some controversy…….. muscarinic agonists – muscarine

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