How Drugs Control the Brain Flashcards
what is the GABAergic system?
widespread distribution throughout the brain
inhibitory interneurons - keep excitation in check
many epilepsy treatments act to enhance GABA transmission
what happens if there is too much/too little GABA?
too much: loss consciousness and coma
too little: leads to convulsions and seizures
what are the main neuronal types?
projection neurons: glutamate
local interneurons: GABA
how is inhibition of cortical pyramidal neurons controlled?
information is transferred from excitatory glutamergic synapses to pyramidal neuron dendrite
excitation (information) travels along dendritic tree to soma and axon initial segment (could initiate action potential)
along dendro-somatic-axonal axis, information can be differently filtered by GABAergic synapses processing specific, basic and plastic properties
main families of GABA receptor
GABA(A) ionotropic receptors - fast IPSPs, mostly GABAergic interneurons
GABA(B) metabotropic receptors - slow IPSPs, both pre and postsynaptic
GABA (C) = recently discovered 3rd class - similar to GABA(A)
GABA (A) ionotropic receptors
heteropentameric structures - 2 alpha + 3 more subunits
Cl- channel gates by binding of 2 agonist molecules (GABA)
Cl- potential is near resting potential, increasing Cl- permeability
hyperpolarises the neuron
decreases depolarising effect of excitatory input
what is picrotoxin?
non-competitive antagonist of GABA(A) receptor
can cause convulsions
comes from fishberry, no clinical uses
direct agonists and antagonists of GABA(A) receptors
muscimol (agonist)
bicuculline (antagonist)
indirect agonists of GABA(A) receptors
benzodiazepines - increases receptor affinity for GABA
barbituates - incerase duration of channel opening
alcohol
how do benzodiazepines work?
binding site is on alpha subunit of GABA(A) receptor
changes conformation of receptor, so GABA activation of receptor is more effective - channel opens more frequently
effects of benzodiazepines
anxiolytic and hypnotic drugs with rapid onset
cause sedation, reduce convulsions, relax muscles, cause amnesia
how do barbituates work?
bind at different sites on receptor
enhance GABA (A) activity
effects are additive -
how does alcohol work?
interacts with NMDA, glycine, nicotinic and serotonin receptors
low doses: mile euphoria, anxiolytic
high doses: incoordination, amnesia
GABA (B) metabotropic receptors
Gi coupled - inhibits adenylyl cyclase
G beta-gamma gated K+ channels - K+ conductance increases, Ca2+ conductance presynaptically decreases
slow hyperpolarising current (late IPSP)
inhibition does not have same behavioural outcome as inhibition of GABA (A) receptors
what is baclofen?
GABA (B) receptor agonist
used as muscle relaxant to reduce spasticity
e.g. in Huntington’s disease
what do glutamate neurons do?
primary route of sensory and motor information and relay neurons between brain areas
what do GABA neurons do?
interneurons: maintain balance between excitation and inhibition
what are diffuse modulatory systems?
specific populations of neurons that project diffusely and modulate activity of glutamate and GABA neurons in target areas
examples of diffuse modulatory systems
dopaminergic (DA) serotonergic (5-HT) noradrenergic (NA) adrenergic cholinergic (ACh) histaminergic
patterns of communication in the nervous system
point-to-point
hormones released by hypothalamus
ANS neurons activating body tissues
diffuse modulatory system with divergent axonal projections
what is the dopaminergic system?
dopamine neurons : cell bodies in midbrain which project to forebrain involves 3 systems: nigrostriatal mesolimbic mesocortical
types of dopamine receptors
metabotropic receptors
D1-D5
can produce both EPSPs and IPSPs (depends on subtype and coupled G proteins)
D1-like, D2-like
what are D1-like dopamine receptors?
D1 and D5 coupled to Gs stimulate adenylyl cyclase stimulate phospholipase C postsynaptic
what are D2-like dopamine receptors?
D1, D2 and D2 coupled to Gi inhibit adenylyl cyclase open K+ channels, close Ca2+ channels postsynaptic and presynaptic (D3 autoreceptors)
what is the nigrostriatal system?
cells bodies in the substania nigra project to the striatum (caudate nucleus and putamen)
important part of basal ganglia involved in movement
what can dysfunction of the nigrostriatal system cause?
Parkinson’s disease
Huntington’s disease
what is Parkinson’s disease?
destruction of DA projections from SN to basal ganglia
what is Huntington’s disease?
destruction of DA target neurons in striatum
which drugs act on the nigrostriatal system?
L-dopa, monoamine inhibitors (MAOi), dopamine receptor agonists
= treatments for Parkinson’s disease
what is the mesolimbic system?
cell bodies in ventral tegmental are (VTA) project to the limbic system - nucleus accumbens
role in reinforecement (reward) in several categories of stimuli eg. drugs of abuse
psychomotor stimulants
cocaine
amphetamine
immediate effects of psychomotor stimulants on the mesolimbic system
feeling of increased alertness and self confidence
sense of exhilaration and euphoria
decreased appetite
in large doses: stereotypy and psychosis
peripheral effects that mimic activation of ANS (increased HR and BP, pupil dilation)
long-term effects of psychomotor stimulants on the mesolimbic system
natural rewards (water, food, sex) increase DA transmission, leading to reinforcement of associated behaviours increase DA by cocaine short-circuits the pathway: drug taking behaviours are reinforced downregulation of endogenous DA system (craving)
what is the mesocortical system?
VTA projections to prefrontal cortex
roles in function such as working memory and planning
what can mesocortical system dysfunction cause?
schizophrenia
which drugs can affect the mesocortical system?
typical and atypical antipsychotics
how do typical antipsychotics work?
DA receptor antagonists
increase DA turnover - lose autoreceptor inhibition
blockage of postsynaptic receptors leads to upregulation
e.g. chlorpromazine, haloperidol
side effects of typical antipsychotics
action on other dopaminergic systems
extrapyramidal side effects (EPS) - tardive dyskinesia, etc
system becomes supersensitive due to chronic blockade
how to atypical antipsychotics work?
specific to receptor subtype
e.g. clozapine - antagonist of D4 receptors (only in cortex)
reduce psychosis associated with schizophrenia without EPS
what does the serotonergic system have functions in?
mood, sleep, pain, emotion, appetite
many receptors - metabotropic and ionotropic
which drugs can affect the serotonergic system?
SSRIs
MDMA
LSD
how do SSRIs work?
increase serotonin function by preventing reuptake
treatment for anxiety and depression
effects not seen for 2-3 weeks
increased availability of serotonin triggers downstream pathways
long term modulatory effects (second messenger cascades, gene transcription)
how does MDMA work?
causes serotonin (+noradrenaline) receptors to run in reverse increased release of serotonin and blocked reuptake
how does LSD work?
hallucinogen
causes dreamlike state with altered sensory perception
potent agonist at 5-HT1 A receptors in raphe nucleus
hallucinogenic properties at 5-HT2 A receptors in prefrontal cortex
what is the noradrenergic system?
projections from locus coeruleus throughout brain role in arousal and attention metabotropic receptors alpha adrenergic: alpha 1 = Gq, alpha 2 = Gi beta adrenergic - Gs best activated by novel non painful stimuli
what is the adrenergic system?
primarily in lateral tegmenatal area projecting to thalamu and hypothalamus
act on alpha and bet adrenergic receptors
what is the periphery cholinergic system?
acetylcholine at NMJ
synapses at autonomic ganglia
what is the central cholinergic system?
basal forebrain complex: cholinergic innervation of hippocampus and neocortex
brainstem complex: innervates dorsal thalamus and telencephalon
controls excitability of sensory relay neurons
provide cholinergic link between brain stem and basal forebrain complex
peripheral disorders of the cholinergic system
myasthenia gravis
what is myasthenia gravis?
auto-immune disease
destroys cholinergic receptors in the muscle
muscle weakness and eventual loss of muscle activity
central (brain) disorders of the cholinergic system
Alzheimer’s disease
addition (nicotine)
epilepsy - mutations in nicotinic receptor genes
other psychiatric disorders - comorbidity with smoking
what is Alzheimer’s disease?
loss of cholinergic neurons in basal ganglia
possibly underlies deficits in memory associated with disease
what to acetylcholinesterase inhibitors do?
prolong acetylcholine action at the synapse
treatment for Alzheimer’s: physotigmine
treatmetn for Myasthenia gravis: neostigmine
botox - prevents release of ACh at NMJ
latrotoxin - depletes ACh at NMJ
types of muscarinic receptors
M1, M3, M5: via Gq to phophatidylinositol hydrolysis (smooth muscles and glands)
M2, M4: via Gi to inhibit cAMP (smooth and cardiac muscle)
lead to opening or closing of K+, Ca2+ or Cl- channels
post and presynaptic receptors
prsynaptic autoreceptors provide negative feedback to stop ACh release
what are muscarinic receptors?
metabotropic ACh receptors
muscarine = agonist found in poisonous mushroom
atropine = antagonist, belladonna alkaloid from deadly nightshade
what are nicotinic receptors?
ionotopic ACh receptors
vary in pharmacology, selectivity, kinetics and conductance
located pre and post synaptically
5 sububits surrounding a central pore
nicotine = agonist
Na+ and Ca2+ depolarisation and direct transmitter release
nicotinic muscle receptors
2x alpha 1, beta, delta and gamma subunits
at neuromuscular junction
antagonist = curare - instant paralysis
nicotinic neuronal receptor
heteromeric combination of alpha 3, 4, 5 and beta 2, 3, 4
homomeric receptros of alpha 7, 8, 9
alpha-3 beta-4 on autonomic ganglia
alpha-4 beta-2 and alpha-7 are most common brain receptors
what is the histaminergic system involved in?
arousal and attention reactivity of vestibular system mediation of allergic responses influence brain blood flow 3 g-protein coupled receptors
