some controversy……..

Muscarinic agonists – Muscarine

some controversy…….. Muscarinic agonists – Muscarine Muscarinic antagonists Synthetic 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 mao homovanillic acid (HVA) pnmt catecholamines MHPG mao

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 system 2 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 2 nd 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)hindbrain

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 functionshindbrain

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 pathwayshindbrain

medulla hindbrain

pons – Contains part of the reticular formation Nuclei important for sleep and arousalhindbrain

pons – Contains part of the reticular formation Nuclei important for sleep and arousal – Specific nuclei include Raphe (5HT) – sleep and dreaming Locus coerulus (NE) - arousalhindbrain

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 Cerebellumhindbrain

Sensory information – reticular formation movement – substantia nigra - midbrain

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

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

S ome 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