Winter Pharmacology CNS Intro

Learning, Memeory, Cognition, Arousal, Attention

Pathways:
From Nucleus basalis of meynert and septum to cerebral cortex and hippocampus; Degeneration = Alzheimers

Corpus Striatum = in balance with DA neurons

M4 receptor dysfnx = Szhizophrenia
M1 widely distributed (IP3 DAG) = excitation
M2 hippocampus and Cortex Gi, K+ hyperpolarize
Nicotinic excitatory

Drugs: Nicotine, Muscarinic Recdeptor Agonists, Cholinesterase Inhibitors

ACh Receptor, Dysfnx implicated in Schizophrenia

Gq widely distributed, causes excitation

Gi decrease cAMP, increase K+ hyperpolarize = inhibitory

found in hippocampus and cortex

Noradrenergic cell bodies in locus ceruleus and reticular formation, project widely throughout brain

NE invovled in affective disorders (& maybe anxiety)
Depleted NE = Depression

alpha1 Gq
Alpha2 presynaptic are inhibiotry, post synaptic hyperpolarize
Beta1: widely distributed
Beta2: cerebellum

Cocaine & some anti-depressants inhibit re-uptake, amphetamine causes release

Beta 1 = widely distributed
Beta 2 = Cerebellum

Nigro-striatal system involved in movement; Degeneration = Parkinson's

Overabundance of cortical DA = Schizophrenia

Dopaminergic pathways from Ventral Tegmental area to nucleus accumbens of prefrontal cortex are involved in reinforcement and addiction

many subtypes 1-5 all are metabotropic and inhibitory
D1 oddly increases cAMP
Presynaptic D2 inhibitory decrease Ca2+ influx
Postsynaptic D2 Gi

Schizophrenic Symptoms

Projects from raphe nucleus to limbic system and cerebral cortex

Tryptophan Hydroxylase is the Rate Limiting Enzyme
MAO breaks it down

Seems to promote sleep, regulate appetite, body temperature, neuroendocrine release

Altered in depression, OCD
Excess in Sleepiness
Reduced in Anxiety

Major inhibitory AA NT, frequently in interneurons

Wide distribution in brain as well as spinal cord

GABAa ionotropic 5 subunit ligand gated chloride channel, site of ETOH, barbituate, and benzodiazepine action; enhancement relieves anxiety, inhibition produces seizures

GABAb G proteins either inhibit Ca2+ or promote K+ mvmnt; site of antispasmodic Baclofen activity

Major excitatory AA transmitter in the CNS
wide distribution

N-Methyl-D-Aspartate NMDA receptor increases Na+ and Ca++ influx: virtually all neurons, responds to glutamate or aspartate, requires glycine to fnx; normally blocked by Mg++ released at depolarization; required fo rmemory leaning long term potentiation; excess involved in seizures, neurotoxicity after stroke or ischemia

alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid AMPA receptor: all neurons

Kainic acid receptor- hippocampus, cerebellum and spinal cord

Metabotropic either blocks Ca2+ and cAMP and inhibits, blocks K+ and excites or increases IP3 and DAG and excites

N-Methyl-D-Aspartate NMDA receptor: virtually all neurons

responds to glutamate or aspartate, requires glycine to fnx: increases Na+ and Ca++ influx

normally blocked by Mg++ released at depolarization; may be blocked by PCP

required fo rmemory leaning long term potentiation;

excess involved in seizures, neurotoxicity after stroke or ischemia

Major inhibitory NT in CNS, from interneurons of the spinal cord

increases Cl- conductance

strychnine sensitive receptors will cause convulsions w/ strichnine

strichnine insensitive receptors will modulate NMDA; useful for modulating memeory, pain, or damage produced by glutamate+NMDA after stroke

She really breezed through these

Glycine, from interneurons of the spinal cord

increases Cl- conductance

strychnine sensitive receptors will cause convulsions w/ strichnine

strichnine insensitive receptors will modulate NMDA; useful for modulating memeory, pain, or damage produced by glutamate+NMDA after stroke

Glycine, from interneurons of the spinal cord

increases Cl- conductance

strychnine sensitive receptors will cause convulsions w/ strichnine

strichnine insensitive receptors will modulate NMDA; useful for modulating memeory, pain, or damage produced by glutamate+NMDA after stroke

GABAa Wide distribution in brain as well as spinal cord, frequently in interneurons.; ionotropic 5 subunit ligand gated chloride channel, site of ETOH, barbituate, and benzodiazepine action; enhancement relieves anxiety, inhibition produces seizures

Glycine Major inhibitory NT in CNS, from interneurons of the spinal cord, increases Cl- conductance. Strychnine sensitive receptors will cause convulsions w/ strichnine. Strichnine insensitive receptors will modulate NMDA; useful for modulating memeory, pain, or damage produced by glutamate+NMDA after st

ACh: Inhibitory M2 receptors in the hippocampus and cortex decrease cAMP and increase K+.

NE: postsynaptic alpha 2 receptors: Inhibitory, decrease cAMP and increase K+.

NE: Beta1 widely distributed, decrease cAMP and increase K+.

DA: postsynaptic D2: inhibitory: decrease cAMP and increase K+.

Some Inhibitory 5HT receptors increase K+
Some excitatory 5HT receptors decrease K+ conduction

GABAb inhibotory: increase K+ or decrease Ca++

Excitatory metabotropic Glutamate receptor decreases K+
Glutamate NMDA permeable to K+, Ca2+ and Na+

Excitatory nicotinic receptors

Excitatory Glutamate NMDA receptor permeable to Na+, Ca2+ and K+

ACh: Inhibitory M2 receptors in the hippocampus and cortex decrease cAMP and increase K+.

NE: postsynaptic alpha 2 receptors: Inhibitory, decrease cAMP and increase K+.

NE: Beta1 widely distributed, decrease cAMP and increase K+.
NE: Beta1 found in cerebellum, increase cAMP

D1: increase cAMP
DA: postsynaptic D2: inhibitory: decrease cAMP and increase K+.

Inhibitory presynaptic Metabotropic glutamate receptor decreases ca++ and cAMP

NE: presynaptic alpha 2 receptors: decrease Ca++

DA: presynaptic D2 receptors decrease Ca++

GABAb inhibotory: increase K+ or decrease Ca++

Glutamate NMDA permeable to K+, Ca2+ and Na+

Inhibitory presynaptic Metabotropic glutamate receptor decreases ca++ and cAMP

Learning, Memeory, Cognition, Arousal, Attention

Pathways:
From Nucleus basalis of meynert and septum to cerebral cortex and hippocampus; Degeneration = Alzheimers

Corpus Striatum = in balance with DA neurons

M4 receptor dysfnx = Szhizophrenia
M1 widely distributed (IP3 DAG) = excitation
M2 hippocampus and Cortex Gi, K+ hyperpolarize
Nicotinic excitatory

Drugs: Nicotine, Muscarinic Recdeptor Agonists, Cholinesterase Inhibitors

NE invovled in affective disorders (& maybe anxiety)
Depleted NE = Depression

alpha1 Gq
Alpha2 presynaptic are inhibiotry, post synaptic hyperpolarize
Beta1: widely distributed
Beta2: cerebellum

Cocaine & some anti-depressants inhibit re-uptake, amphetamine causes release

Serotonin

Tryptophan Hydroxylase is the Rate Limiting Enzyme
MAO breaks it down

Seems to promote sleep, regulate appetite, body temperature, neuroendocrine release

Altered in depression, OCD
Excess in Sleepiness
Reduced in Anxiety

GABA and Glutamate

Glycine, from interneurons of the spinal cord

increases Cl- conductance

strychnine sensitive receptors will cause convulsions w/ strichnine

strichnine insensitive receptors will modulate NMDA; useful for modulating memeory, pain, or damage produced by glutamate+NMDA after stroke