postsynaptic receptors protein embedded in membrane mechanism for neurotransmitter to influence postsynaptic activity by binding to receptor

Neurotransmitters and Receptors There are different varieties of receptors. Some respond fast Called Ionotropic Direct reaction to the transmitter

Neurotransmitters and Receptors Different varieties of receptors: Other types of receptors respond more slowly. Indirectly Called Metabotropic, or G protein-coupled Initiates a second signal (messenger) inside the neuron.

Neurotransmitters and Receptors Inactivation: Termination of Synaptic Transmission Metabolism Re‑uptake

E

Neurotransmitters and Receptors Acetylcholine—first to be recognized, because of peripheral actions Synthesis Acetyl-CoA (in mitochondria) + choline (from diet)

Choline+ Acetyl cOA Acetylcholine (ACh) Acetylcholine cHat (choline acetyl transferase) Acetylcholine (ACh) Choline +acetate AChE (Acetylcholinesterase)

Neurotransmitters and Receptors Inactivation: Acetylcholinesterase (AChE) After action in postsynaptic cleft, AChE degrades ACh to choline and acetate, which are taken back up into the neuron.

ACh found in both CNS (brain and SC) and PNS (Somatic and autonomic NS)

Acetylcholine (ACh) Functions (in PNS) Functions (in CNS) memory, sensory processing, movement, REM sleep Functions (in PNS) many psychotropics have anti ACh effects

Acetylcholine (ACh) cholinergic receptor subtypes 2 classes labeled by agents that act as agonists at receptor

Acetylcholine (ACh) nicotinic – muscle, neuronal - majority are ionotropic at least 17 subtypes some muscular; some CNS number of nicotinic receptors are growing…..

Nicotinic drugs….. nicotinic agonists – nicotinic antagonist varenicline (Chantix) – smoking cessation partial agonist nicotinic antagonist “botox”- botulism toxin

Acetylcholine (ACh) muscarinic – 5 subtypes discovered so far; all metabotropic (M1-M5)

Some Pharmacological Actions for M ACh antagonists scopolamine – motion sickness some meds for asthma treating side effects of some PD meds

Acetylcholine (ACh) malathion, parathion, (pesticides) ways to alter ACh activity AChE inhibitors some “irreversible” AChE inhibitors: malathion, parathion, (pesticides) nerve gas (Sarin) “reversible cognitive enhancers donepezil (Aricept)

Disease states that involve ACh neurons MG – myasthenia gravis autoimmune disease affecting NMJ Alzheimers Disease - AD temporary “fixes” for these disease states “reversible” AChE inhibitors -tacrine (Cognex), donepezil (Aricept) Strategy in both cases………

Anticholinergic Side Effects can include confusion, blurred vision, constipation, dry mouth, light-headedness, urinary retention, loss of bladder control.

choline rich foods Whole eggs, liver, beef steak, and soy are among foods naturally rich in choline.

catecholamines Dopamine (DA) Norephinephrine (NE)

catecholamines NE and E are synthesized from their precursor DA with the appropriate enzymes present

tyrosine hydroxylase DA decarboxylase DA β hydroxylase PNMT

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

Neurotransmitters and Receptors Catecholamines Synthesis Tyrosine Dopamine Norepinephrine Termination Re-uptake Monoamine oxidase (MAO)

metabolism metabolism – MAOA AND MAOB enzymes 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 catecholamines Tyrosine hydroxylase (rate limiting step) TH DOPA Aromatic acid decarboxylase mao homovanillic acid (HVA) Dopamine (DA) DA-β-hydroxylase mao MHPG pnmt Norepinephrine (NE) Epinephrine (E)

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 – D1 and D2 families

NE (norepinephrine) 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 receptor subtypes receptor subtypes alpha 1 and 2; β 1 – 3

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

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

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 anticonvulsants are being considered for various psychiatric disorders

modulatory effects

glutamate found in high concentrations in brain serves many functions receptor subtypes: tremendous work done in recent years

glutamate receptor subtypes: current potential interests 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?

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