Lecture 1: Intro to CNS Pharmacology

Acetylcholine

Learning and memory

Cognition

Attention

Wakefulness, arousal

Cholinergic pathways from nucleus basalis of Meynert and septum to cerebral cortex and hippocampus degenerate in Alzheimer’s disease

Cholinergic neurons balance the effect of dopamine neurons in the corpus striatum

Interaction with DA in striatum

Schizophrenia

Nicotinic and muscarinic receptors

M1 muscarinic receptors widespread + activate phospholipase C, increasing IP3 and DAG levels

M2 muscarinic receptors are found primarily in hippocampus + cortex → Decrease cAMP and increase K+ conductance → Inhibition of neurons

Nicotinic receptors are excitatory + coupled to Na+ channels

Norepinephrine

Cell bodies are found in the locus coeruleus and the reticular formation, + project widely throughout the brain

Mood → Lack leads to depression

May be involved in anxiety

Pain regulation- descending spinal cord

Learning and memory

Attention and arousal

Stress depletes NE

Alpha and beta receptors

α1 receptors: activate PLC, increase IP3 and DAG

α2 receptors: presynaptic, decrease Ca+ influx; postsynaptic, increase K+ conductance and decrease cAMP

β1 receptors: widely distributed, increase cAMP, decrease K+ conductance

β2 receptors: found in cerebellum, increase cAMP

Dopamine

Dopamine neurons in the nigro-striatal pathway degenerate in Parkinson’s disease, causing movement disorders

Overabundance of cortical dopamine may cause symptoms of schizophrenia

Dopaminergic pathways from the ventral tegmental area to the nucleus accumbens and prefrontal cortex are involved in reinforcement and play a role in addiction

Reward + reinforcement

D1, D2, D3, D4, D5 are metabotropic and inhibitory

D1 receptors increase cAMP

Presynaptic D2 receptors decrease Ca+ influx

Postsynaptic D2 receptors decrease cAMP and increase K+ conductance via Gi

Serotonin (5-HT)

Projects from the raphe nucleus to the limbic system + cerebral cortex

Mood

Anxiety

Obsessive compulsive disorder

Hunger or appetite

Perception

5-HT1A: increase K+ conductance and cause hyperpolarization

5-HT2A: increase IP3 and DAG, decrease K+ conduction, important in schizophrenia

5-HT3A: ligand gated ion channel, increase cation conductance, involved in nausea

Gamma-amino butyric acid (GABA)

Amino acid that is the main inhibitory neurotransmitter in the brain + also found in spinal cord

Frequently found in interneurons that modulate the responsiveness of other neuronal pathways

GABAA receptor is ionotropic + increases Cl- conductance → rapid inhibition of neuronal activity

Site of action for barbiturates, benzodiazepines, and alcohol

Enhancement of GABAA activity relieves anxiety

Inhibition of GABAA receptors can produce seizures

GABAB receptors are also inhibitory, G-proteins → Either decrease Ca+ conductance or increase K+ conductance

IPSPs in some brain areas have a fast and slow component due to stimulation of GABAA and then GABAB receptors

Glutamate

Major excitatory amino acid neurotransmitter

Wide distribution in the CNS

Receptors are ionotropic and metabotropic

Ionotropic receptors are excitatory and increase cation conductance:

NMDA receptor increases Na+ + Ca+ influx

AMPA receptor

Kainic acid (kainate) receptor

Metabotropic glutamate receptors interact indirectly with ion channels via G-proteins

Either inhibitory (presynaptic), decreasing Ca+ + cAMP or excitatory, decreasing K+ + increasing IP3 + DAG

Kainate receptors are found in the hippocampus, cerebellum + spinal cord

Excess glutamate + NMDA receptor activity → Seizures

Excessive release of glutamate + overstimulation of NMDA receptors may cause neurotoxicity occurring after stroke or ischemia

Glycine

Inhibitory - Cl- conductance

Modulates NMDA receptor

Endorphins/enkephalins/dynorphin

Opioid receptors

decrease pain

pleasure, reinforcement

mu, kappa and delta receptors

Substance P

excitatory, mediates pain transmission

Neuropeptide Y

regulate food intake and fat storage