(From Dr. Glasser’s Lecture, 25-26 July 2000, by Brian Buschman)
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There are two types of receptors in the nervous system:
1) Ionic receptors that function by opening an ion channel when the NT binds the receptor.
2) Metamatrophic receptors which function via second messengers, often G-proteins. Usually the will use the second messenger system to change the permeability to some ion.
Neuromodulation is the non-specific action on a neuron that alters the neurons sensitivity to excitation or inhibition.
ACh has both nicotinic (ionic) and muscarinic (metamatrophic) receptors. Bungarotoxin, botulinum toxin and curiae are competitive antagonists for ACh.
M1 receptors have been found in the brain in the nucleus basalis. Damage to the nucleus basalis will cause loss of ACh in the brain.
The straitonigral tract also uses ACh to function on the M receptors.
These include NE, Epi, dopamine and 5-HT. In humans Epi is usually a hormone and NE a NT. Epi is produces in the adrenal medulla which functions like a sympathetic ganglion.
NE is mainly found in the locus cerillius. Drugs that increase NE elevate mood and those that decrease NE cause depression.
There are a few Epi releasing neurons projecting all over the place in the brain but nothing significant for us right now.
There are five classes of dopamine receptors which are all G-protein coupled. The dopamine neurons come in three projection lengths which each have a different functional role:
1) Ultra-short function in neurons of olfaction and the retina.
2) Intermediate length neurons such as in the tubeloinfundibular system. Work at the level of the hypothalamus to inhibit prolactin release.
3) Long neurons function in the nigrostraital and mesocortical (mesolimbic) systems which use D2 receptors. Drugs that block D2 receptors decrease the rate of self stimulation. Schizophrenia involves too much dopamine from the nigrostraital tract. Thus causes up regulation of D2 receptors in the mesolimbic system as well as in the nigrostraital system. Antipsychotic drugs block D2 receptors and function on both the nigrostraital and mesocortical systems. These are drugs like halidol. Besides the desired effects they also cause tardive dyskenesia because of the side effects on the mesocortical system.
There is a new class of drugs that selectively target D4 receptors to work as anti-psychotics because D4 receptors are found in the nigrostraital tract but not in the mesolimbic system.
Addiction is use of a substance despite the negative effects. It is believed to cause increase in dopamine working on D2 receptors in the nucleus acumbens which actually causes the psychological dependency.
There are many classes of seretonin receptors and most have many subclasses. Most are metamatrophic and we don’t care about the little exception to that rule. In the brain 5-HT6 and 5-HT7 are in the limbic system and have a high affinity for antidepressant drugs. 5-HT comes fro the raphe it’s fibers project all over the place.
LSD works on the 5-HT2 receptor as do hallucinogens from cactus and mushrooms. Excasity works by an initial stimulation of happiness as it causes massive release of 5-HT and then is followed by severe depression as the 5-HT runs out.
Drugs to increase 5-HT cause happiness and drugs to decrease 5-HT cause depression. MAO inhibitors work to increase 5-HT but are bad as antidepressants because of their effects with Epi and NE. Instead, we use SSRIs (selective seretonin reuptake inhibitors). Drugs must be administered for 4-6 weeks before effects begin to be noticed.
NE and 5-HT play a role in sleep and in regulating body temperature.
H1, H2 and H3 receptors are all metamatrophic and are all found in the brain. H1 antihistamines are drugs like benadryl that are used for antiallergic effects. H2 blockers are drugs like cimetadine that bock HCl secretion from parietal cells. In the brain there are histamine projections all over the place. This is why taking benadryl induces sleep.
Adenosine in a neuromodulator that causes CNS depression. Caffeine is a stimulant because it inhibits adenosine receptors.
Asp is the NT in some pyramidal cells.
Glu is the excitatory NT of the CNS. It has at lease 11 classes of metamatrophic receptors. There are three types that we care about:
1) Kainate receptors act through a second messenger system to cause Na+ and K+ permeability changes.
2) AMPA receptors work by the same mechanism as kainate receptors.
3) NMDA receptors are strange in that they have Mg2+ that blocks the Ca2+ channels. The channels are not able to open, even if stimulated, unless the membrane is already partly depolarized by kainate and AMPA receptors. The NMDA receptors have both good and bad effects.
a. The good effect is called LTP (long term potentiation) where the depolarization lasts for a long time after stimulated. It’s a type of enhanced post synaptic response. While the LTP is happening the postsynaptic membrane releases CO or NO back on the presynaptic membrane as a way to ask for more Glu. LTP functions in the hippocampus in memory formation.
b. The bad is that Glu is not degraded by an enzyme in the cleft but is taken back up via active transport. The mechanisms for release can easily release too much Glu to the point that it over saturates the tissue and causes excessive Ca2+ influx. When excessive Ca2+ flows into the cell then it acts as a free radical and destroys the cells near the infarct.
GABA is found all over the place since it’s the main inhibitatory NT of the brain. There are two main classes of GABA receptors:
1) GABAA receptors are ionotropic by increasing Cl- permeability. The GABAA receptors also binds benzadiazopenes (valium), EtOH and barbiturates by other sites on the receptors.
2) GABAB receptors are metamatrophic and ultimately work by causing a K+ efflux.
Gly usually works as an inhibitatory NT but it is excitatory on NMDA receptors of Glu to help with the initial depolarization. Like GABA it increases Cl- permeability.
Strychnine antagonizes Gly receptors and causes convulsions.
Most anesthetics work on GABAB (K+) and Glu (Cl-) receptors.
Substance-P is a large molecule NT that is found in the substancia gelatinousa and functions in pain transmission via C-fibers. It can also be found in the nigrostraital pathway and hypothalamus for endocrine regulation.
These bind receptors for morphine.
There are little neurons in the substancia gelatinousa that presynaptically inhibit C-fibers in the analgesic response. These use an unknown enkephalene to do the job.
There are three types of opoid receptors, m, k and d. The m and k receptors all are G-protein related and open K+ channels. d receptors work by closing Ca2+ channels. The receptors are found scattered all over the brain. b-Endorphin works on m and d receptors.
Other large molecule NT’s include CCK, VIP and Angiotensin II.
NO and Co function in retrograde transmission onto Glu releasing membranes. They are associated with the NMDA receptor.
There is only one small molecule found in any given terminal but there may be up to 27 different large molecule NTs in the same terminal membrane or even the same vesicle. If the nerve is stimulated at a low frequency then there will only be the release of the small molecule NT. High frequency discharge is associated with the release of both small and large molecule NTs. When the large molecule NTs are released with the small ones they act as cotransmitters to increase the effect.
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