some controversy some controversy Muscarinic agonists Muscarine some

some controversy……. .

some controversy……. . Muscarinic agonists – Muscarine

some controversy……. . Muscarinic agonists – Muscarine Muscarinic antagonists Synthetic and natural-

monoamines � DA – dopamine � NE – norepinephrine � 5 HT - serotonin

DA (dopamine) � CNS - reward, movement, motivated behaviors, executive function? � numerous DA pathways in CNS of importance for psychotropics…. .

DA receptor subtypes � DA receptor subtypes ◦ 2 major families – D 1 and D 2 families

NE (norepinephrine) � 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

NE receptor subtypes � receptor subtypes ◦ alpha 1 and 2; β 1 – 3

How are catecholamines taken removed from the synapse? � Catecholamines removed by reuptake: ◦ DAT – DA transporter ◦ NET – NE transporter

metabolism � metabolism – ◦ far slower than ACh by ACh. E

metabolism � metabolism – ◦ far slower than ACh by ACh. E ◦ MAO enzymes (monoamine oxidase)

metabolism � metabolism – ◦ far slower than ACh by ACh. E ◦ MAO enzymes (monoamine oxidase) �MAOA AND MAOB enzymes �MAO A – more selective for NE and 5 HT

metabolism � metabolism – ◦ far slower than ACh by ACh. E ◦ MAO enzymes (monoamine oxidase) �MAOA AND MAOB enzymes �MAO A – more selective for NE and 5 HT �MAO B- more selective for DA

� Major metabolites: ◦ Important when trying to study potential differences ◦ DA - dopac and HVA ◦ NE - MHPG -(3 -methoxy-4 -hydroxyphenethyleneglycol)

Tyrosine catecholamines Tyrosine hydroxylase (rate limiting step) TH DOPA Aromatic acid decarboxylase Dopamine (DA) DA-β-hydroxylase o ma Norepinephrine (NE) mao homovanillic acid (HVA) MHPG pnmt Epinephrine (E)

5 HT � 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 5 HT in whole body is in brain) � cannot cross bbb so……

5 HT � behavioral behavior � abnormal role (CNS): sleep, aggressive function implicated in: ◦ schizophrenia, depression, phobic disorders, OCD, eating disorders, migraine, etc

5 HT � synthesis ◦ amino acid precursor – tryptophan

5 HT � synthesis ◦ amino acid precursor – tryptophan ◦ elimination of dietary tryptophan can significantly lower brain 5 HT levels

5 HT � synthesis ◦ amino acid precursor – tryptophan ◦ elimination of dietary tryptophan can significantly lower brain 5 HT levels ◦ foods high in tryptophan; �nuts (ie walnuts, almonds), tofu, milk, eggs, certain cheeses, turkey, seafood, seeds

5 HT � receptor subtypes- many – at least 18 subtypes have been identified - probably best way to group 5 HT 1 and 5 HT 2 families; - some are metabotropic; some ionotropic

5 HT � reuptake ◦ SSRIs main mechanism for terminating � breakdown – major metabolite 5 HIAA

amino acid neurotransmitters � pervasive throughout the brain � classified into 2 general categories ◦ excitatory (glutamate, aspartate) ◦ inhibitory (GABA, glycine) � amino acids are more difficult to classify as nt

GABA � 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 A � 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

glutamate � 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 (m. GLUR) ◦ families within these ◦ role of neuromodulators � current potential interests ◦ reducing neurotoxicity, psychiatric disorders, substance use disorders, Alzhemiers Disease?

memantine � 2005 – first non ACh. E inhibitor for treating AD � Only approved for advanced (not early stage) � uncompetitive low-to-moderate affinity NMDA receptor antagonist � Multiple other uses possible

More about histamine ◦ 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

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

Autonomic NS has two components 1. Sympathetic NS “fight or flight” activated during emergencies, stress and/or arousal

2. Parasympathetic nervous system � Maintain homeostasis, energy restoration ◦ physiological changes:

2 nd part of the PNS is the somatic nervous system � voluntary nervous system ◦ sensory and motor nerves ◦ connection between all motor nerves and muscle (NMJ – neuromuscular junction) are nicotinic ACh synapses

2 divisions of the nervous system � CNS – Central Nervous System � PNS – Peripheral Nervous System ◦ brain, spinal cord ◦ Somatic, autonomic

brain � 3 main divisions of brain ◦ hindbrain; midbrain; forebrain

hindbrain Medulla

hindbrain � 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 functions

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 functions ◦ Various ascending and descending pathways

hindbrain medulla

hindbrain � pons ◦ Contains part of the reticular formation �Nuclei important for sleep and arousal

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

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

midbrain � Sensory information ◦ reticular formation � movement ◦ substantia nigra -

forebrain � cortical and subcortical structures

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

Some subcortical structures � thalamus

The thalamus communicates with much of the cerebral cortex serving as a sensory and motor information relay.

Some subcortical structures � thalamus � hypothalamus

Some subcortical structures � thalamus � hypothalamus � limbic system

Some subcortical structures � thalamus � hypothalamus � limbic system � basal ganglia

Some major nt pathways

3 major DA fiber tracts �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

Neurotransmitters and Receptors Peptides � Opioids ◦ ◦ Mu Delta Kappa Endorphins and enkephalins are opioids � Substance P