some controversy……
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some controversy……. some controversy……. Muscarinic agonists – Muscarine. some controversy……. Muscarinic agonists – Muscarine Muscarinic antagonists Synthetic and natural-. monoamines. DA – dopamine NE – norepinephrine 5HT - serotonin. catecholamines. - PowerPoint PPT PresentationTRANSCRIPT
some controversy……..
some controversy……..
Muscarinic agonists –Muscarine
some controversy……..Muscarinic agonists –Muscarine
Muscarinic antagonistsSynthetic and natural-
• DA – dopamine• NE – norepinephrine• 5HT - serotonin
monoamines
• NE and E are synthesized from their precursor DA with the appropriate enzymes present
catecholamines
tyrosine hydroxylase-rate limiting step
tyrosine hydroxylase
DA decarboxylase
tyrosine hydroxylase
DA decarboxylase
DA β hydroxylase
PNMT
• CNS - reward, movement, motivated behaviors, executive function?
• numerous DA pathways in CNS of importance for psychotropics…..
DA (dopamine)
• DA receptor subtypes– 2 major families – D1 and D2 families
DA receptor subtypes
• In CNS- arousal; role in depression, possible role in spinal analgesia, possible motivated behaviors such as hunger, thirst, sex, anxiety, drug reward?
• NE is in both the CNS and PNS
NE (norepinephrine)
• receptor subtypes– alpha 1 and 2; β 1 – 3
NE receptor subtypes
• Catecholamines removed by reuptake:– DAT – DA transporter– NET – NE transporter
How are catecholamines taken removed from the synapse?
• metabolism –– far slower than ACh by AChE
metabolism
• metabolism –– far slower than ACh by AChE– MAO enzymes (monoamine oxidase)
metabolism
• metabolism –– far slower than ACh by AChE– MAO enzymes (monoamine oxidase)
• MAOA AND MAOB enzymes• MAO A – more selective for NE and 5HT
metabolism
• metabolism –– far slower than ACh by AChE– MAO enzymes (monoamine oxidase)
• MAOA AND MAOB enzymes• MAO A – more selective for NE and 5HT• MAO B- more selective for DA
metabolism
• Major metabolites:– Important when trying to study potential
differences
– DA - dopac and HVA– NE - MHPG -(3-methoxy-4-hydroxy-
phenethyleneglycol)
Tyrosine
Tyrosine hydroxylase (rate limiting step)TH
DOPA
DA-β-hydroxylase
Dopamine (DA)
Norepinephrine (NE) Epinephrine (E)
Aromatic acid decarboxylase
maohomovanillic acid (HVA)
pnmt
catecholamines
MHPGmao
• more recent in our history of studying NT• similarity to LSD• found early in high concentrations in the gut• found in many non neuronal cells (only ~ 1 – 2% of 5HT in
whole body is in brain)• cannot cross bbb so……
5HT
• behavioral role (CNS): sleep, aggressive behavior
• abnormal function implicated in:– schizophrenia, depression, phobic disorders, OCD,
eating disorders, migraine, etc
5HT
• synthesis– amino acid precursor – tryptophan
5HT
• synthesis– amino acid precursor – tryptophan
– elimination of dietary tryptophan can significantly lower brain 5HT levels
5HT
• synthesis– amino acid precursor – tryptophan
– elimination of dietary tryptophan can significantly lower brain 5HT levels
– foods high in tryptophan;• nuts (ie walnuts, almonds), tofu, milk, eggs, certain
cheeses, turkey, seafood, seeds
5HT
• receptor subtypes-many – at least 18 subtypes have been identified
- probably best way to group 5HT1 and 5HT2 families;
- some are metabotropic; some ionotropic
5HT
• reuptake main mechanism for terminating– SSRIs
• breakdown – major metabolite 5HIAA
5HT
• pervasive throughout the brain• classified into 2 general categories
– excitatory (glutamate, aspartate)– inhibitory (GABA, glycine)
• amino acids are more difficult to classify as nt
amino acid neurotransmitters
• first identified in leg of lobster• causes hyperpolarization of neurons• highest concentrations in brain and spinal
cord and virtually absent in peripheral nerve or other organs
• does not cross bbb easily
GABA
• stored in synaptic vesicles (like other nt)• usually removed from synapse via transporter
(GAT)• GABA also found in glia• receptor subtypes:
– GABA A – ionotropic – clinically important– GABA B - metabotropic
GABA
• mediates anxiolytic, sedative, anticonvulsant, muscle-relaxant and amnesic activity
• subunit compositions appear to vary from one brain region to another and even between neurons within a given region
• linked to chloride channel
GABA A
modulatory effects
• found in high concentrations in brain• serves many functions• GAD (enzyme – can convert glutamate to
GABA)
glutamate
• found in high concentrations in brain• serves many functions• GAD (enzyme – can convert glutamate to
GABA)• receptor subtypes:
– tremendous work done in recent years
glutamate
• receptor subtypes:– NMDA, ionotropic, various other receptors
including metabotropic GLU R (mGLUR) – families within these– role of neuromodulators
• current potential interests– reducing neurotoxicity, psychiatric disorders,
substance use disorders, Alzhemiers Disease?
glutamate
memantine
• 2005 – first non AChE inhibitor for treating AD• Only approved for advanced (not early stage)• uncompetitive low-to-moderate affinity
NMDA receptor antagonist• Multiple other uses possible
– acts as a neurotransmitter; also released during immune response; also found in gut
– antihistaminergic effects: • drowsiness, dry mouth, dizziness, sleepiness, upset
stomach, decreased coordination, fatigue, weight gain, dry mouth and throat, upset stomach, fluttery heartbeat, loss of appetite, hives, sleepiness, vision problems
More about histamine
• Overview of nervous system
PNS - peripheral nervous system2 components- autonomic and somatic
1. autonomic nervous system
- “involuntary”- role in emotion and stress- controls smooth muscles, cardiac
muscles and glands
1. Sympathetic NS“fight or flight”activated during emergencies, stress and/or arousal
Autonomic NS has two components
• Maintain homeostasis, energy restoration– physiological changes:
2. Parasympathetic nervous system
• voluntary nervous system– sensory and motor nerves
– connection between all motor nerves and muscle (NMJ – neuromuscular junction) are nicotinic ACh synapses
2nd part of the PNS is the somatic nervous system
• CNS – Central Nervous System– brain, spinal cord
• PNS – Peripheral Nervous System– Somatic, autonomic
2 divisions of the nervous system
• 3 main divisions of brain
– hindbrain; midbrain; forebrain
brain
hindbrain
Medulla
• medulla– Contains part of the reticular formation – (nuclei
involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness)
hindbrainhindbrain
• medulla– Contains part of the reticular formation – (nuclei
involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as
– Nuclei important for vital functions
hindbrainhindbrain
• medulla– Contains part of the reticular formation – (nuclei
involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as
– Nuclei important for vital functions
– Various ascending and descending pathways
hindbrainhindbrain
medulla
hindbrain
• pons– Contains part of the reticular formation
• Nuclei important for sleep and arousal
hindbrainhindbrain
• pons– Contains part of the reticular formation
• Nuclei important for sleep and arousal
– Specific nuclei include• Raphe (5HT) – sleep and dreaming• Locus coerulus (NE) - arousal
hindbrainhindbrain
• pons– Contains part of the reticular formation
• Nuclei important for sleep and arousal
– Specific nuclei include• Raphe (5HT) – sleep and dreaming• Locus coerulus (NE) - arousal
• Cerebellum
hindbrainhindbrain
• Sensory information– reticular formation
• movement– substantia nigra -
midbrainmidbrain
• cortical and subcortical structures
forebrain
frontal
parietal
temporal occipital
4 lobes of cerebral cortex
• Frontal– Motor function– Prefrontal – higher “executive function”
4 lobes of cerebral cortex• Frontal
– Motor function• Prefrontal – higher “executive function”
• Parietal– Somatosensory function
• Temporal– Audition– emotion
• Occipital– vision
Prefrontal cortex
Prefrontal cortex
• thalamus
Some subcortical structures
The thalamus communicates with much of the cerebral cortex - serving as a sensory and motor information relay.
• thalamus • hypothalamus
Some subcortical structures
• thalamus • hypothalamus• limbic system
Some subcortical structures
• thalamus • hypothalamus• limbic system• basal ganglia
Some subcortical structures
Some major nt pathways
• Mesolimbic/cortical – – Involved in reward, possible role in schizophrenia
• Projects to nucleus accumbens and parts of the limbic system
• nigrostriatal – – Important in initiation of movement; system that
degenerates in Parkinsons disease• projections from the substantia nigra to the basal ganglia
• tuberofundibular – – Important for hormonal release via hypothalamus and
pituitary gland
3 major DA fiber tracts
Peptides• Opioids
– Mu– Delta– Kappa– Endorphins and
enkephalins are opioids
• Substance P
Neurotransmitters and Receptors