Lecture 8-12 (Textbook+note version) Flashcards
———-make up a small but important group of neurotransmitters and hormones called catecholamines. The term catecholamine is derived from the fact that the members
of this group all share two chemical similarities: —-
- DA, NE, and the related substance epinephrine (EPI)
- a core structure of catechol and a nitrogen-containing group called an amine
monoamines (4)
Dopamine + Norepinephrine + Epinephrine + Serotonine
transmitters that possess one amine group
The adrenal medulla secretes —– into the bloodstream, where they act as —–. You will recall from Chapter 3 that stimulation of catecholamine secretion from the adrenal glands is a vital part of the physiological response to —-.
- EPI and NE
- hormones
- stress
Hormone vs Neurotransmitter
The synthesis of catecholamine neurotransmitters occurs in several steps:
- The biochemical pathway begins with the amino acid tyrosine. Like other amino acids, tyrosine is obtained from dietary protein and is transported from the blood into the brain.
- Neurons that use DA as their transmitter contain only the first two enzymes, tyrosine hydroxylase (TH) and aromatic
amino acid decarboxylase (AADC), and thus the biochemical pathway stops at DA - In contrast, neurons that need to synthesize NE also possess the third enzyme, which is called dopamine β-hydroxylase (DBH).
- The conversion of tyrosine to dihydroxyphenylalanine (DOPA) by TH occurs at a slower rate than subsequent reactions in the biochemical pathway. Consequently, TH is the rate-limiting enzyme in the pathway because it determines the overall rate of DA or NE formation.
The activity of TH is regulated by a variety of factors, including how much DA or NE is present within the nerve terminal. High catecholamine levels tend to —- TH, thus serving as a negative feedback mechanism. Another important factor is the rate of cell firing, because neuronal activity has a —– effect on TH. The mechanism by which cell firing stimulates TH activity is through phosphorylation of the enzyme.
- inhibit
- stimulatory
These elegant mechanisms of phosphorylation activation and catecholamine feedback inhibition enable dopaminergic and noradrenergic neurons to carefully control their rate of neurotransmitter formation. When the levels are too high, —- is inhibited and catecholamine synthesis is slowed. But when the neurons are activated and firing at a high rate, such as during stress, —- is stimulated and catecholamine synthesis accelerates to keep up with the increased demand.
- TH
- TH
Although the enzymes involved in synthesizing catecholamines
(as well as other classical transmitters like acetylcholine and serotonin) can be found throughout the neurons using those transmitters, the rate of synthesis is greatest at the ——.
nerve endings near the sites of transmitter release
Role of l-DOPA
- Catecholamine formation can be increased by
the administration of biochemical precursors such as
tyrosine and l-DOPA. Furthermore, certain cognitive
functions such as working memory can be modestly
but measurably enhanced by tyrosine administration
under conditions of high cognitive demand or stress
(reviewed by Hase et al., 2015; Jongkees et al., 2015). - Such enhancement is thought to occur because dopaminergic and noradrenergic neurons are activated under
the aforementioned conditions, and therefore tyrosine
supplementation provides the necessary substrate to
keep up with the demand for increased neurotransmitter synthesis. - Dopamine cannot cross blood-brain but L-DOPA can (give to make more dopamine), used to give with Carbidopa to prevent L.Dopa from being converted to something else.
Vescular packagig is important because (2)
Vesicular packaging is important not only because it provides a means of releasing a predetermined amount of neurotransmitter (usually several thousand molecules per vesicle), but also because it protects the neurotransmitter from degradation by enzymes within the nerve terminal.
Vesicular monoamine transporter (VMAT) (3)
What + type + blocked by
- A specific protein in the vesicle membrane is responsible for vesicular catecholamine uptake. This protein recognizes several different monoamine transmitters and therefore is called the vesicular monoamine transporter (VMAT).
- There are actually two related VMATs: VMAT1 is found in the adrenal medulla, whereas VMAT2 is present in the brain.
- Both of these vesicular transporters are blocked by an
interesting drug called reserpine, which comes from the roots of the plant Rauwolfia serpentina (snake root)
Blocking the vesicular transporter means that —-. As a result, both transmitters temporarily —— in the brain. The behavioral consequence of this neurochemical effect is sedation in animals and depressive symptoms in humans.
- DA and NE are no longer protected from breakdown within the nerve terminal
- drop to very low levels
The sedative effects of reserpine could be reversed by restoration of catecholamines with —–, the —–
- DOPA
- immediate biochemical precursor of DA
Release of catecholamines normally occurs when ——-. Certain drugs, however, can cause a release of catecholamines independently: —–
- a nerve impulse enters the terminal and triggers one or more vesicles to release their contents into the synaptic cleft through the process of exocytosis
- The psychostimulants amphetamine and methamphetamine. In humans, amphetamine and methamphetamine produce increased alertness, heightened energy, euphoria, insomnia, and other behavioral effects. They interact with VMAT to cause release of neurotransmitter into synapse and block reuptake
In contrast to the behavioral sedation associated with reserpine-induced catecholamine depletion, catecholamine release leads to ——. In laboratory animals such as rats and mice, this activation may be shown by increased locomotor activity. At high doses, locomotor activation is replaced by stereotyped behaviors consisting of intense sniffing, repetitive head and limb movements, and licking and biting.
- behavioral activation
Firing pattern of the neuron is yet another factor that influences catecholamine release. This has
been studied extensively in midbrain dopaminergic
neurons, which fire in two different patterns. In single-spiking mode, the cell generates action potentials
(“spikes”) that appear at —- intervals but with
a typical average frequency of 4 to 5 Hz (4–5 spikes
per second). Excitatory input to the cell can switch it
from single-spiking mode to — mode, which is
characterized by trains of 2 to 20 spikes at a frequency of approximately 20 Hz. The difference between
these firing modes can be seen in firing patterns of dopaminergic neurons within the ventral tegmental area (VTA) in a rat under conditions of quiet wakefulness,
slow-wave sleep, rapid-eye-movement (REM) sleep,
and feeding: —– can be seen during REM sleep
and feeding, which is the result of —–. DA released when the cell is in single-spiking mode is often called —- release,
whereas DA released in burst mode is called —-
release.
- irregular
- burst
- Burst firing
- greater dopaminergic neuronal activation
- tonic
- phasic
Ascending dopamine pathways: nigrostriatal pathway (2)
location + role + cell number
- Axons of dopaminergic neurons in the substantia nigra ascend to a forebrain structure known as the caudate–putamen or dorsal striatum.
- motor function + reward + associative leaning/operant learning
- A9
Ascending dopamine pathways: mesolimbic dopamine pathway
location + role + cell number
- Some of the axons from these neurons travel to various structures of the limbic system, including the nucleus accumbens (the major component of the ventral striatum), septum, amygdala, and hippocampus.
- locomotor behaviour, reward
- A10
Ascending dopamine pathways: mesocortical
dopamine pathway
location + role + cell number
- Other DA-containing fibers from the VTA go to the cerebral cortex, particularly the prefrontal cortex (PFC).
- Addiction + executive functions
- A10
In the early stages of research on DA receptors, investigators discovered that D1 and D2 have opposite effects on the second-messenger substance cyclic adenosine monophosphate (cAMP):
D1 receptors stimulate the enzyme adenylyl cyclase, which is responsible for synthesizing cAMP (see Chapter 3). Consequently, the rate of cAMP formation is increased by stimulation of D1 receptors. In contrast, D2 receptor activation inhibits adenylyl cyclase, thereby decreasing the rate of cAMP synthesis. These opposing effects can occur because the receptors activate two different G proteins: Gs in the case of D1 receptors, and Gi in the case of D2 receptors
locus coeruleus (LC)
location + number
- the LC sends fibers to almost all areas of the forebrain, thereby providing nearly all of the NE in the cortex, limbic system, thalamus, and hypothalamus (FIGURE 5.15). The LC also provides noradrenergic input to the cerebellum and the spinal cord.
- a small area of the pons that contains a dense collection of noradrenergic neurons corresponding roughly to the A6 cell group (according to the numbering system described previously).
