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receptor subtypes.7,8 The m1 receptors are abundant in

the cerebral cortex, striatum, and hippocampus. The m2 

receptors are very rare in brain tissue; they are found in

significant quantities only in the medial septum and pons

and in lesser amounts in the thalamus. The distribution of m3 

receptors is similar to that of m1 receptors, but m3 receptorsare also found in several thalamic nuclei and brainstem

nuclei. The m4 receptors are found in the cortex, striatum,

and hippocampus, and the m5 receptors are found in very

low levels in the hippocampus and some brainstem nuclei.

Bovine brain studies have also revealed that muscarinic

receptors are found in the vestibular nuclei.9 Localization

of receptor subtypes to specific areas of the brain allows

for the possibility of designing drugs that have a more

specific action.

Another regulatory substance in the vestibular nuclei

is histamine. H1, H2, and H3 receptors are present in the

medial vestibular nucleus.1,10 Field-potential recordings

demonstrate that the H1 antagonist diphenhydramine

decreases firing of polysynaptic pathways in the lateral

vestibular nucleus.1,11 

Other inhibitory actions in the vestibular nuclei are me-

diated by γ -aminobutyric acid (GABA). Two subclassesof GABA receptors––GABA A and GABA B––are found

in the vestibular nuclei. GABA A receptors are bound by

benzodiazepines for agonist effects. GABA B receptors

bind baclofen for agonist effects. Neurons from the con-

tralateral vestibular nuclei and Purkinje fibers from the

cerebellum are believed to exert their inhibitory effects

via this GABAergic system.4 

Neurokinin type 1 (NK 1) receptors have been found in

some vestibular afferents.4 NK 1 receptors bind substance P,

which is a neuroactive peptide. Substance P is thought to

be involved in many actions throughout the body, includ-

ing the transmission of painful stimuli, but its role in the

vestibular system is unclear at this time.12

 Other receptors found in the vestibular nuclei include D2 

dopaminergic receptors, 5-HT1A and 5-HT2(serotoninergic)

receptors, andα2- andβ1-adrenergic receptors (table).4,13,14 

Norepinephrine, which binds adrenergic receptors, has

been reported to block neuronal firing in the medial ves-

tibular nucleus while it stimulates neurons in the lateral

vestibular nucleus.1,15 

 The cerebellum

 The cerebellum is believed to function as a regulator of

movement and posture by comparing movement intention

with movement performance and regulating the actions

of descending motor neurons. Information gathered on

movement intention is called internal feedback . Sensory

information about motor performance is called external

feedback . Vestibular stimuli, representing spatial orienta-

tion, are also regarded as external feedback. The cerebellum

compares internal and external feedback signals in order

to regulate performance. The cerebellum is also believed

to contain a conceptual internal model that reflects normal

sensory congruities for a given movement or posture.

When the comparison of the internal and external feedback

signals does not fall within the parameters of this internal

model, a sensory mismatch is said to exist. These sensory

 Table. Anatomic distribution of receptors25-37 

Area Vestibular

Receptor postrema PCRF/NTS Cerebellum nuclei Cortex

AMPA/NMDA + + + + +

Muscarinic + + + + +

Histaminic H2  H3  H1  H1, H2, H3  H1, H2, H3 

GABAergic GABA A GABA A GABA A, GABA A, GABA A,GABA B GABA B GABA B

Dopaminergic D2, D3  D2, D3, D4  D3  D2  D1, D2, D4, D5 

Serotoninergic 5-HT3  5-HT1A, 5-HT3  5-HT2  5-HT1A, 5-HT2  5-HT2, 5-HT3 

α-Adrenergic + + α2  α2  α2 

β-Adrenergic + + β1, β2  β1  β1, β2 

Key: PCRF = parvicellular reticular formation; NTS = nucleus tractus solitarius; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA = N-methyl-D-aspartate; GABA = γ -aminobutyric acid.

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Organizational model

 The currently understood model for the production of

vertigo or motion sickness includes a system in which

information is gathered from vestibular, visual, proprio-

ceptive, and cortical activity (figure). This information is

then compared with an internal model of expected inputcongruity. Detection of a stimulus mismatch promotes the

symptoms associated with vertigo and motion sickness.

 This comparator also serves to promote habituation to new

environmental stimuli or compensation for erroneous input

caused by disease.

It is interesting that some medications that are excellent

antiemetics do not prevent vertigo or motion sickness.

One such medication, ondansetron, is often used for the

prevention of chemotherapy-induced nausea. It acts on

5-HT3  receptors in the area postrema. Activity in this

location would not necessarily prevent stimulation of the

vestibular nuclei from ultimately causing nausea and vomit-

ing. However, patients who are particularly susceptible to

motion sickness also demonstrate increased responses to

other vomiting center stimuli. This may provide a rationale

for the use of general antiemetics in vertigo associated

with nausea.23,24 

 The role of medications in treating vertigo and motion

sickness will be reviewed in part II of this article in an

upcoming issue.

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