Neurochemistry / Pharmacology Flashcards
What are the categories of neurotransmitters and examples of each? Which are the two neurotransmitters of the peripheral nervous system?
Amino acids
i. Glutamate
ii. γ-Aminobutyric acid (GABA)
iii. Aspartic acid
iv. Glycine
b. Peptides
i. Vasopressin
ii. Somatostatin
iii. Neurotensin
c. Monoamines
i. Norepinephrine (NE)
ii. Dopamine (DA)
iii. Serotonin (5-hydroxytryptamine [5-HT])
iv. Acetylcholine (ACh)
Peripheral NS - ACh and NE
ACh:
Location, Role, Types of receptors and their location,
Specific Diseases and Drugs: presynaptic NMH release blockade, postsynaptic NMJ receptor blockade, anticholinesterases, conditions that increase ACh concentrations
Location:
i. Autonomic ganglia, ii. Parasympathetic postganglionic synapses, iii. Neuromuscular junction (NMJ)
iv. Renshaw cells of spinal cord
Roles:
i. Thermal receptors ii. Chemoreceptors iii. Taste iv. Pain perception (possibly)
Receptors:
a. Muscarinic receptors i. Subtypes (A) M1, 3, 5: activate phosphatidyl inositide hydroxylase (B) M2, 4: inhibit adenyl cyclase
b. Nicotinic receptors
Both nicotinic and muscarinic are in all sympathetic and parasympathetic preganglionic synapses, muscarinic only in postanglionic parasympathetic terminals and postganglionic sympathetic sweat glands. Nicotinic only at NMJ and adrenal medulla.
a. Presynaptic NMJ release blockade
i. Botulinum toxin: block presynaptic vesicle mobility
ii. Lambert-Eaton syndrome: block presynaptic Ca2+ channels
iii. Sea snake venom
b. Postsynaptic NMJ receptor blockade
i. Myasthenia gravis: ACh receptor antibody
ii. Succinylcholine: depolarizing blockade
iii. Curare: nondepolarizing blockade
iv. α-Bungarotoxin: irreversible ACh receptor blockade
- Anticholinesterases
a. Reversible
i. Neostigmine ii. Pyridostigmine iii. Physostigmine iv. Donepezil, galantamine, rivastigmine, tacrine
b. Irreversible
i. With irreversible anticholinesterases, receptors can be regenerated with pralidoxime (peripherally) and atropine (centrally).
ii. Agents (A) Organophosphates (B) Carbamates (C) Nerve gas
- Conditions/medications that increase ACh concentration a. Acetylcholinesterase inhibitors
i. Pyridostigmine ii. Physostigmine iii. Edrophonium
iv. Donepezil, galantamine, rivastigmine, tacrine
v. Organophosphates vi. Black widow venom
vii. β-Bungarotoxin
b. Enhances of neurotransmission
i. Pyridostigmine ii. 3,4-diaminopyridine
Dopamine: location, receptor types, changes in PD, HD, Schizophrenia, Inactivation of DA
Two primary DA-receptor types found in striatum: D1 (stimulatory) and D2 (inhibitory)
Four main dopaminergic tracts
(A) The nigrostriatal tract accounts for most of the brain’s DA.
(B) The tuberoinfundibular tract controls release of prolactin via D2 receptors. (C) The mesolimbic tract
(D) The mesocortical tract
Schizophrenia: normal D1 receptors and DA transporter, increased D2 receptors in caudate and putamen with decreased linkage between D1 and D2
PD: decreased DA transporter, increased D1 and D2 receptors, normal linkage.
HD- decreased receptors and receptor linkage
Inactivation: MAO and COMT
Norepinephrine (NE): location, effect of drugs, inhibition
Most concentrated in CNS within locus ceruleus of the pons followed by
lateral tegmental area
Stored in vescicles then released: iii. Inhibition of transport (A) Reserpine (B) Tetrabenazine iv. NE is displaced from vesicles by: (A) Amphetamine (B) Ephedrine
Metabolised by COMT:
Reuptake inhibited by: (a) Cocaine
(b) Tricyclic antidepressants (TCAs) (desipramine) (c) Tetracyclic antidepressant (maprotiline)
(d) Selective serotonin reuptake inhibitors (SSRIs)
Lithium: decreases release and increases reuptake
Epinephrine:
Location, synthesis,
Epinephrine is found with NE in:
(A) Lateral tegmental system (B) Dorsal medulla (C) Dorsal motor nucleus
(D) Locus ceruleus
Synthesis:epinephrinesynthesisoccursonlyinadrenalmedullaviaphenyleth-
anolamine N-methyltransferase.
Medications: which receptors do they act on: Neuroleptics Clozapine Amphetamines MAOIs Cocaine TCAs Risperidone and tetrabenazine Selegiline
i. Neuroleptics
(A) Based on D2- and D4-receptor antagonism in the mesolimbic and mesocortical pathways
(B) Antagonism of nigrostriatal pathways produces extrapyramidal side effects.
(C) Antagonism in the chemoreceptor trigger zone produces antiemetic effect. (D) Older neuroleptics mainly block D2 receptor but can block multiple
DA receptors.
(E) D2 affinity correlates to efficacy.
(F) Clozapine
(1) Neuroleptic that is more selective for the D1 and D4 receptors; also binds to: 5-HT2 receptor, α1-adrenergic receptor, muscarinic receptor, histamine (histamine1) receptor
(2) DA neurons in ventral tegmentum develop depolarization inactivation, but neurons in the substantia nigra do not have this effect (i.e., minimal parkinsonism).
ii. Amphetamines
(A) Increase release of DA and NE centrally and peripherally (B) Decrease reuptake of DA
iii. MAOIs: decrease metabolism of DA
iv. Cocaine: blocks reuptake of DA and NE
v. TCAs: block reuptake of DA
vi. Reserpine and tetrabenazine: prevent vesicle storage of DA, epinephrine, and
5-HT, both centrally and peripherally
vii. Selegiline and rasagiline: MAOB inhibitor, increasing DA stores
Serotonin: location, receptors and their agonists / antagonists
Only 1% to 2% of 5-HT in the body is in the brain; widely distributed in platelets, mast cells, (90%) is found in the enterochromaffin cells of the gastrointestinal tract, cardiovascular (vasoconstriction).
In CNS: i. Raphe nuclei that project to the limbic system
ii. Pons/upper brainstem iii. Area postrema
iv. Caudal locus ceruleus v. Interpeduncular nucleus
vi. Facial (cranial nerve VII) nucleus
Receptors:
5-HT1: thermoregularion, sexual behaviour, hypotension
5-HT1a: buspirone (agonist)
5-HT1b/d: sumitriptan (agonist)
5-HT2: vascular contraction, platelet aggregation
5-HT1c and 5-HT2 LSD (agonist), pizotifen, clozapine, ritanserin (antagonists)
5-HT3: ion channels:
metoclopramide, ondansetron, cocaine (antagonists)
Storage disrupted by reserpine and tetrabenazine
Release: increased by amphetamines and fenfluramine
Increased release / blocked reuptake: clomipramine, amitryptiline
Reuptake blocked by:
(A) TCAs: inhibit NE and 5-HT reuptake by presynaptic nerve terminals (B) SSRIs (fluoxetine, sertraline): selectively prevent the reuptake of 5-HT (C) Clomipramine: although a TCA, it is an SSRI.
Switching from SSRI to MAOI and vice versa?
Must wait 2 to 3 weeks after stopping MAOI before initiating SSRI
v. Must wait 5 weeks after stopping SSRI before initiating MAOI
GABA: location of highest concentration, receptors
Effects of benzos, valproate, vigabatrin, caffeine, barbituates
Highest concentration in the basal ganglia
(A) Cerebellum: (granule cell layer) (B) Cortex
(C) Hippocampus
(D) Basal ganglia
GABA-A and -B receptors
a. Inhibitors of GABA transaminase i. Valproic acid
ii. Vigabatrin 6.
a. Benzodiazepines
i. Increase the frequency of chloride channel opening ii. Enhance the effect of GABA on GABA-A receptors
b. Caffeine: neutralizes the effects of benzodiazepines by inhibiting GABA release
c. Barbiturates: prolong the duration of opening
MAOI names?
Complications of MAOI and cheese? MOA?
Treatment?
a. MAOA: clorgyline
b. MAOB: selegiline, pargyline, rasagiline
c. Nonspecific MAOIs: phenelzine, isocarboxazid, tranylcyprominecritically elevated blood pressure when eating tyramine containing foods on MAO-A inhibiting drugs - MAO in GI system usually prevents ingestion of large amounts of tyramine. with MAOI - can ingest large amounts tyramine - causes sudden occipital headache, sweating, fever,, neck stiffness and photophobia.
Treatment: phentolamine 5mg IV or nifedipine 10mg sublingual
Glycine and aspartate?
Glycine is an inhibitory NT of the cord for inhibitory interneurons (renshaw cells) - these inhibit anterior motor neurons of the spinal cord
Aspartate primarily located in the ventral spinal cord and is excitatory increases likelihood of depolarization
Histamine - location,
Highest concentration in hypothalamus within CNS
Action potential: explain
Self propagating regenerative change in membrane potential.
Resting membrane potential:
Potential = -70 mV
( K+ in and Na+ out) Resting membrane potential based on outward K+ current through
passive leakage channels
2. Depolarization:
(A) Potential = +40 mV
(B) Dependent on sodium permeability
(1) Voltage-gated opening of sodium channels increases Sodium permeability and membrane potential decreases from (–70 mV) toward 0.
(b) When the membrane potential reaches approximately –55 mV, sodium channels open dramatically.
(c) The transient increase in sodium permeability allows results in membrane potential of +40 mV.
(d) Voltage-dependent potassium channels will also open in conjunction with sodium channels
- Repolarization:
closure of voltage-gated sodium channels reestablishes po- tassium as the determining ion of the membrane potential.
depending on the ionic currents flowing through the transmistter operated channels two types of postsynaptic potentials are generated following synaptic transmittion EPSP: sodium inward current prevails, causes propogation of AP
IPSP: occurs when K+ outward current prevails and causes hyperpolarization making it difficult to propergate
What do postganglionic sympathetic neurons to sweat glands use?
ACh
What protein does Botox work on?
SNAP-25 protein
