some controversy…….. muscarinic agonists – muscarine
TRANSCRIPT
some controversy……..
some controversy……..
Muscarinic agonists –Muscarine
some controversy……..Muscarinic agonists –Muscarine
Muscarinic antagonistsSynthetic and natural-
DA – dopamine NE – norepinephrine 5HT - serotonin
CNS - reward, movement, motivated behaviors, executive function?
numerous DA pathways in CNS of importance for psychotropics…..
DA receptor subtypes◦ 2 major families – D1 and D2 families
In CNS- arousal; role in depression, possible role in spinal analgesia, possible motivated behaviors such as hunger, thirst, sex, anxiety, attention?
NE is in both the CNS and PNS
receptor subtypes◦ alpha 1 and 2; β 1 – 3
Catecholamines removed by reuptake:◦ DAT – DA transporter◦ NET – NE transporter
metabolism –◦ far slower than ACh by AChE
metabolism –◦ far slower than ACh by AChE◦ MAO enzymes (monoamine oxidase)
metabolism –◦ far slower than ACh by AChE◦ MAO enzymes (monoamine oxidase)
MAOA AND MAOB enzymes MAO A – more selective for NE and 5HT
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
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……
behavioral role (CNS): sleep, aggressive behavior
abnormal function implicated in:◦ schizophrenia, depression, phobic disorders, OCD,
eating disorders, migraine, etc
synthesis◦ amino acid precursor – tryptophan
synthesis◦ amino acid precursor – tryptophan
◦ elimination of dietary tryptophan can significantly lower brain 5HT levels
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
receptor subtypes-many – at least 18 subtypes have been identified
- probably best way to group 5HT1 and 5HT2 families;
- some are metabotropic; some ionotropic
reuptake main mechanism for terminating◦ SSRIs
breakdown – major metabolite 5HIAA
pervasive throughout the brain classified into 2 general categories
◦ excitatory (glutamate, aspartate)◦ inhibitory (GABA, glycine)
amino acids are more difficult to classify as nt
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
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
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
modulatory effects
found in high concentrations in brain serves many functions GAD (enzyme – can convert glutamate to
GABA)
found in high concentrations in brain serves many functions GAD (enzyme – can convert glutamate to
GABA) receptor subtypes:
◦ tremendous work done in recent years
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?
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
Overview of nervous system
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
Maintain homeostasis, energy restoration◦ physiological changes:
voluntary nervous system◦ sensory and motor nerves
◦ connection between all motor nerves and muscle (NMJ – neuromuscular junction) are nicotinic ACh synapses
CNS – Central Nervous System◦ brain, spinal cord
PNS – Peripheral Nervous System◦ Somatic, autonomic
3 main divisions of brain
◦ hindbrain; midbrain; forebrain
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)
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
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
medulla
hindbrain
pons◦ Contains part of the reticular formation
Nuclei important for sleep and arousal
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
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
Sensory information◦ reticular formation
movement◦ substantia nigra -
cortical and subcortical structures
frontal
parietal
temporal occipital
Frontal◦ Motor function◦ Prefrontal – higher “executive function”
Frontal◦ Motor function
Prefrontal – higher “executive function”
Parietal◦ Somatosensory function
Temporal◦ Audition◦ emotion
Occipital◦ vision
Prefrontal cortex
Prefrontal cortex
thalamus
The thalamus communicates with much of the cerebral cortex - serving as a sensory and motor information relay.
thalamus hypothalamus
thalamus hypothalamus limbic system
thalamus hypothalamus limbic system basal ganglia
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
Peptides Opioids
◦ Mu◦ Delta◦ Kappa◦ Endorphins and
enkephalins are opioids
Substance P