Timothy C. Hain, MD • Page last modified: July 31, 2022
This page discusses the chemicals that are used to transmit motion from the inner ear into the brainstem, and are used in processing signals within the brain that are related to the inner ear. This information is useful in understanding drug treatment of vertigo as well as responses to injury.
This diagram is simplified. In addition to the semicircular canals, the otoliths also provide V1 type input. At the V2 level, a major termination is the cerebellum.
Adapted from https://www.wileyessential.com/neuroanatomy/flashcards/c06_2/c06_2.html.
There are at least three major neurotransmitters involved in the "three neuron arc" between the vestibular hair cells and oculomotor nuclei that drives the vestibulocular reflex. There are also a host of other neurotransmitters which modulate function of the vestibular system. The diagram above does not contain cross-connections, but only the "straight through" pathways. Most of the interesting stuff is in the cross connections.
V1 refers to the peripheral sensory neuron located between the vestibular sensors (the hair cells), and the vestibular nucleus. V2 is located in the vestibular nucleus. V3 could be any number of other neurons, but here we mean it to mean the output neurons in the oculomotor nucleus. This is a very simplified way of looking at things as there is an immense amount of neuroanatomy.
One can become overwhelmed by the detail and miss the "forest for the trees". We understand this problem and will attempt to organize material so that the more important things are obvious.
Another problem is that considering neurotransmitters in local sense -- i.e. what is in the vestibular system, leaves out the context -- the rest of the nervous system. Manipulation of a neurotransmitter that is used for consciousness, for example, is often impractical.
A final problem is that almost every one of these neurotransmitters plays a role in compensation. Usually their precise role is hard to figure out. As a general rule, drugs that "slow you down" reduce compensation, and ones that "speed you up" enhance compensation.
Major excitatory neurotransmitters in the vestibular system.
Glutamate is the major excitatory neurotransmitter at vestibular afferents (Serafin et al, 1992), V1 above, as well as with neurons of the vestibular nuclei, or V2 above, where they may also release aspartate. Glutamate interacts with several subreceptors including NMDA, AMPA, and KA, and metabotrophic receptors (Soto et al, 2013). The NMDA glutamate receptors determine the basal discharge and tonic response, while the non-NMDA receptors seem to modulate responses to high-frequency mechanical stimulation (Soto et al, 2013). Drugs that affect glutamate tend to affect the entire brain, as glutamate is a major CNS neurotransmitter. In other words, if you shut down glutamate, you shut down everything. Weak glutamate drugs, such as memantine (an antagonist) are generally not useful in treating dizziness. Glutamate drugs can be hallucinogenic (such as phencyclizine -- a NMDA glutamate antagonist), and overdose induces intense nystagmus.
There are other excitatory amino-acids that may be important. Aspartate is also used at the V2 synapse. So far, this has not been used in vestibular medicine.
Acetylcholine (ACH) is mainly a central agonist affecting muscarinic receptors in the vestibular nucleus. In the periphery, it is the mediator of the efferent synapses (Soto et al, 2013). However there are also nicotinic receptors, as well as M1 and M5 expressed in vestibular afferent neurons (Soto et al, 2013). The significance of their efferent action is probably negligable, The situation with respect to the other cholinergic receptors is somewhat uncertain.
Centrally acting ACH drugs are commonly used for treatment of dizziness. Peripherally acting ACH drugs, such as glycopyrrolate, are rarely encountered (i.e. they usually dobn't work). This probably means that the role of peripheral ACH is minor, while central ACH is major.
There are numerous ACH receptor types (Nm, Nn, and M1-5). The Nm and Nn are "nicotinic", and the M1-5 are "muscarinic". Receptors found in the pons and medulla, presumably those involved with dizziness, are almost exclusively of the M2 subtype (Barton et al, 1994), but both muscarinic and nicotinic receptors are found centrally. Although acetylcholine is also a widely distributed neurotransmitter in the brain as a whole, drugs that affect acetylcholine are heavily used in vestibular medicine, as they suppress nystagmus and vertigo. Examples are meclizine and scopolamine. Scopolamine is a nonselective ACH antagonist. There is no reason to believe that any one nonselective ACH antagonist (e.g. scopolamine) is better than any other ACH antagonist (e.g. meclizine, and many other antihistamines), but scopolamine has no central antihistamine component (which is associated with sleepiness and weight gain). Oral versions of scopolamine would seem equally likely to work as patches (e.g. drugs for IBS) for motion sickness.
ACH agonists, such as physiostigmine can induce motion-sickness in experimental models (Soto et al, 2013). Neostigmine, another ACH agonist but one which does not cross the blood brain barrier, does not have any significant vestibular effects. It seems likely that ACH agonists would decrease thresholds for vestibular signals, but to our knowledge, this has not been studied.
Anticholinergics also affect compensation, producing a reversible overcompensation if administered after compensation has been attained to a vestibular imbalance (Zee, 1988).
Major inhibitory neurotransmitters (i.e. GABA)
Gamma-aminobutyric acid (GABA) and glycine are inhibitory neurotransmitters found in connections between second order vestibular neurons and onto oculomotor neurons (Spencer et al, 1992). Stimulation of the two types of GABA receptors, GABA-A and GABA-B, have similar effects on vestibular pathways (Neerven et al, 1989), but specific GABA-B agonists, such as baclofen, decrease the duration of vestibular responses in animal models (Cohen et al, 1987). Baclofen has not proven very useful in vestibular medicine (e.g. Devalck et al, 1989). Drugs that affect GABA, mainly benzodiazepines, are heavily used in vestibular medicine, as they suppress dizziness as well as anxiety.
Minor transmitters of various kinds, roughly in order of importance.
Histamine (H1-H3) is found diffusely in central vestibular structures and centrally acting antihistamines modulate symptoms of motion sickness (Takeda et al, 1989). Both the H1 and H2 subtypes of histamine receptors affect vestibular responses (Serafin et al, 1992). The H3 receptor is an autoreceptor and thus affects H1 and H2. The H4 receptor affects primary vestibular neurons (Desmadryl et al, 2012). A drug that increases histamine, betahistine, is heavily used in vestibular medicine, and it is thought to affect H3 and H4. Antihistamines, generally H1 antagonists, that do not cross the blood brain barrier are not useful for dizziness (such as most allergy medications). Centrally acting antihistamines generally cause sleepiness and increase appetite, resulting in weight gain over time.
Norepinephrine is an excitatory neurotransmitter. It is involved centrally in modulating the intensity of reactions to vestibular stimulation (Wood, 1979) and also affects adaptation. Both alpha (1 and 2) and beta receptors are found in the vestibular nucleus. Drugs that manipulate norepinephrine are generally not used in vestibular medicine, aside from manipulation of alertness, that may be diminished by other drugs. According to Soto et al (2013), the vestibule receives sympathetic innervation.
Dopamine is another excitatory neurotransmitter, and it affects vestibular compensation. Dopamine blockers reduce nausea. While dopamine agonists and antagonists are readily available to treat many medical conditions, think major tranqulizers, only a few (flunarizine, cinnarizine) are used to treat dizziness. It seems likely that they might reduce compensation.
Glycine is generally an inhibitory neurotransmitter in the CNS. Glycine receptors "colocate" with GABA receptors (Soto et al, 2012). Glycine is a "co-agonist" for glutamate, playing an excitatory role (Trist, 2000). Strychnine, which is a strong antagonist of glycine, can cause death through loss of inhibition of muscle activation and spasms. Because of this mixture of inhibition and excitation, it is difficult to understand what glycine is doing in the vestibular system.
Serotonin receptors are also found in the vestibular nerve and vestibular nucleus (5HT-1, 2 and 7, according to Soto et al, 2013), but the functional significance of this uncertain (Ahn and Balaban, 2010). CGRP co-localizes with 5HT-1F (Soto et al, 2013). Withdrawal from serotonergic drugs, such as SSRI antidepressants, is commonly associated with vertigo, and serotonin depletion can cause severe dizziness (Soto et al, 2013). It has been speculated that this is due to loss of inhibition of glutamate -- in other words, increased vestibular responses as glutamate is excitatory (Smith PF, Darlington CL, 2010). There is some equivocal data suggesting that serotonin agonists such as sumatriptan (a 5-HT1-d and1-b agonist), used for migraine can prevent motion sickness. Serotonin is one of the numerous neurotransmitters involved with nausea, and drugs that block the 5-HT3 receptor such as ondansetron are very effective.
Nitric oxide is also produced in the vestibular nucleus, and may play a role in compensation (Soto, 2013).
Cannabinoid receptors are present in the central vestibular circuitry, but their action is presently unclear (Smith, 2006). It is well known that recreational use of substances that contain THC often reduce nausea.
According to Soto et al (2013), hair cells and efferent neurons release numerous other neuroactive substances including CGRP (which co-localizes with 5HT1-1F), substance-P, opiod peptides, ATP, and adenosine. Several CGRP antagonist are available for migraine treatment, but do not seem useful for dizziness.
Other neurochemical apparatus in the vestibular system
Calcium channels: These are not neurotransmitters but rather are methods that neurotransmitter release is triggered. The subtypes of L, N and T are reportedly active in the vestibular system (Soto et al, 2013). In the CNS, the N or P/Q type are the ones that participate in neurotransmitter release. Because calcium channels are ubiquitous, then may affect both input and output to the vestibular system (Soto et al, 2013). Many of the calcium channel blockers used to treat vertigo are very sloppy drugs with other actions. For example, flunarizine (Rascol et al, 1989). Flunarizine is a powerful dopamine antagonist.