Central Nervous System Neuropharmacology [1]

Question 1

Acetylcholine: roles as CNS neurotransmitters in hierarchical vs diffuse neuronal system

Answer 1

Function: Coordinated movement and cognitive functions (motivation, memory, and learning).

Question 2

Acetylcholine: List the precursors and key enzymes for their synthesis and transporters involved in their storage

Answer 2

Synthesis: Catalyzed by choline acetyl transferase (CAT) - not rate-limiting step (choline uptake)

Storage: ACh is taken up into storage vesicles and packaged for release by the action of the vesicleassociated
transporter (VAT)

Question 3

Acetylcholine: Describe their synaptic inactivation mechanisms

Answer 3

ACh action in the synapse is terminated by enzymatic degradation catalyzed by acetyl-cholinesterase (AChE) located in the synapse

Question 4

Acetylcholine: Describe their receptors and signal transduction systems

Answer 4

1. Muscarinic receptors
   M1-M3: Gq&raquo_space; stimulate PLC activity
   M2-M4: Gi/o&raquo_space; inhibit adenylyl cyclase activity
2. Nicotinic receptors: NN&raquo_space; opens receptor-gated cation channel [ionotropic]

Question 5

Monoamine (DA-NE-Epi): roles as CNS neurotransmitters in hierarchical vs diffuse neuronal system

Answer 5

• Dopamine: Initiation of voluntary movement, necessary for reward –related behaviors, cognitive control of behavior including working memory and control of attention
• Norepinephrine: Regulation of arousal, attention, vigilance, sleep-wake cycle, fear response / anxiety, mood / emotion; descending pathways modulate afferent pain signals
• Serotonin: Influences sleep, arousal, attention, processing of sensory information in cerebral cortex, important aspect of emotion and mood regulation, pain pathways, and eating / drinking behaviors.

Question 6

Monoamine (DA-NE-Epi): List the precursors and key enzymes for their synthesis and transporters involved in their storage

Answer 6

• Catecholamine (NE and DA): Rate-limiting enzyme for both DA and NE synthesis is tyrosine hydroxylase (TH)
• Indoleamine (5HT): Rate-limiting enzyme for 5HT synthesis is tryptophan hydroxylase (TpH)

Similar for all monoamines. Transmitter is taken-up into storage vesicle via the vesicular fmonoamine transporter (VMAT) where it is both packaged for release and protected from degradation by intraneuronal monoamine oxidase (MAO).

Question 7

Monoamine (DA-NE-Epi): Describe their synaptic inactivation mechanisms

Answer 7

Synaptic activity of monoamines is terminated primarily by the action of presynaptic membrane transporters that take the transmitter back into the nerve terminal, i.e., REUPTAKE. Once in the cytosol the transmitter can be inactivated by MAO or transported into the vesicle by VMAT.

Specific transporters exist for each of the monoamines:

• Dopamine transporter (DAT)
• Norepinephrine transporter (NET)
• Serotonin transporter (SERT)

Question 8

Amino acid transmitters (GABA-Glu): roles as CNS neurotransmitters in hierarchical vs diffuse neuronal system

Answer 8

Major inhibitory neurotransmitter in CNS, present at 30-40% of all CNS synapses, both postsynaptically (GABAA and GABAB) and presynaptically (GABAB).

Question 9

Amino acid transmitters (GABA-Glu): List the precursors and key enzymes for their synthesis and transporters involved in their storage

Answer 9

Synthesis intertwined with the synthesis of glutamate (major

excitatory transmitter) via the GABA shunt - formed from Glutamate via GAD (glutamic acid decarboxylase)

Question 10

Amino acid transmitters (GABA-Glu): Describe their synaptic inactivation mechanisms

Answer 10

Action of GABA at synapse terminated by reuptake into the presynaptic nerve terminal and surrounding glial cells; GABA transporter similar to monoamine reuptake transporters.

Question 11

Amino acid transmitters (GABA-Glu): Describe their receptors and signal transduction systems

Answer 11

• GABAA: Opens ligand-gated Cl- channel&raquo_space;> decreases neuronal excitability (IPSPs) [ionotropic]
• GABAB : Gi/o&raquo_space;> inhibit adenylyl cyclase, decrease Ca++ conductance, open K+ channel

Question 12

Develop an understanding of how pharmacologic agents can act to potentiate or decrease the activity of neurotransmitter substances at a synapse by interfering with vesicular storage, by blocking uptake, by blocking metabolism, or by interacting with specific receptors for neurotransmitter substances.

Answer 12

Ok, I’ll work on that.

Question 13

Relate drug action at molecular targets in the synapse to pharmacologic responses in various CNS disorders

Answer 13

x

Question 14

Monoamine (DA-NE-Epi): Describe the synaptic inactivation mechanisms of NOREPINEPHRINE

Answer 14

Norepinephrine

• α1 adrenergic: Gq  stimulation of phospholipase C activity
• α2 adrenergic: Gi/o  inhibition of adenylyl cyclase activity K+ channel opening
• β1 adrenergic: Gs  stimulation of adenylyl cyclase activity
• β2 adrenergic: Gs  stimulation of adenylyl cyclase activity

Question 15

Monoamine (DA-NE-Epi): Describe the synaptic inactivation mechanisms of DOPAMINE

Answer 15

Dopamine

• D1 dopamine receptor: Gs  stimulation of adenylyl cyclase activity
• D2 dopamine receptor: Gi/o  inhibition of adenylyl cyclase activity

Question 16

Monoamine (DA-NE-Epi): Describe the synaptic inactivation mechanisms of SEROTONIN

Answer 16

Serotonin

• 5HT1A, 1B, 1D: Gi/o  inhibition of adenylyl cyclase activity and opens K+ channel
• 5HT2A, 2B, 2C: Gq  stimulation of phospholipase C activity - closing of Ca++ channel
• 5HT3: Ligand-gated cation channel - excitatory [ionotropic]
• 5HT4: Gs  stimulation of adenylyl cyclase activity

Question 17

Pathophysiological role of Acetylcholine

Answer 17

• Alzheimer’s disease
• Parkinson’s disease
• Schizophrenia

Question 18

Pathophysiological role of Serotonin

Answer 18

Depression
 Anxiety disorders
 Schizophrenia
 Eating disorders

Question 19

Pathophysiological role of Dopamine

Answer 19

 Schizophrenia
 Parkinson’s disease
 Restless leg syndrome
 Obsessive-compulsive anxiety disorder
 Attention deficit / hyperactivity disorder
 Drug abuse

Question 20

Pathophysiological role of Norepinephrine

Answer 20

 Mania
 Depression
 Anxiety disorders (panic attack, posttraumatic stress disorder)
 ADHD

Question 21

Pathophysiological role of GABA (γ-aminobutyric acid)

Answer 21

• Generalized anxiety disorders
• Seizure disorders
• Sleep disorders
• Alcohol abuse and withdrawal
• Huntington disease