Neurophysiology Module 9

Introduction

The monoamines are neurotransmitters that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). Typically, the monoamines activate G proteins to exert their effects at the synapse, although there is one exception described below.

Monoaminergic systems, the networks of neurons that utilize monoamine neurotransmitters, are involved in the regulation of cognitive processes such as emotion, arousal, and certain types of memory.

The monamines are normally separated into three groups:

Group	Characteristics	Members
Histamine	Derived from decarboxylation of the amino acid histidine	Histamine
Catecholamines	Have a catechol (benzene with two hydroxyl side groups at carbons 1 and 2) and a side-chain amine	Epinephrine, Dopamine, Norepinephrine
Tryptamines	Contain an indole ring structure, so structurally similar to the amino acid tryptophan	Serotonin, Melatonin

 

All of the molecules listed above are used as neurotransmitters by the central nervous system, but we will focus on the following three with the most important roles: dopamine, norepinephrine, and serotonin.

All of the monoamines are reuptaken into the presynaptic nerve terminal through monoamine transporters. Each of the monamines we will focus on has its own transporter, but since dopamine and norepinephrine are similar molecules, the norepinephrine transporter can reuptake dopamine, and vice versa. Many drugs used to treat mental health disorders, as well as recreational drugs such as cocaine, have their actions on the monoamine transporters. For example, most modern antidepressant drugs work on the principal of blocking these re-uptake transporters.

There are many, many subtypes of monoamine receptors, and thus we will only focus on generalities. These receptors are both presynaptic and postsynaptic.

Serotonin

Neurons that synthesize serotonin (also called 5-hydroxytryptamine, or 5-HT) are mainly located in nuclei at the midline of the brainstem, called the raphe nuclei (raphe means "seam" in Greek). Generally, the raphe nuclei in the caudal brainstem (in the medulla) project to the brainstem and spinal cord, while the rostral raphe nuclei (in the pons and midbrain) project to much of the diencephalon and telencephalon.

The axons of the raphe nucleus neurons branch extensively, and provide inputs to neurons scattered throughout the brain and spinal cord. Hence, a relatively small number of cells have widely branching axons that affect many postsynaptic targets. In addition, there are 7 subtypes of serotonin receptors (labeled 5HT1-5HT7), with a further division within subtypes. Since activating each subtype has different intracellular effects mediated through G-proteins, the actions of serotonin in the nervous system are very, very complex. However, some of the behaviors mediated through serotoninergic neurotransmission should be highlighted:

• Pain control. Activation of serotonin neurons with projections to the spinal posterior horn alters pain sensation
• Nausea. Drugs that block the 5-HT3 receptor such as ondansetron are highly effective in treating most forms of nausea, except that associated with motion sickness. Curiously, the 5-HT3 receptor is one of the few monoamine receptors that is ionotropic; binding of serotonin to the 5HT3 receptor opens a cation channel.
• Sleep
• Mood (hence, serotonin reuptake inhibitors are commonly used to treat depression).

Norepinephrine

Norepinephrine is synthesized by most sympathetic postganglionic neurons as well as groups of neurons in the brainstem whose axons branch extensively. The largest of the norepinephrine-producing cell groups is located in a nucleus in the pons called locus coeruleus. Locus coeruleus neurons contain melanin crystals, such that the nucleus appears as a black dot in brainstem sections through the pons.

Norepinephrine binds to two main subtypes of metabotropic receptors: α and β. The α subtype can be divided into the α-1 and α-2 subtypes. The β subtype can be divided into β-1, β-2 and β-3 receptors, although β-3 receptors are mainly in peripheral tissues (not the CNS) and are less important than the other subclasses.

The actions of norepinephrine binding to these receptors is summarized in the table below:

Receptor	Effects of binding to the receptor
α1	Activates phospholipase C, resulting in an increase in intracellular Ca2+
α2	Decreases cAMP by inhibiting adenylate cyclase
β (all subtypes)	Increases cAMP by activating adenylate cyclase

Based on this information, it appears that binding of ligand to α2 and β receptors would have opposite effects. While it is true that effects of transmitter binding to α1 and β receptors produces excitatory responses, whereas binding of norepinephrine to α2 causes inhibitory responses, there is a complication. In the central nervous system, α2 receptors are mostly presynaptic autoreceptors, such that ligand binding to the receptor reduces norepinephrine release from the nerve terminal. In contrast, α1 and β receptors are usually postsynaptic.

Dopamine

Dopamine is mainly a neurotransmitter of the central nervous system, although some peripheral tissues (e.g., cells in the kidney) also use dopamine as a signaling molecule. There are 5 main subtypes of dopamine receptors (D1-D5), all of which exert their effects by activating G-proteins. Most dopamine receptors are postsynaptic, but some are presynaptic (autoreceptors).

Most dopaminergic neurons are located in two midbrain areas, substantia nigra pars compacta and the ventral tegmental area. Neurons in substantia nigra pars compacta project to regions of the basal ganglia called the striatum, parts of the brain that are involved in movement control. Degeneration of these connections (nigro-striatal pathway) results in Parkinson's disease. These connections will be discussed during the second week of the class. Dopamine-producing neurons in the ventral tegmental area project to prefrontal cortex, and structures of the limbic system. These connections are a fundamental part of the brain's reward system, and also have roles in cognition. Changes in dopaminergic transmission in this pathway can result in psychiatric diseases, including schizophrenia and attention deficit hyperactivity disorder. These connections will be discussed during this course, and in the psychiatry course.

---

Summation

Now that we have discussed a bunch of neurotransmitters, let's review what they do by watching a movie from the KhanAcademy.
If the movie does not play in this window, or you would like to see it in a window of alternate size, download it from this link.