Chapter 5: Catecholamines Flashcards
Catcholamines
Part of monoamine or biogenic amine group
- dopamine- dopaminergic
- norepinephrine- noradrenergic
- epinephrine- adrenergic
Catecholamines are synthesized from the amino acid […]
Tyrosine
- is obtained from the diet (protein)
- Transported from blood to brain
Tyrosine —>
DOPA
DOPA
Enzyme: tyrosine hydroxylase (TH)
- rate-limiting enzyme
- adds -OH group
- regulated by how much DA or NE is present in nerve terminals
- high catecholamine levels inhibit TH (negative feedback)
Cofactors: Fe2+, O2, BH4
DOPA —>
Dopamine
Enzyme: Aromatic amino acid decarboxylase (AADC)
- nonselective
- removes -COOH group
Cofactors: pyridoxal phosphate (vitamin B6)
Dihydroxyphenylalanine (L-DOPA)
Converted to dopamine (DA) in the brain
- administered with peripheral decarboxylase inhibitors
- crosses BB and then is decarboxylated
Dopamine —>
Norepinephrine
Enzyme: dopamine beta- hydroxylase (DBH)
- adds -OH group
Cofactors: Cu2+, O2, Ascorbic acid (vitamin C, reducing agent)
Norepinephrine —>
Epinephrine
Enzymes: para-N-methyltransferase (PNMT)
- adds methyl group
Cofactors: S-adenosylmethionine (SAM)
- methyl donor
TH is critical point in catecholamine synthesis
- TH is rate-limiting enzyme
- TH is regulated by end- product inhibition
- negative feedback
- more DA and DOPA, less TH activity (reduces speed) - Activated by phosphorylation
- increases neural activity increases TH activity
- PKA, PKC/ERK, CaMKII (increases Ca2+ release)
- Ser 40, Ser 31, and Ser 19 in the regulatory domain of TH
Catecholamine are loaded into vesicles by […]
Vesicular monoamine transporter (VMAT)
Vesicular packaging- protects NT from degradation by enzymes within nerve terminals
- blocked from DAT located on nerve terminal
- blocked by reserpine
- DA and NE are no longer protected from breakdown in nerve terminal
- causes sedation in animals and depression in humans - energy provided by a proton gradient
- ATP- drive H+ pump acidified vesicles lumen
VMAT 1- found in adrenal medulla
VMAT 2- in brain
Alpha- methyl-para-tyrosine (AMPT)
Depletes catecholamines by inhibiting tyrosine hydroxylase
- causes return of depressive symptoms
Reserpine
Depletes catecholamines by inhibiting vesicular uptake
- found in snake root
6- hydroxydopamine (6-OHDA)
Damages or destroys catecholaminergic neurons
- taken up by DAT in nerve terminals
- interrupts oxidative phosphorylation and kills nerve terminals
Psychostimulants […] and […] cause release of catecholamines independently of nerve terminals
Psychostimulants amphetamine and methamphetamine cause release of catecholamines independently of nerve terminals
Release of catecholamines is decreased by […]
Release of catecholamines is decreased by autoreceptor activation
- occurs when nerve impulse enters terminal vesicles to release contents into synaptic cleft through exocytosis
- located on cell bodies, terminals, and dendrites of DA and NE neurons
Dopamine D2 autoreceptors
- terminal autoreceptors (synapse activity)
- inhibition of voltage-gated Ca2+ channels (reduce DA release by reducing amount of activity-mediated Ca2+ for exocytosis)
- activation of voltage-gated K+ channels (indirectly reduce Ca2+ influx by shortening duration of AP entering terminal)
- DA released by first few impulses stimulates terminal autoreceptors and reduces amount of DA released by later APs
- Autoreceptors inhibit release indirectly by reducing rate of firing of cell
- Firing pattern of neuron also influence catecholamine release
- Tonic release of DA: single-spiking mode (cell generates APs that appear at irregular intervals but with average frequency of 4-5 Hz)
- Phasic release of DA: burst mode (trains of 2-20 spikes at 20 Hz) - Both DA and NE axons form en passant synapses where fibers swell (varicosities_ along lengths filled with synaptic vesicles and represent sites of neurotransmitter release
Noradrenergic alpha2 autoreceptors
- alpha2 agonist clondine (Catapres)
- alpha2 antagonist yohimbine
- antagonist- enhance rate of release by preventing normal inhibition
- yohimbine- increase NE cell firing and NE release (can induce anxiety) - clinically important in opioid withdrawal and anxiety/ stress- related disorders
Catecholamine releases leads to […] and […] at high doses
Catecholamine releases leads to behavioral activation and stereotyped behavior at high doses
- stereotyped behavior- intense sniffing, repetitive movements and licking and biting
- comes from increasing stimulation of DA receptors from nucleus accumbens and striatum
Inactivation mechanisms are important targets of psychoactive substances
Reuptake:
- DA transporter (DAT)
- NE transporter (NET)
- Na+/MA-ATPase
Enzymatic Degradation:
- Monoamine oxidase (MAO)
- MAO-A: NE metabolism
- MAO-B: DA metabolism - Catechol-O-methyl transferase (COMT): DA metabolism
Metabolites
Breakdown products
DA metabolites:
- homovanillic acid (HVA)
- Dopac
- used as rough estimate of how much DA is used
NE metabolites:
- 3- methoxy-4-hydroxyphenylglycol (MHPG)
- vanillymandelic acid (VMA)
Phenelzine (Nardil)
Increases catecholamine levels by inhibiting monoamine oxidase (MAO)
Amphetamine
Releases catecholamines
Cocaine and methylphenidate
Inhibit catecholamine reuptake
There are 2 primary groups of DA neurons, that give rise to 3 pathways
Substantia Nigra (A9)
- nigrostriatal pathway
Ventral Tegmental Area (VTA) (A10)
- Mesolimbic pathway
- mesocortical pathway
Substantia Nigra (A9)
- projects to the striatum
- nigrostriatal pathway- pathway from substantia nigra to dorsal striatum
- substantia nigra ascend to caudate-putamen or dorsal striatum
Ventral tegmental area, VTA (A10)
Projects to lambic structures and cortex- includes nucleus accumbens, septum, amygdala, and hippocampus
- mesolimbic pathway- has affects on prefrontal cortex
- mesocortical pathway
DA cell groups and pathways
Substantia Nigra (A9)
- Nigrostriatal
- Activation
- Motivation
- Cognition
- Facilitate voluntary movement
VTA (A10)
- Mesolimbic
- Behavioral arousal
- Reward learning - Mesocortical
- Attention
- Working memory
Hypothalamus (A12): paraventricular nucleus—> median eminence
- Tuberohypophyseal- collection of nerves in tubular part of hypothalamus
- prolactin release
Parkinson’s disease
Loss of DA neurons in substantia nigra and denervation of dorsal striatum
Al DA receptors are […]
GPCRs
There are […] types of DA receptors
There are 5 types of DA receptors
D1- like:
- D1 and D5
- Gs coupled
- Stimulate adenylyl cyclase activity
D2- like:
- D2, D3, D4
- Gi coupled
- inhibit adenylyl cyclase activity
- increase gk, hyperpolarize
Nigrostriatal pathway components
Caudate-putamen
Globus pallidus
Mesolimbic pathway components
Olfactory tubercule
Nucleus accumbens
Mesocortical pathway components
Anterior olfactory nucleus
Cerebral cortex
Hippocampus
Lateral septum
Apomorphine
Stimulates DA receptors general (agonist)
- D1/ D2 agonist- promote behavioral activation
- hyperlocomotion
- behavioral stereotypies
- intense sniffing
- head bobbing
- licking, biting
SKF 38393
Stimulates D1 receptors (agonist)
- selective D1 agonist
- promotes grooming
Quinpirole
Stimulates D2 and D3 receptors (agonist)
- D2/ D3 agonist
- increases exploratory behaviors- locomotion, sniffing
SCH 23390
Blocks D1 receptors (antagonist)
- cataleptic
Haloperidol
Blocks D2 receptor (antagonist)
- inhibits behavioral activation - cataleptic - antipsychotic
DA regulates […] along a continuum
DA regulates behavioral activation along a continuum
Lethargy—> locomotion (normal) —-> stereotypies
Reducing DA synthesis or release impairs behavioral activation
AMPT blocks TH activity
Reserpine blocks VMAT
[…] blocks TH activity
AMPT blocks TH activity
- associated with relapse into depression following positive response to antidepressant medication
Reserpine block […]
Reserpine block VMAT
- sedation in animals
- depression in humans
Neurotoxic damage to DA neurons impairs […]
Neurotoxic damage to DA neurons impair behavioral activation
- 6-OHDA selectively damages DA neurons
- 6-OHDA is reuptaken by DAT - Bilateral central lesions induce:
- sensory neglect/ processing deficits
- motivational deficits (cease eating or drinking)
- Parkinsonism motor deficits (loss of nigrostriatal neurons)
Unilateral 6-OHDA lesions to the SNpc
Ipsilateral rotation:
- always move towards lesioned side
- loss of DA input to lesion side
- DA releases behavior on the intact side
Contralateral rotation:
- behavioral super-sensitivity
- D2 receptor up-regulation
VTA DA neurons involved in reward get input from […] and project to […]
VTA DA neurons involved in aversive stimuli get input from […] and project to […]
VTA DA neurons involved in reward get input from lateral dorsal tegmentum (LDT) and project to nucleus accumbens (NAc) [mesolimbic]
VTA DA neurons involved in aversive stimuli get input from lateral have null (LHb) and project to medial PFC (mPFC) [mesocortical]
Behavioral deficits in KO mice are generally similar
TH -/- knock-out (KO)
- lethal-loss of NE results in abnormal heart development - knockout at birth: die at birth
Dopamine-deficient (DD) mice
- helps look at selectivity - deficient feeding, drinking, grooming, locomotor, behaviors - deficits can be rescued by restoring DA to the nigrostriatal pathway and caudate-put amen (dorsal striatum) - ability to synthesize catecholamines was lacking only in DA cells - DA neurons aren’t damaged; just can’t produce DA - DD mice lack DA throughout development bc genetic manipulations are performed at early embryonic stage
D2 receptors are both […] and […]
D2 receptors are both autoreceptors and normal postsynaptic receptors
- leads to inhibition of prolactin secretion
- have higher affinity for DA than D1 receptors
D1 vs D2 receptors
- D1 receptors stimulate adenylyl cyclase which synthesizes cAMP
- D2 receptors inhibit adenylyl cyclase, which decreases cAMP synthesis
- D2 stimulate activation of G-protein that enhances K+ channel opening
D1 and D2 receptor agonists promote […]
DA receptor antagonists suppress spontaneous behaviors ([…])
D1 and D2 receptor agonists promote behavioral activation
- apomorphine, SKF 38393, quinpirole
DA receptor antagonists suppress spontaneous behaviors (catalepsy)
- haloperidol, SCH 23390
Loss of DA transmission results in behavioral super-sensitivity due to receptor up-regulation
6- OHDA lesions
- ipsilateral rotation - contralateral rotation when challenged with apomorphine
Chronic D2 antagonist
- haloperidol - behavioral supersensitivity
Receptor Up-Regulation
Lack of normal NT input causes neurons to increase sensitivity by making more receptors
Behavioral Supersensitivity
Haloperidol treatment stopped to unblock D2 receptors and subjects are given DA agonists, they respond more strongly than controls not treated with haloperidol
- 6-OHDA can also cause behavioral sensitivity
- long-lasting depletion of DA
DA: sedation, catalepsy
- AMPT
- reserpine
- 6- OHDA
- SCH 23390, D1
- haloperidol, D2
Hyperlocomotion, behavioral stereotypies
- amphetamine
- cocaine, methylphenidate
- apomorphine, D1/ D2
- SKF 38393, D1
- quinpirole, D2/ D3
NE- containing neurons are found in parts of brain stem called […] and […]
NE- containing neurons are found in parts of brain stem called pons and medulla
Central NE arises from the […]
Central NE arises from the locus coeruleus (A6)
- nearly all the NE innervation to cortex, diencephalon, lambic system, cerebellum, spinal cord, thalamus and hypothalamus
NE neurons in Sympathetic NS
Autonomic ganglia
Chromaffin cells of the adrenal medulla
LC NE neuron firing=
LC NE neuron firing= arousal
- Projections from LC to medial septal, medial preoptic, and lateral hypothalamus areas have been implicated in wakefulness- promoting effects of NE
There are […] groups of adrenergic receptors
There are 2 groups of adrenergic receptors
- Alpha and beta
Alpha- AR
- a1 Gq- couples to phospholipase C (PLC)
- increase [Ca2+]i - a2 Gi- coupled to adenylyl cyclase
- decrease cAMP
- terminal autoreceptor
- cause inhibition of noradrenergic cell firing and reduction in NE release from terminals
Beta- AR
Beta1 and Beta2
Both B1 and B2 are Gs- coupled to adenylyl cyclase
- increase cAMP
Adrenoreceptors
Founds in cerebral cortex, thalamus, hypothalamus, and cerebellum, hippocampus, and amygdala
Phenylephrine
Stimulate a1- receptors (agonist)
Clonidine
Stimulates a2- receptors (agonist)
Prazosin
Blocks a1- receptors (antagonist)
Yohimbine
Blocks a2- receptors (antagonist)
Propranolol
Blocks B-receptors generally (antagonist)
Adrenergic agonists in the LH promote […]
Adrenergic agonists in the LH promote wakefulness
- Phenylephrine
- Isoproterenol
Phenylephrine
a1- AR agonist
- reduced time in slow-wave and REM
- increased time awake
Isoproterenol
Non-selective B-AR agonist
- increased wake-time/ reduced REM
- no effect on slow-wave
Adrenergic input to the PFC can improve or impair […]
Adrenergic input to the PFC can improve or impair working memory
- a2-AR
- high affinity for NE
- improves performance - a1- AR
- low affinity for NE
- impairs performance
a2- AR agonists
- guanfacine and clonidine
- improve performance on delayed response task
Noradrenergic control of […]
Noradrenergic control of emotional memory
Passive avoidance learning
- foot shock induces fear/ stress
EPI and GC’s released from the adrenal glands; NE from LC
- EPI activates B-AR’s on vagaries afforestation and in liver
- CNS NE potentiates central fear/ anxiety mechanisms
*info transmitted by vagus could reach LC and engage memory mechanisms by stimulating release of central NE
