CNS Pharmacology Flashcards
Forebrain
Cerebrum Thalamus Hypothalamus Amygdala Hippocampus
Midbrain
Midbrain
Hindbrain
Pons
Cerebellum
Medulla Oblongata
Chemical synaptic transmission: excitation
INCREASES probability that neuron membrane potential reaches threshold and fires action potential.
Chemical synaptic transmission: inhibition
DECREASES probability that neuron membrane potential reaches threshold and fires action potential.
Fast neurotransmitters (NT’s)
Voltage gated
Ligand gated
Slow Neurotransmitters
- Receptor–>G-protein–> + Ion channel
2. Receptor–>G-protein–>2nd messenger–> enzyme–> diffusible messenger–> +ion channel
NT class: Amino Acids
Excitatory: Glutamate
Inhibitory: GABA and Glycine
Classes of NT’s: biogenic AMINES
ACh
Catecholamines: NE and Dopa
Serotonin
Histamine
Classes of NT’s: Purines
ATP
Adenosine
Classes of NT’s: Neuropeptides
Endorphins
Substance P
Classes of NT’s: NO and Endocannabinoids (anandamide)
Not stored in synaptic vesicles
Generated in response to increases in intracellular Ca and freely diffuse out neurons
Antagonist: compensation
Upregulation
SENSITIZATION
Ex: chronic antipsychotics (block dopa) induce production of more dopamine receptors=hyperkinetic D.O.
Delayed onset of therapeutic effects
Agonist compensation
Down regulation
DESENSITIZATION
Delayed onset of therapeutic effects of antideprssants which block 5-HT uptake
Mechanisms of receptor desensitization:
Receptor Phosphorylation
Receptor Internalization
Receptor Down-regulation: decrease expression of that receptor
Glutamate
Major UBIQUITOUS excitatory NT
Glutamate’s role in learning and Memory Function
Memories stored by enhancing Gluta-synaptic transmission via LTP.
Requires sufficient Ca influx through NMDA receptors.
Glutamate’s role in Epilepsy
Imbalance in excitation and inhibition
Some anti-epileptics block glutamate receptors
Glutamate and Excitotoxicity
Excessive stimulation–> excessive Ca influx–> neuronal damage–> neurodegeneration
Stroke, ALS, MS
Glutamate and Dissociative anesthesia
I.E. catatonia, amnesia, analgesia
Ketamine blocks NMDA receptors
Glutamate and Drug abuse
PCP in NMDA receptor antagonist
Reducing NMDA receptor activity can cause HALLUCINATIONS
GABA
Major inhibitory NT
2 groups of neurons: interneurons and projecting neurons
Interneurons of GABA
Local circuit neurons: neocortex, thalamus, striatum, hippocampus, cerebellum, spinal cord
Projecting neurons of GABA:
Striatum–>globus pallidus–>thalamus/subs nigra
Loss of these in HUNTINGTONs chorea
Projecting neurons of GABA
Septum–> Hippocampus
Substantia nigra–> thalamus/superior colliculus
Projecting neurons of GABA that promote sleep
Ventrolateral preoptic area–>nuclei of reticular activating system (RAS)
2 types of GABA receptors
GABA(a)
GABA (b)
GABA(a) functions
Fast inhibitory transmission:
- INcrease in Cl channel hyperpolarization
- Decrease membrane resistance
- Modulatory sites for: benzo’s and barbiturates
GABA(b) functions
Slow inhibitory transmission:
Baclofen is a GABA(b) agonist and reduces mm spasms by INCREASING inhibition in spinal cord.
Clinical importance of GABA: all drugs stimulating GABA cause an increase in Cl influx
Epilepsy (benzo’s and barbiturates)
Anxiety D.O.
Insomnia
Agitation
RAS:
GABA from VLPO (ventrolateral preoptic nc) INHIBITS RAS.
Orexin neruons EXCITE RAS
Cholinergic Neurons in CNS
Interneurons: neocortex, striatum, hippocampus
Projecting: brain stem to thalamus, basal forebrain to neocortex, hippo, and amygdala; peripheral neurons (autonomic, motor)
Adenosine and forebrain
Affects basal forebrain constellation of cholinergic neurons including basal nc of Meynert
2 cholinergic receptor types:
Nicotinic: fast
Muscarinic: slow
Clinical importance of Cholinergic receptors:
Modulates: sleep-wake cycle, arousal, attention
Parkinsonism
Memory
Parkinsonism and cholinergic neurons
Muscarinic receptors oppose dopamine effects in striatum.
Loss of dopa neurons=striatal imbalance, corrected by increasing dopa or reducing muscarinic activity
Memory and cholinergic neurons
Alzheimers: loss of basal forebrain cholinergic neurons
Antimuscarinic induced delirium
Mutations in nicotinic channels: Autosomal dominant frontal lobe nocturnal epilepsy; congenital myasthenic syndromes
Norepinephrine
Projecting brainstem neurons in:
Locus coeruleus to neocortex, hippocampus, thalamus, cerebellum, spinal cord–> attention and arousal
Tegmental region of Reticular formation to hypothalamus, basal forebrain, spinal cord–> autonomic and endocrine regulation.
Clinical importance of NE
- Arousal, attention, sleep cycles: LC efferents
- ADHD and Narcolepsy treated w/amphetamine-like compounds
- Cognition: NE enhances memory formation.
- Some TCA’s like amitriptyline block reuptake of NE
- Adrenergic stimulation of hypothalamus decreases appetite.
- Pain perception (spinal cord): NE excites enkephalin producing interneurons in spinal cord to inhibit pain transmission during stress response.
Serotonin: 5HT
Released by projecting neurons from 2 different raphe nuclei:
- RN to neocortex, thalamus, hypothalamus, amygdala, striatum.
- RN to brain stem, cerebellum, spinal cord
5HT receptors
Different actions: 14 different subtypes
Clinical importance of 5HT
- Depression: SSRI’s
- Panic D.O.: SSRI’s
- OCD: SSRI’s
- Migraine: agonists like sumatriptan, presynaptic meds block release of vasodilators, postsynaptic ones cause DIRECT vasoconstriction***
- Chemotherapy induced emesis: 5HT3 receptors in area postrema (medulla): block w/odansetron
- Pain perception by spinal cord: serotonin from PT’s stimulate pain sensory nn endings; serotonergic nn stimulate encephalin neruons in spinal cord.
- Schizo: atypical antipsychotics block 5ht2
- LSD: 5 ht agonist
Dopamine’s tuberoinfundibular pathway
From hypothalamus to pituitary: regulate prolactin synthesis and release
Dopamine nigrostriatal pathway
From substantia nigra to striatum: regulate motor planning and execution
Dopamine mesolimbic pathway
From ventral tegmental area (VTA) to Nucleu Accumbens: regulates goal directed and reward behavior
Dopamine mesocortical pathways
From the VTA to neocortex
Dopamine in Parkinson’s disease:
Neurodegeneration of DA neurons in SN: relative loss of dopaminergic activity in nigrostriatal pathways: hypokinetic
Dopamine in Huntington’s Chorea:
Neurodegeneration of striatal GABAergic neurons: relative excess of dopaminergic activity in nigrostriatal pathway: HYPERkinetic
Dopamine in Schizophrenia
Relative excess of activity in mesolimbic and mesocortical pathways.
Extrapyramidal side effects from Antipsychotics.
Dopamine in Drug Addiction
Increase of dopamine in mesolimbic pathway
Dopamine in hyperprolactinemia
Dopamine inhibits prolactin
Histamine
Posterior hypothalamus–> CNS
Regulation of arousal
Many drugs block it=sedation
Opioid peptides
Regulate pain pathways at spinal and supraspinal levels
Clinically: Agonists (morphine) analgesic, important addiction drugs
Role of tissue damage
releases many compounds which enhance nociceptive transmission to dorsal horn of spinal cord.
What do enkephalins do?
inhibit pain transmission in dorsal horn by inhibiting release of glutamate and substance P from C fibers and stimulation of K+ channels on projection neurons.
Enkephalin 2:
Enkephalin or morphine
inhibits presynaptic release of glutamate and substance P and postsynaptic increase K+
Adenosine receptors
ATP, co-transmitter
Metabolized to adenosine upon release
Clinically: Xanthines block adenosine receptors producing arousal.
Endocannabinoids
Cannabinoid (CB) Receptors: G-protein coupled receptors
Derived from arachidonic acid
Reuptake pump and intracellular degradation
Often located on axon terminals: stimulation inhibits neurotransmitter release.
Endocannabinoids:
Modulation of: Pain control of movement regulation of body temperature Emesis Appetite learning and memory cognition and neuroendocrine control
