CNS neuropharmacology Flashcards
Behaviors linked to pre frontal cortex
executive function and attention, motor, pain, negative symptoms (guilt, suicidality)
Behaviors linked to basal forebrain
memory
Behaviors linked to nucleus accumbens
delusions, hallucinations, reward
Behaviors linked to striatum
motor
Behaviors linked to thalamus
pain, sensory relay
Behaviors linked to hypothalamus
sleep
Behaviors linked to cerebellum
motor
Behaviors linked to spinal cord
pain
Behaviors linked to hippocampus
memory
Behaviors linked to amygdala
fear, anxiety panic
List the precursors and key enzymes for the synthesis of acetylcholine
Acetyl-CoA + Choline > ACH + CoA (catalyzed by choline acetyl transferase)
Describe the inactivation mechanisms for acetylcholine
acetylcholinesterase
Which receptors does Ach bind to and what are its actions
Muscarinic receptors: (M1-M3: Gq stimulate PLC activity) (M2-M4: Gi/o inhibit adenylyl cyclase activity). Nicotinic receptors: Nn opens receptor-gated cation channel [ionotropic]
CNS location of ACH
Produced in cell bodies in brain stem and basal forebrain of neurons that widely project to cerebral cortex and hippocampus
Name compounds that affect ACH release, activation and degredation
Botulism decreases release, black widow spider venom increases release, Nicotine (nicotinic agonist), Benztropine (muscarinic antagonist) and diphenhydramine (muscarinic antagonist) all work at the receptor. Donepezil is an ACHE inhibitor
List the precursors and key enzymes for the synthesis of biogenic amines
Catecholamines: Tyrosine > tyrosine hydroxylase converts to L-Dopa (rate limiting) > dopamine > Norepinephrine > epinephrine. Indoleamine (5-HT): Tryptophan > tryptophan hydroxylase converts to 5-OH-tryptophan (rate limiting) > 5-HT > 5-HIAA
How are monoamines stored
Transmitter is taken-up into storage vesicle via the vesicular monoamine transporter (VMAT) where it is packaged for release and protected from
degradation by intraneuronal monoamine oxidase (MAO).Transmitter is taken-up into storage vesicle via the vesicular monoamine transporter (VMAT) where it is packaged for release and protected from
degradation by intraneuronal monoamine oxidase (MAO).Transmitter is taken-up into storage vesicle via the vesicular monoamine transporter (VMAT) where it is packaged for release and protected from
degradation by intraneuronal monoamine oxidase (MAO).
Monoamine termination of action
reuptake by presynaptic membrane: dopamine transporter (DAT), norepinephrine transporter (NET), serotonin transporter (SERT)
List receptors/second messengers for 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
List receptors/second messengers for dopamine
D1 dopamine receptor: Gs stimulation of adenylyl cyclase activity. D2 dopamine receptor: Gi/o inhibition of adenylyl cyclase activity
List receptors/second messengers for serotonin
5HT1A, 1B, 1D: Gi/o inhibition of adenylyl cyclase activity and K+ channel opening. 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
CNS location for dopamine, norepinephrine and serotonin
Dopamine: Substantia nigra > neostriatum pathway (nigrostriatal), ventral tegmental area >
limbic cortex (mesolimbic), ventral tegmental area > frontal cortex pathway (mesocortical),
hypothalamus > pituitary (tuberoinfindibular pathway). Norepinephrine: Cell bodies in pons and brain stem (locus ceruleus) projecting to all levels of brain Serotonin: Cell bodies in raphe regions of pons / upper brain stem that project to all levels of brain. Dopamine: Substantia nigra > neostriatum pathway (nigrostriatal), ventral tegmental area >
limbic cortex (mesolimbic), ventral tegmental area > frontal cortex pathway (mesocortical),
hypothalamus > pituitary (tuberoinfindibular pathway). Norepinephrine: Cell bodies in pons and brain stem (locus ceruleus) projecting to all levels of brain Serotonin: Cell bodies in raphe regions of pons / upper brain stem that project to all levels of brain. Dopamine: Substantia nigra > neostriatum pathway (nigrostriatal), ventral tegmental area >
limbic cortex (mesolimbic), ventral tegmental area > frontal cortex pathway (mesocortical),
hypothalamus > pituitary (tuberoinfindibular pathway). Norepinephrine: Cell bodies in pons and brain stem (locus ceruleus) projecting to all levels of brain Serotonin: Cell bodies in raphe regions of pons / upper brain stem that project to all levels of brain.
Function of dopamine, norepinephrine and seretonin
dopamine: initiate voluntary movement, rewar related behaviors, working memory, control of attention. Norepi: arousal, attention, vigilance, sleep wake cycle, fear, anxiety. Serotonin: sleep, arousal, attention, sensory info processing, emotion/mood, pain, eating/drinking
List drugs that work on norepi action via synthesis, storage, release or termination
a-methyl-p-tyrosine decreases synthsis. Reserpine inhibits storage (VMAT). Amphetamine increases release (NET). Cocaine-Bupropion-Venlafaxine inhibit termination (NET) and Phenelzine inhibits termination (MAOa)
Where do pseudoephedrine, clonidine, mirtazapine and propranolol act
α1 > Pseudoephedrine [indirect ag]
α2 > Clonidine [ag] / Mirtazapine [antag]
β 1-2 > Propranolol
α1 > Pseudoephedrine [indirect ag]
α2 > Clonidine [ag] / Mirtazapine [antag]
β 1-2 > Propranolol
α1 > Pseudoephedrine [indirect ag]
α2 > Clonidine [ag] / Mirtazapine [antag]
β 1-2 > Propranolol
Synthesis of GABA
glutamate > glutamic acid decarboxylase converts to GABA (gamma-aminobutyric acid)
Termination of GABA
reuptake into presynaptic nerve and glial cells by GABA transporter
List 3 drugs that work on GABA at the synapse and their functions
Benzodiazepines: Bind to GABAa (on post-synaptic membrane) receptor to facilitate GABA inhibitory action. Tiagabine: Inhibits reuptake of GABA by
transporter. Vigabatrin: Inhibits degradation by GABA-T (GABA transaminase)Benzodiazepines: Bind to GABAa (on post-synaptic membrane) receptor to facilitate GABA inhibitory action. Tiagabine: Inhibits reuptake of GABA by
transporter. Vigabatrin: Inhibits degradation by GABA-T (GABA transaminase)Benzodiazepines: Bind to GABAa (on post-synaptic membrane) receptor to facilitate GABA inhibitory action. Tiagabine: Inhibits reuptake of GABA by
transporter. Vigabatrin: Inhibits degradation by GABA-T (GABA transaminase)
GABA receptors and second messengers
GABAa: Opens ligand-gated Cl- channel > decreases neuronal excitability (IPSPs) [ionotropic]. GABAB : Gi/o > inhibit adenylyl cyclase, decrease Ca++ conductance, open K+ channel
GABA location/ function
brain and spinal cord - major inhibitory neurotransmitter of CNS
Glutamate synthesis
Glutamine > converted to glutamate by glutaminase
Glutamate termination
reuptake by neuron via neuronal glutamate transporter, or uptake by glial cell transporter where it is converted to glutamine by glutamine synthetase, then taken up by neuron
Glutamate receptors and second messengers
NMDA: Increase Ca++ influx. AMPA: Increase Na+ and Ca++ influx. Kainate: Increase Na+ influx. R1-R5 (Group I): Gq > stimulation of phospholipase C activity. R2-R3 (Group II): Gi/o > inhibition of adenylyl cyclase activity-inhibit VSCC-activate K+
channels. R4-R6-R7-R8 (Group III): Gi/o > inhibition of adenylyl cyclase activity-inhibit VSCCNMDA: Increase Ca++ influx. AMPA: Increase Na+ and Ca++ influx. Kainate: Increase Na+ influx. R1-R5 (Group I): Gq > stimulation of phospholipase C activity. R2-R3 (Group II): Gi/o > inhibition of adenylyl cyclase activity-inhibit VSCC-activate K+
channels. R4-R6-R7-R8 (Group III): Gi/o > inhibition of adenylyl cyclase activity-inhibit VSCC
Alzheimer’s disease pathology and treatment related to cholinergic pathway
Pathology: decreased muscarinic-cholinergic function
Treatment: cholinesterase inhibitors: DonepezilPathology: decreased muscarinic-cholinergic function
Treatment: cholinesterase inhibitors: Donepezil
Parkinson’s disease pathology and treatment related to cholinergic pathway
Pathology: muscarinic-cholinergic overactivity
Treatment: muscarinic antagonist: Benztropine Pathology: muscarinic-cholinergic overactivity
Treatment: muscarinic antagonist: Benztropine
Psychoses pathology and treatment related to cholinergic pathway
Pathology: [??] decreased nicotinic-cholinergic function. Treatment: nicotinic agonist: Nicotine
Depression pathology and treatment related to adrenergic pathway
Pathology: decreased NE activity in cortical areas
Treatment: increase NE activity (acutely) by
1. decrease termination (NET)( Venlafaxine-Amitriptyline), 2. decrease degradation > increase storage - release (MAOA)(Phenelzine) or 3. increase release >α2 antagonist ( Mirtazapine)Pathology: decreased NE activity in cortical areas
Treatment: increase NE activity (acutely) by
1. decrease termination (NET)( Venlafaxine-Amitriptyline), 2. decrease degradation > increase storage - release (MAOA)(Phenelzine) or 3. increase release >α2 antagonist ( Mirtazapine)
Pain pathology and treatment related to adrenergic pathway
Pathology: abnormal neurotransmission in pain pathway (NE). Treatment: decrease termination (NET): Venlafaxine-Amitriptyline
Anxiety pathology and treatment related to adrenergic pathway
Pathology: excessive NE neuronal activity. Treatment: β1-β2 antagonist: Propranolol
Pathology: excessive NE neuronal activity. Treatment: β1-β2 antagonist: Propranolol
Describe roles of L-dopa, amphetamine, Ropinirole, aripiprazole, haloperidol, cocaine and bupropion on the dopaminergic synapse
L-Dopa increases synthesis, amphetamine increases release, Ropinirole is a D2 agonist, Aripiprazole is dopamine partial agonist, haloperidol is D2 antagonist, cocaine inhibits reuptake and bupropion inhibits reuptake (NDRI)
Parkinson’s disease pathology and treatment related to dopaminergic pathway
Pathology: decreased DA activity in nigrostriatal pathway. Treatment: increase striatal dopamine levels by 1. increase synthesis: L-dopa. 2. increase receptor activation: Ropinirole. 3. decrease degradation, increase storage - release: Carbidopa (DDC) -Selegiline (MAOB) - Entacapone (COMT)
Psychoses pathology and treatment related to dopaminergic pathway
Pathology: increased DA activity in mesolimbic pathway. Treatment: dopamine D2 antagonist: Haloperidol
Describe the roles of Fenfluramine, Buspirone, sumatriptan, clozapine, ondansetron, propranolol, fluoxetine, venlafaxine and clomipramine on the serotoninergic system
Fenfluramine increases release, Buspirone is a 5HT1A Partial Agonist, Sumatriptan is a 5HT1D Agonist , Clozapine is a 5HT2A Antagonist, Ondansetron is a 5HT3 Antagonist, Propranolol is a β1-β2 Antagonist, Fluoxetine is a SSRI inhibitor, Venlafaxine is a SNRI inhibitor, Clomapramine is a TCAD reuptake inhibitor
Depression pathology and treatment related to seretonin pathway
Pathology: decreased 5HT activity in cortical areas
Treatment: increase 5HT activity (acutely) by 1. decrease termination (SERT): Fluoxetine-Venlafaxine. 2. decrease degradation: increase storage - release: (MAOA): PhenelzinePathology: decreased 5HT activity in cortical areas
Treatment: increase 5HT activity (acutely) by 1. decrease termination (SERT): Fluoxetine-Venlafaxine. 2. decrease degradation: increase storage - release: (MAOA): Phenelzine
Pain pathology and treatment related to seretonin pathway
Pathology: abnormal neurotransmission in pain pathway. Treatment: decrease termination (SERT): Venlafaxine-Duloxetine
anxiety pathology and treatment related to seretonin pathway
Pathology: excessive amygdala activity (low 5HT activity). Treatment: increase 5HT activity (acutely) by 1. decreaseing termination (SERT): Fluoxetine-Venlafaxine. 2. Partial agonist at 5HT1a: Buspirone
Roles of Diazepam-zolpidem, phenobarbital-alcohol, sevoflurane, flumazenil, baclofen, vigabatrin and tiagabine on the GABAergic pathway
Diazepam-zolpidem, phenobarbital-alcohol and sevoflurane are all GABAa agonists, Flumazenil is a GABAa antagonist, Baclofen is a GABAb agonist, Vigabatrin inhibits degradation and Tiagabine inhibits reuptak
Seizure pathology and treatment related to GABA pathway
Pathology: depressed GABA activity leads to increased spread. Treament: GABA agonists: BDZs-Barbituates
anxiety pathology and treatment related to GABA pathway
Pathology: excessive amygdala activity (low GABA activity). Treatment: GABA agonist: benzodiazepines
Insomnia pathology and treatment related to GABA pathway
Path: excessive amygdala activity/decreased GABA activity. Treatment: GABA agonist: Z drugs (zolpidem)- benzodiazepam
Anesthesia related to GABA pathway
Barbituates used to increase GABA
Roles of lamotrigine, memantine, ketamine, alcohol on glutamatergic pathway
lamotrigine decreases release, memantine, ketamine, and alcohol are NMDA antagonists
Alzheimers pathology and treatment related to glutamate pathway
Pathology: increased neuronal excitotoxicity
Treatment: decrease excitotoxicity via NMDA-R block: Memantine
Pain pathology and treatment related to glutamate pathway
Pathology: abnormal neurotransmission in pain pathway. Treatment: decrease Glu activity via NMDA-R block: ketamine
Seizure pathology and treatment related to glutamate pathway
Pathology: enhanced Glu activity leads to increased spread of excessive neuronal discharge. Treatment: decrease Glu release via VSCC block: Lamotrigine
Anesthesia related to glutamate pathway
nitrous oxide decreases glut activity via NMDA-R block
