
the drug have been attributed primarily to its blockade of DAT. This
view has been recently supported by the absence of cocaine-induced
locomotor stimulation in a strain of mutant mice engineered to lack this
molecule. In fact, psychostimulants produce a paradoxical locomotor
suppression in these animals that has been attributed to their blockade of
the serotonin transporter. The rewarding properties of cocaine have also
been attributed primarily to dopamine transporter inhibition, although
other targets mediate these effects as well, since cocaine still has reward-
ing effects in mice lacking the dopamine transporter. It appears that
serotonergic as well as dopaminergic mechanisms may be involved.
Transporters may also provide routes that allow neurotoxins to enter and
damage monoaminergic neurons; examples include the dopaminergic
neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and
the serotonergic neurotoxin MDMA.
Vesicular Monoamine Transporter
In addition to the reuptake of monoamines into the presynaptic
nerve terminal, a second transport process serves to concentrate
and store monoamines within synaptic vesicles. The transport
and storage of monoamines in vesicles may serve several pur-
poses: (1) to enable the regulated release of transmitter under
appropriate physiological stimulation, (2) to protect mono-
amines from degradation by MAO, and (3) to protect neurons
from the toxic effects of free radicals produced by the oxida-
tion of cytoplasmic monoamines. In contrast with the plasma
membrane transporters, a single type of vesicular monoamine
transporter is believed to mediate the uptake of monoamines
into synaptic vesicles within the brain. Consistent with this,
blockade of this vesicular monoamine transporter by the antihy-
pertensive drug reserpine (Serpasil) has been found to deplete
brain levels of serotonin, norepinephrine, and dopamine and to
increase the risk of suicide and affective dysfunction.
Receptors
Ultimately, the effects of monoamines on CNS function and
behavior depend on their interactions with receptor molecules.
The binding of monoamines to these plasma membrane proteins
initiates a series of intracellular events that modulate neuronal
excitability. Unlike the transporters, multiple receptor subtypes
exist for each monoamine neurotransmitter (Table 1.4-1).
Serotonin Receptors
The 5-hydroxytryptophan type 1 (5-HT
1
) receptors comprise
the largest serotonin receptor subfamily, with human subtypes
Table 1.4-1
Monoamine Receptors: Overview
Transmitter
Subtype
Primary Effector
Proposed Clinical Relevance
Histamine
H
1
H
2
H
3
H
4
↑
PI Turnover
↑
AC
↓
AC
↓
AC
Antagonists used as antiallergenic and anti-inflammatory agents, also
promote sedation, weight gain
Antagonists used to treat peptic ulcers, GI reflux, and GI bleeding
Antagonists proposed to treat sleep disorders, obesity, dementia
Possible role for antagonists as anti-inflammatory agents
Epinephrine/
Norepi-
nephrine
a
1A,B,D
a
2A,B,C
b
1
b
2
b
3
↑
PI Turnover
↓
AC
↑
AC
↑
AC
↑
AC
Antagonists used in management of prostate disease
Agonists sedative and hypertensive
Regulation of cardiac function, antagonists may be anxiolytic
Agonists used as bronchiodilators
Possible role for agonists to treat obesity
Serotonergic 5HT
1A,1B,1D,1E,1F
5-HT
2A
, 5-HT
2B
,
5-HT
2C
5-HT
3
5-HT
4
5-HT
5
, 5-HT
6
, 5-HT
7
↓
AC,
↑
GIRK
currents
↑
PI Turnover
Na
+
channel, cell
membrane
depolarization
↑
AC
↑
AC
Partial agonists (buspirone) anxiolytic, role in hippocampal neurogenesis;
5-HT1B/D antagonists used as antimigraine agents (triptans)
2A antagonists
→
antipsychotic effects, 2A agonists
→
hallucinogens;
2B agonism
→
cardiac valvulopathy
2C agonists
→
under development as anorexigens, antiepileptics?
Agonists (ondansetron) are antiemetics.
Partial agonists used in IBS (tegaserod)
Unclear
Unclear
Antagonists may have antidepressant potential
Dopaminergic D
1
-like family (D
1
,
D
5
)
D
2
-like family (D
2
,
D
3
, D
4
)
↑
AC
↓
AC
D
1
agonists used in Parkinson’s disease
D
2
antagonists are antipsychotics (e.g., haloperidol)
D
3
agonists used in Parkinson’s disease, restless legs syndrome (e.g.,
pramipexole)
From Sadock BJ, Sadock VA, Ruiz P.
Kaplan & Sadock’s Comprehensive Textbook of Psychiatry
. 9
th
ed. Philadelphia: Lippincott Williams & Wilkins; 2009:71.
