Chapter 3 Central nervous system - general information

Question 1

Treatable neurotransmission diseases

Answer 1

• too few NT molecules binding to postsynaptic neurons (e.g. depression, parkinson’s disease)

Question 2

norepinephrine

Answer 2

• leading hypothesis suggests that depression is caused by impaired monoamine (e.g., norepinephrine, dopamine, and serotonin) neurotransmission
• drugs that induce monoamine release are for attention deficit disorder and narcolepsy

Question 3

dopamine

Answer 3

• amino acid Tyrosine => dopa (hydroxylated) => dopamine (decarboxylated) in presynpatic neuron
• degraded by monoamine oxidase A in the brain and monoamine oxidase B outside the CNS and by catechol-O-methyl transferase (COMT)

Receptors classified
1) D1 (excitatory)
2) D2 (inhibitory)

• Apomorphine is a D2 agonist

Important dopaminergic pathways
1) nigrostriatal pathway (substantia nigra to striatum) — influence voluntary movement through basal ganglia motor loops. Along with the mesolimbic and mesocortical dopaminergic pathways, the nigrostriatal dopamine pathway can also influence other brain functions, including cognition, reward, and addiction.
2) neurons of the chemoreceptor trigger zone of the medulla (controls vomiting)
3) projections from hypothalamus to intermediate lobe of the pituitary (thought to regulate prolactin release)

• dopamine-stimulated adenylate cyclase (associated with D1 receptor activation) can be inhibited by antipsychotic drugs
• plus block D2 dopamine recpetors
• suggesting psychoses result from overstimulation of dopamine receptors
• Parkinson’s disease — caused by too little dopaminergic input from substantia nigra into striatum; loss of nigrostriatal dopamine neurons l/t relative dec in dopamine input (inhibitory) compared to acetylcholine input

D1: memory, attention, impulse control, regulation of renal function, locomotion
D2: locomotion, attention, sleep, memory, learning

D1 receptors are located mainly in the striatum and the cerebral cortex and are involved in movement regulation, motivation, and attention–as mentioned above (1). When D1 receptors are activated, it causes a release of the secondary messenger cAMP (cyclic adenosine monophosphate) which activates the PKA protein (protein kinase A) and leads to the phosphorylation of target proteins (4).

D2 receptors, meanwhile, are primarily located in the striatum, the substantia nigra, and the hypothalamus. They are similarly involved in movement regulation and motivation, but D2 receptor activation–as well as following the dopamine pathway described above–can inhibit certain signalling pathways.

Question 4

Serotonin 5-HT (5-hydroxytryptamine)

Answer 4

• amino acid tryptophan ==> hydrodyxlated then decarboxylated => form 5-HT or serotonin
• INSIDE neuron => 5-HT is stored (in vesicles) [released then taken back up in presynpatic neurons then recycled or metabolized]

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• released from inhibitory neurons (raphe nuclei of pons and medulla)
• stimultes 5-HT1 or 5-HT2 receptors (distingushed by specific antagonist ketanserin (5-HT2-specific)

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• LSD (lysergic acid diethylamide) is potent agonist of both receptors

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• Role as NT, but inc small intestine motility and modulates vasodilation
• 90% of 5-HT is stored in enterchromaffin cells of small intestine
• Depression, attention deficit d/o, headaches d/t serotonergic imbalances

Serotonin plays a key role in such bodily functions as mood, sleep, appetite, anxiety, digestion, blood clotting and sexual desire.

Question 5

Acetycholine

Answer 5

• binds to muscarinic and nicotinic receptors
• cholinergic antagonist is used to tx Parkinson’s disesae to correct ach imbalance and dopamine neurotransmission created by degradation of dopaminergic nerves
• e.g Rivstigmine (cholinesterase inhibitor) — Alzheimer’s disease for symptomatic treatment [cholinergic in this case)

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• Cholinergic and anti-cholinerigc drugs are otherwise not used to tx CNS d/o’s

Question 6

GABA or gamma amino butryic acid

Answer 6

• inhibitory amino acid NT of brain interneurons and other cerebral neurons
• Glutamate (catalyzed by enzyme glutamic acid decarboxylase) into GABA
• Released from presynaptic then binds to GABA-A or B receptors

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* GABA receptors reside on two subunits (of a four subunit receptor that regulates cl- ion channel)
* GABA activation ==> induces cl- influx into neuron
* causing hyperpolarization of neuron; making it difficult to fire when stimulated by excitatory NT

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• Benzodiazepines — enhance actions of GABA at GABA-A receptors but not at GABA-B receptors
• This includes barbiturates with similar effect ==> tx anxiety, seizures and as sedatives or muscle relaxants

Question 7

Excitatory amino acids (EAA)

Answer 7

• glutamate (excitatory NT in many areas of brain)
• Stimulation of EAA receptors => causing inc’d cation conductance l/t depolarization or stimluates phosphatidyl inositol turnover (variety of cellular processes with relevance to health and disease that include B cell activation and autoantibody production, insulin sensitivity, neuronal dynamics, endocytosis and cell migration.)

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• important in learning, memory, and other brain fx
• Glutamate-induced exitoy toxicity implicated in pathogenesis of Alzheimer’s disease, huntington’s disease, stroke, epilepsy, and ALS
• Riluzole protects neurons from glutamate toxicity in animals + slows progression of ALS

Question 8

Opioids

Answer 8

• Endoprhines, enkephalins, and dynorphins
• all are opiate receptor agonists cleaved from a protein called pro-opiomelanocortin
• **located along periaqueductual gray matter and other brain areas*

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* morphine and other related drugs act at opiate receptors to relieve pain
* during stress or pain, endogenous peptides act on these same opiate receptors

Question 9

Other neuropeptides

Answer 9

• e.g endogenous opiate peptidse
• continued – substance P, vasoactive intestinal peptide
• d/t variety of 3d shapes difficult to assess chemistry of peptide recpetor interactions (no chemical agonists other than morphine or any antagonists have been identified for peptide receptors)