Page 1 of 5
Chapter 5: Catecholamines Catecholamines
Catecholamine Synthesis, Release, and Inactivation
- Classical transmitters like catecholamines are manufactured in biochemical steps
- Synthetic pathways regulate the amount of transmitter available for release
- Precursor therapy can boost transmitter synthesis and release in undamaged cells
- Neurotransmitter depletion can be valuable in certain experimental settings
- Catecholamine synthesis occurs in several steps with speci c enzymes acting as catalysts
- TH is the rate-limiting enzyme in the pathway and inhibits the overall rate of DA or NE
formation
- Phosphorylation of enzymes like PKA, PKG, PKC, C, and CaMKII can increase enzyme
activity and caterolamine synthesis.
Catecholamines are synthesized by a multi-step pathway in which tyrosine hydroxylase
catalyzes the rate-limiting step
- Classical transmitters like catecholamines are manufactured in biochemical steps
- Synthetic pathways regulate the amount of transmitter available for release
- Precursor therapy can boost transmitter synthesis and release in undamaged cells
- Neurotransmitter depletion can be valuable in certain experimental settings
- Catecholamine synthesis occurs in several steps with speci c enzymes acting as catalysts
- TH is the rate-limiting enzyme in the pathway and inhibits the overall rate of DA or NE
formation
- Phosphorylation of enzymes like PKA, PKG, PKC, C, and CaMKII can increase enzyme
activity and caterolamine synthesis.
Catecholamine storage and release are regulated by vesicular uptake, autoreceptor activity, and
cell ring rate
- Catecholamines are transported into synaptic vesicles for later release
- Vesicular packaging is important for releasing neurotransmitters and protecting them from
degradation by enzymes within the nerve terminal
- The vesicular monoamine transporter (VMAT) is responsible for catecholamine uptake
- Reserpine, a drug from the roots of the plant Rauwol a serpentina, is an irreversible inhibitor
of both VMAT1 and VMAT2, leading to sedation in animals and depressive symptoms in
humans
- A study by Arvid Carlsson showed that reserpine sedative e ects could be reversed by
replacing it with DOPA, the immediate biochemical precursor of dopamine
- DA plays a critical role in the control of movement in neurological syndromes such as
Huntington's disease, Tourette syndrome, and tardive dyskinesia
- Vesicles grow in size to accommodate extra DA molecules under normal conditions, but can
increase by more than 2-fold with high doses of DA precursor DOPA in mice.
Catecholamines are recycled after release by a process of reuptake
- Inactivation of catecholamines depends on two processes: removal from extracellular uid
and reuptake into postsynaptic or glial cells. neurotransmitter transporters are proteins in the
dopaminergic or noradrenergic neuronal cell membrane that transport neurotransmitters from
their nerve terminals. Neither the DA transporter nor the NE transporter is selective for its
particular neurotransmitter, and neither can take up DA. The importance of transporter-
mediated uptake plays a vital role in cognitive function and cardiovascular function.
Transporter-blocking drugs enhance DA or NE transmission by increasing the amount of
neurotransmitter available to activate receptors for these transmitters. Catecholamine
transporter inhibition is an important mechanism of action of several kinds of psychoactive
fi fi fiff fl
, Page 2 of 5
drugs, including methylphenidate (Ritalin) and amphetamine (Adderall), both of which are
standard treatments for attention-de cit/hyperactivity disorder (ADHD).
Catecholamine levels are regulated by metabolizing enzymes
- Metabolic inactivation is necessary to prevent excessive neurotransmitter accumulation in the
brain
- The initial breakdown of catecholamines involves two enzymes: MAO and COMT
- Two distinct types of MAO (MAO-A and MAO-B) have been identi ed
- Nonselective MAO inhibitors like phenelzine and tranylcypromine have been used in the
treatment of clinical depression
- Selective inhibitors like moclobemide, selegiline, and rasagiline are e ective in elevating brain
DA levels in Parkinson's disease
- COMT is widely expressed and acts on various compounds, including homovanillic acid and
vanillylmandelic acid
- DA has only one major metabolite, HVA, while NE breakdown gives rise to several important
compounds like MHPG and VMA
- Metabolism of NE within the brain leads to MHPG.
Organization and Function of the Dopaminergic System
-
Two important dopaminergic cell groups are found in the midbrain
- Swedish researchers mapped the location of DA- and NE-containing nerve cells and bers in
the brain using a uorescence method in the 1960s
- They developed a classi cation system for catecholamine cell groups designated with A plus
a number from 1 to 16
- Cell groups A1 to A7 are noradrenergic, while groups A8 to A16 are dopaminergic
- The mesolimbic and mesocortical pathways are important to psychopharmacologists
because they have been implicated in the neural mechanisms underlying drug abuse and
schizophrenia
- Dopaminergic neurons in the hypothalamus give rise to the tuberohypophyseal dopamine
pathway, which controls the secretion of prolactin by the pituitary gland
- DA-containing neurons can also be found in sensory structures such as the olfactory bulbs
and retina
- Nerve tracts in the central nervous system are named after the site of origin and termination
sites of the bers.
Ascending dopamine pathways have been implicated in several important behavioral functions
- DA innervation facilitates voluntary movement in the nigrostriatal tract
- Parkinson's disease involves a massive loss of DA neurons and DA denervation of the dorsal
striatum
- Genetic mutations can interfere with DA synthesis and cause symptoms such as hypotonia,
dystonia, and dysfunction of the autonomic nervous system
- Neurotoxins like 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine can
damage dopamine neurons and lesion their ascending pathways
- Animals with bilateral 6-OHDA lesions show severe behavioral dysfunction, including sensory
neglect, motivational de cits, and motor impairment
- Postural asymmetry can also be a result of DA damage, characterized by leaning and turning
towards the damaged side of the brain
- Disruption of the gene for dopamine (THA) in mice can lead to physiological dysfunction and
premature death
- Testing is ongoing to determine the role of dopamine neurotransmitters in neurotransmitter
regulation in behavior and disease.
fi fl fi fi fi fi ff fi
Chapter 5: Catecholamines Catecholamines
Catecholamine Synthesis, Release, and Inactivation
- Classical transmitters like catecholamines are manufactured in biochemical steps
- Synthetic pathways regulate the amount of transmitter available for release
- Precursor therapy can boost transmitter synthesis and release in undamaged cells
- Neurotransmitter depletion can be valuable in certain experimental settings
- Catecholamine synthesis occurs in several steps with speci c enzymes acting as catalysts
- TH is the rate-limiting enzyme in the pathway and inhibits the overall rate of DA or NE
formation
- Phosphorylation of enzymes like PKA, PKG, PKC, C, and CaMKII can increase enzyme
activity and caterolamine synthesis.
Catecholamines are synthesized by a multi-step pathway in which tyrosine hydroxylase
catalyzes the rate-limiting step
- Classical transmitters like catecholamines are manufactured in biochemical steps
- Synthetic pathways regulate the amount of transmitter available for release
- Precursor therapy can boost transmitter synthesis and release in undamaged cells
- Neurotransmitter depletion can be valuable in certain experimental settings
- Catecholamine synthesis occurs in several steps with speci c enzymes acting as catalysts
- TH is the rate-limiting enzyme in the pathway and inhibits the overall rate of DA or NE
formation
- Phosphorylation of enzymes like PKA, PKG, PKC, C, and CaMKII can increase enzyme
activity and caterolamine synthesis.
Catecholamine storage and release are regulated by vesicular uptake, autoreceptor activity, and
cell ring rate
- Catecholamines are transported into synaptic vesicles for later release
- Vesicular packaging is important for releasing neurotransmitters and protecting them from
degradation by enzymes within the nerve terminal
- The vesicular monoamine transporter (VMAT) is responsible for catecholamine uptake
- Reserpine, a drug from the roots of the plant Rauwol a serpentina, is an irreversible inhibitor
of both VMAT1 and VMAT2, leading to sedation in animals and depressive symptoms in
humans
- A study by Arvid Carlsson showed that reserpine sedative e ects could be reversed by
replacing it with DOPA, the immediate biochemical precursor of dopamine
- DA plays a critical role in the control of movement in neurological syndromes such as
Huntington's disease, Tourette syndrome, and tardive dyskinesia
- Vesicles grow in size to accommodate extra DA molecules under normal conditions, but can
increase by more than 2-fold with high doses of DA precursor DOPA in mice.
Catecholamines are recycled after release by a process of reuptake
- Inactivation of catecholamines depends on two processes: removal from extracellular uid
and reuptake into postsynaptic or glial cells. neurotransmitter transporters are proteins in the
dopaminergic or noradrenergic neuronal cell membrane that transport neurotransmitters from
their nerve terminals. Neither the DA transporter nor the NE transporter is selective for its
particular neurotransmitter, and neither can take up DA. The importance of transporter-
mediated uptake plays a vital role in cognitive function and cardiovascular function.
Transporter-blocking drugs enhance DA or NE transmission by increasing the amount of
neurotransmitter available to activate receptors for these transmitters. Catecholamine
transporter inhibition is an important mechanism of action of several kinds of psychoactive
fi fi fiff fl
, Page 2 of 5
drugs, including methylphenidate (Ritalin) and amphetamine (Adderall), both of which are
standard treatments for attention-de cit/hyperactivity disorder (ADHD).
Catecholamine levels are regulated by metabolizing enzymes
- Metabolic inactivation is necessary to prevent excessive neurotransmitter accumulation in the
brain
- The initial breakdown of catecholamines involves two enzymes: MAO and COMT
- Two distinct types of MAO (MAO-A and MAO-B) have been identi ed
- Nonselective MAO inhibitors like phenelzine and tranylcypromine have been used in the
treatment of clinical depression
- Selective inhibitors like moclobemide, selegiline, and rasagiline are e ective in elevating brain
DA levels in Parkinson's disease
- COMT is widely expressed and acts on various compounds, including homovanillic acid and
vanillylmandelic acid
- DA has only one major metabolite, HVA, while NE breakdown gives rise to several important
compounds like MHPG and VMA
- Metabolism of NE within the brain leads to MHPG.
Organization and Function of the Dopaminergic System
-
Two important dopaminergic cell groups are found in the midbrain
- Swedish researchers mapped the location of DA- and NE-containing nerve cells and bers in
the brain using a uorescence method in the 1960s
- They developed a classi cation system for catecholamine cell groups designated with A plus
a number from 1 to 16
- Cell groups A1 to A7 are noradrenergic, while groups A8 to A16 are dopaminergic
- The mesolimbic and mesocortical pathways are important to psychopharmacologists
because they have been implicated in the neural mechanisms underlying drug abuse and
schizophrenia
- Dopaminergic neurons in the hypothalamus give rise to the tuberohypophyseal dopamine
pathway, which controls the secretion of prolactin by the pituitary gland
- DA-containing neurons can also be found in sensory structures such as the olfactory bulbs
and retina
- Nerve tracts in the central nervous system are named after the site of origin and termination
sites of the bers.
Ascending dopamine pathways have been implicated in several important behavioral functions
- DA innervation facilitates voluntary movement in the nigrostriatal tract
- Parkinson's disease involves a massive loss of DA neurons and DA denervation of the dorsal
striatum
- Genetic mutations can interfere with DA synthesis and cause symptoms such as hypotonia,
dystonia, and dysfunction of the autonomic nervous system
- Neurotoxins like 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine can
damage dopamine neurons and lesion their ascending pathways
- Animals with bilateral 6-OHDA lesions show severe behavioral dysfunction, including sensory
neglect, motivational de cits, and motor impairment
- Postural asymmetry can also be a result of DA damage, characterized by leaning and turning
towards the damaged side of the brain
- Disruption of the gene for dopamine (THA) in mice can lead to physiological dysfunction and
premature death
- Testing is ongoing to determine the role of dopamine neurotransmitters in neurotransmitter
regulation in behavior and disease.
fi fl fi fi fi fi ff fi
