What are the two types of synapses?
Electrical:
- Connected via Tight junction
- Ions flow through Connexons
- Bidirectional
Chemical:
- Not directly connected
- Chemical messengers are released via synaptic vesicles not the synaptic cleft and bind to receptors on postsynaptic membrane
- Unidirectional
Where are electrical synapses commonly found?
- Cardiac and smooth muscle
- Epithelial
- Neurons and glia
Where does Ca bind to in the presynaptic neuron To induce vesicle release?
- “Release sites” on the intracellular side of the membrane
What factor determines the concentration of neurotransmitter realeased?
Concentration of extracellular Ca
What are the three principal steps of vesicle release?
- Docking - Lie close to plasma membrane
- Primed vesicles can be induced to fuse with plasma membrane
- Fusion - Vesicle fuse with plasma membrane to release Nt
Differentiate rapid and slow local potential.
Rapid:
- Ionotropic receptors
- Results in direct change in ion conductance
Slow:
- Metabotropic receptors
- Indirectly change ion conductance via 2nd messenger
Differentiate Ionotropic vs metabotropic
Ionotropic Form an ion channel
Metabotropic are indirecty linked with ion channels via signal transduction mechanisms such as GPCR
What are the Different Ionotropic receptors?
Nm/Nn Receptors (Cholinergic)
AMPA/Kainate receptors (glutamate)
NDMA receptor (glutamate + Glycine)
Serotonin receptor (5HT-3)
GABA-A Rceptor
Glycine Receptor
Histamine gated chloride channel
How do Cation vs Anion channels differ in their affect on potentials?
Cation - EPSP
Anion - IPSP
What are the common metabotropic receptors?
- Adrenergic
- Muscarinic
- Dopamine
- Glutamare (mGluR1…)
- Histamine
- Serotonin (5HT-1,2)
- Cannabinoid
- Apioid
What type of channel is the GABA/Glycine channel?
Ion gated Chlorine channel
What type of drugs activate GABA A receptors?
- Alcohol
- Benzodiazepenes
What is GABA?
- Predominant Inhibitory NT
- Deficiency related to seizures
- Respond to EtOH and other drugs
What is an important inhibitory NT is spinal cord and lower brain working on motor activity?
Glycine
What is the activity of Strychnine?
Alters glycine activity
Describe Huntington’s Disease.
- Mutation is X4
- Excessive Trinucleotide CAG repeat
- Loss Of Gabaergic neurons
- Autosomal Dominant
- Decarboxylation of glutamate
- Symptoms start at 40; Involuntary movements, Chorea, atrophy of caudate and putamen
- Friedrichs ataxia
Describe action and location of Ach receptors
- Spinal cord and brain
- Targets organs of autonomic system
Nicotinic: Excitatory and found in Neuromuscular junction
Muscarinic: found predominantly in brain; Inhibitory or excitatory
- Excitation/inhibits target organs
- Movement of muscles
- learning and memory
What are the actions and locations of NE/E?
- Brain, spinal cord, and target organs
- Excitatory
Function:
- Fight/flight
What are locations and functions of dopamine?
- Found mostly in brain; frontal lobs, lambic system, substantially Nigra
- Mostly inhibitory
Functions
- Clunatry movement
- emotional arousal and reward system
- movement and inhibition of movement
*Parkinsons Disease
What are the primary locations and functions of Serotonin?
Location
- brain and spinal cord
- Gut
Function:
- Inhibitory and excitatory
- important in depression and sleep disorders
- Digestion
- emotional arousal
- Too much lead to dilated pupils,, twitching and trembling, confusion, shivering, etc
What is the SIGECAPS?
Diagnosis of depression:
Sleep disturbance Interest (Loss of) Guilt Energy (Low) Concentration (Loss of) Appetite (Loss of) Psychomotor retardation Suicidal
What are the different neuromodulators?
Endorphins - Regulate pain and feeling f reinforcement
Substance P - Sensitivity to pain
Neuroleptic P - Regulate metabolic function, especially eating
NO - retrograde NT, Vasodilation
What is the danger of viagra?
- Viagrea increases NO Vasodilation
- Vasodilation can lead to Severe drops in BP, HA, death
What are here 6 ways to modulate Nt release?
- Rate of synthesis
- Storage rate
- NT release
- Nt reuptake
- Deactivation via enzymes
- block/mimic receptor site attachment
Which neurons in the Sympathetic and parasympathetic systems are cholinergic?
All preganglionic of sympathetic
All postganglionoc of Parasympatheic
What are substances which modulate Ach action?
Hemicholinium - Block uptake of Choline
Vesamicol - Inhibit Ach uptake
Botulinum - Block release of Ach
Compare Nicotinic Ach vs muscarinic Ach transmission.
Nic - ion-gated; Fast EPSP;
Musc - GPCR; Slow EPSP or IPSP
What are common muscarinic agonists?
Pilocarpine & Carbachol: USed to treat paralytic lieu’s, Urine retention, glaucoma, and myasthenia gravis by binding Ach receptors
What is a common Musc antagonists?
Atropine - Dec Ach effectiveness
What is the action of bethanechol?
- Relaxes urinary bladder sphincter
- stimulates cholinergic receptors
What is the primary purpose of Pilocarpine and mitosis in glaucoma patients?
- Helps facilitate outflow of aqueous humor
What is the action os succinylCholine?
Attaches to Nicotinic receptors and depolarize junction; Acts longer as it does not get degraded quickly
What is the action of pancuronium?
Neuromuscular blocker used during surgery, etc.
Depolarizing blocking agents which makes the muscles fibers resistant to further stimulation by Ach
What drugs increase Ach receptor stimulation by inhibiting Ach-esterase?
Neostigmine
Physostigmine
Nerve gases (Sarin)
Pesticides like malathione
What is SLUD Syndrome
Caused by overactivation of Ach receptors
Salivation
Lacrimation
Urination
Defacation
Which Nt system is most affected by Alzheimer’s disease?
Cholinergic system
What are the affects of drugs like tacrine, donepezil, rivastigmine, and glantamine on neurpdegenrative disease??
- ChEIs are used to treat Alzheimer’s disease
- Can slow progression; CANNOT STOP progression
How does Myasthenia Gravis differ from Lambert-Eaton disease?
MG —> Antibodies against Ach
LE —> Antibodies against presynaptic voltage gated calcium channels preventing Ach release
How would MG affect the papillary response?
Papillary response in MG is normal due to it being controlled by M3 receptors
MA only affects Nicotinic receptors
What are the three types of incontinence?
- Overflow
- Stress
- Urge
What muscle is involved in overactive bladder?
Detrusor muscle
What drugs are common modulators of catecholamines?
Metyrosine - Inhibit Tyr hydroxylase —> DEC Dopa
Guanethidine/Bretylium - Inhibit NE transport
Cocaine - Inhibit reuptake of SE/NE; Stim DA
Amphetamine - Inhibits reuptake + INC release of NE
How does Reserpine work?
- Blocks neuronal VMAT2 (vesicular Monoamine transporters) receptors and reduces storage of NE/DA
Why is the max dose sale allowed of pseudoephedrine 20 mg?
Pseudoephedrine modulates adrenergic system by modulating dopamine
How is Tyrosine transported into the nerve terminal, and what modulates it?
Transported via Na symporter
Blocked by cocaine and tricyclics antidepressants
What is the effect of Phenelzine, tranylcypromine, and tyramine? Where will you find these substances?
Cause sympathetic activation when combines with MAOA- inhibitors
Found in Red wine, Cheese, and red meat
What are the main locations of the different subclasses of alpha/beta adrenergic neurons?
Alpha-1: Vascular SM, GU smooth muscle, and heart
Beta-1: Heart and kidney
Beta-2: Brachial smooth muscle, vascular smooth muscle, and genitourinary smooth muscle
What are the main actions of alpha 1 receptors?
- Peripheral vasoconstriction
- Increased Contractile
- DEC HR
What is the main actions of Alpha-2 adrenergic receptors?
Peripheral vasodilation
What are the actions of Beta-1 receptors?
- Increased HR
- Increased Contractile Force
- Increased Automaticity
What are the main effects of Beta-2 receptor activation?
- Peripheral Vasodilation
- Bronchodilation
- Uterine smooth muscle relaxation
- GI smooth muscle relaxation
What are the main effects of activation of dopaminergic adrenergic receptors?
Renal Vasodilation
Mesenteric Vasodilation
What is the 2nd messenger systems for alpha-1 and alpha-2 adrenergic receptors?
Alpha-1 —> PLC to PIP2 system
Alpha-2 —> Inhibits adenylyl cyclase
What are important modulators of alpha/beta receptors?
Phenylephrine —> Alpha 1
Clonidine —> Alpha 2
Dobutamine - Beta 1
Terbutaline —> Beta 2
Why is Epinephrine a “last resort.”
Exerts combined alpha and beta agonist activity which has effects on peripheral vasoconstriction in GI and renal beds.
How does Epinephrine dose affect receptor activation?
Low dose —> Only Beta2 resulting in vasodilation on skeletal muscle and decrease peripheral resistance
Intermediate dose —> Both Alpha2/Beta2 equally resulting in no peripheral resistance
High Dose —> Alpha1 will predominate causing vasoconstriction, peripheral resistance, and INC BP
How does Dobutamine differ from use of dopamine?
- Less risk of tachycardia
- No effect of Wedge pressure
- No effect on Renal blood flow
What system is the endocannabinoid system thought to be involved in?
- Feeding behavior
- Control of food intake
- Energy balance
What is Rimonabant?
CB receptor antagonist; reduces excess body weight