How drugs control the brain Flashcards
Where is GABA mainly used?
Inhibitory interneurons - keep the excitation in check
Which neurotransmitter uses glutamine?
Projection neurons
Which neurotransmitter controls local interneurons?
GABA
Describe the GABA(A) ionotropic receptor
Ligand gated Cl- channel
Fast IPSPs
Mainly GABAergic interneurons
Heteropentameric structure 2 alpha and 3 more subunits
CL- channel gated by the binding of two agonist molecules. Cl - potential is near resting potential increasing chloride permeability hyperpolarizing the neuron decreasing the depolarizing effects of the excitatory input
Describe GABA(B) metabotropic receptors
G protein coupled receptors
Indirectly coupled to K+ and Ca2+ channel through 2nd messengers
Slow IPSPs
Both pre and postsynaptic
Name a direct agonist of the GABA(A) receptor
Muscimol
Name a direct antagonist of GABA(A) receptor
Bicuculline
Name an indirect agonist of GABA(A) receptor
Benzodiazepine - binding increase the receptor affinity for GABA, increase frequency of channel opening, anxiolytic and hypnotic drugs with rapid onset but less satisfactory in the long run (addiction)
Barbiturates increase the duration of channel openings (anaesthesia)
Alcohol
Describe how benzodiazepines work
Benzodiazepine binding site on the a subunit of GABA(A) receptor
benzodiazepine binds to a subunit, changes conformation of the receptor so GABA activation of receptor is more effective.
What are the effects of benzodiazepine
Effects to: reduce anxiety cause sedation reduce convulsions relax muscles cause amnesia
Describe the action of alcohol and barbiturates on the GABA(A) channel
to enhance GABA(A) activity and effects are additive - combining the two can be fatal
Alcohol also interacts with NMDA, glycine, nicotinic and serotonin receptors.
Low doses of alcohol - mild euphoria and anxiolytic effects Higher doses - incoordination, amnesia
Name an agonist of a GABA(B) channel
Baclofen
Describe how the GABA(B) receptor works
Gi coupled - inhibits adenylyl cyclase
Gbg gated K+ channels
increases K+ conductance
decreases Ca2+ conductance (presynaptically)
Slow hyperpolarizing current (late inhibitory postsynaptic potential)
What is the main function of glutamate neurons?
primary route of sensory and motor information and relay neurons between brain areas
What is the main function of GABA neurons?
interneurons, maintain balance between excitation and inhibition
List some patterns of communication in the nervous system
Point-to-point systems
Hormones released by the hypothalamus
ANS neurons activating body tissues
Diffuse modulatory system with divergent axonal projections (not classical synapse)
Where are the dopamine neurons?
Cell bodies in the midbrain and project into the forebrain
What does the nigrostriatal system do?
75% of brain dopamine
Motor control
Cell bodies in the substantia nigra project to the striatu, (caudate nucelus and putamen) Importnat part of basal ganglia involved in movement.
What does the mesocortical system do?
Responds to addictions and the environment
VTA projections to prefrontal cortex
Role in functions such as working memory and planning.
Describe the D1 like receptor (1 and 5)
Gs - stimulate adenylyl cyclase
- stimulate phospholipase C
postsynaptic
Describe the D2 like receptor (2,3,4)
Gi - inhibit adenylyl cyclase - open K+ channels - close Ca2+ channels postsynaptic presynaptic autoreceptors (D3)
What maintains the balance of dopamine concentration?
Balance of D1 and D2
Describe dysfunction of the nigrostriatal system
Parkinsons disease - destruction of DA projections from SN to basal ganglia
Huntington’s disease - destruction of DA target neurons in striatum
What drugs are used in the treatment of parkinsons?
L-DOPA, Monoamine oxidase (MAO) inhibitors, Dopamine receptor agonists -treatments for Parkinson’s Disease
What is the mesolimbic system?
cell bodies in ventral tegmental area (VTA) project to the limbic system, nucleus accumbens (NAcc)
Role in reinforcement (reward) of several categories of stimuli, including drugs of abuse
Describe the dysfunction of the mesolimbic system
Addiction - most drugs of abuse lead to enhanced DA release in the NAcc
Name some drugs that affect the mesolimbic system
e.g. Cocaine and Amphetamine - psychomotor stimulants
Immediate effects
- give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite.
- large doses can cause stereotypy and psychosis
- cause peripheral effects that mimic activation of the sympathetic division of the ANS, increased heart rate and blood pressure, dilation of pupils etc.
Long-term effects
- natural rewards, e.g. water, food, sex increase DA transmission and leads to reinforcement of associated behaviours
- increased DA by cocaine etc. short circuits pathway, drug taking behaviours become reinforced
- downregulation of endogenous DA system - craving
Describe dysfunction of the mesocortical system
Scizophrenia
Name some drugs affecting the mesocortical system
Typical antipsychotics (e.g. chlorpromazine and haloperidol)
- DA receptors antagonists (pre and postsynaptic)
- Increase DA turnover - lose autoreceptor inhibiton
- Blockade of postsynaptic receptors - upregulation
Antipsychotic effects - action in mesocortical system
Side effects - action on other dopaminergic systems
Extrapyramidal side effects (EPS) - tardive dyskinesia etc.
(chronic blockade causes system to become supersensitive)
Atypical antipsychotics (e.g. clozapine)
- specific to receptor subtype
e.g. Clozapine - antagonist of D4 receptors (cortex only)
Reduce psychosis associated with schizophrenia
Antipsychotic effects without EPS
Describe the serotonergic system
Nine raphe nuclei in reticular formation with diffuse projections
-each projects to a different part of the brain
Descending projections to cerebellum and spinal cord (pain)
Ascending reticular activating system (with LC)
Dorsal and medial raphe, project throughout the cerebral cortex
raphe neurons fire tonically
during wakefulness
quiet during sleep
List the functions of the serotonergic system
mood
sleep
pain
emotion
appetite
Name a selective serotonin reuptake inhibitor SSRI
Fluoxetine (PROZAC)
Describe how selective serotonin reuptake inhibitors work
increase serotonin function by preventing its uptake
treatment for depression and anxiety disorders
but depression not a simple case of low serotonergic tone
(effects not seen for 2-3 weeks)
increased availability of serotonin triggering downstream pathways
- long term modulatory effects
- second messenger cascades, gene transcription etc. synthesizing new receptors and changing pathways and cascades in the cell
How does MDMA (ecstasy) affect the serotonergic system?
causes serotonin (and norepinephrine) transporters to run in reverse increased release of serotonin and blocked reuptake
Describe how LSD affects the serotonergic system affects the serotonergic system?
Causes a dreamlike state with altered sensory perceptions
LSD potent agonist at 5HT1A receptors in raphe nucleus
Hallucinogenic properties at 5HT2A receptors in prefrontal cortex
Describe the noradrenergic system
Projections form the Locus Coeruleus throughout the brain
Role in arousal and attention
Metabotropic receptors
Alpha adrenergic receptors
a1 Gq
a2 Gi
Beta adrenergic receptors
b1, 2 and 3 Gs
Describe the adrenergic system
Primarily in lateral tegmental area, projecting to thalamus and hypothalamus.
Acts on a- and β- adrenergic receptors
Describe the cholinerggic system
In the periphery
Acetylcholine at NMJ and
synapses in the autonomic ganglia
In the brain
Basal forebrain complex
Cholinergic innervation of the
Hippocampus and the neocortex
Brain stem complex
innervates the dorsal thalamus and telencephalon
-control excitability of sensory relay neurons and provide a cholinergic link between the brain stem and basal forebrain complex
List some disorders of the cholinergic system
Peripheral
Myasthenia gravis
Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity
Brain
Alzheimer’s disease
Loss of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease.
Addiction: nicotine addiction
Epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with mutations in nicotinic receptor genes.
Other psychiatric disorders
Comorbidity with smoking
How do acetylcholinesterase inhibitors work?
Prolong action of acetylcholine at the synapse
- Treatment for Alzheimer’s disease (e.g. physostigmine)
- Treatment for Myasthenia gravis (neostigmine)
How does botox work?
Prevents release of ACh at the NMJ
How does latrotoxin work?
Permanent release - depletes ACh at NMJ
Name the two types of acetylcholine receptor
Muscarinic - metabotropic
Nicotinic - ionotropic
What is the agonist of the muscarinic receptor?
Muscarine
What is the antagonist of the muscarinic receptor?
Atropine
Describe the action of muscarinic receptors - metabotropic
Lead to opening or closing of K+, Ca2+ or Cl- channels
hyperpolarization or depolarization (cell type/receptor type dependent)
Pre and postsynaptic receptors
Presynaptic autoreceptors - negative feedback - stop ACh release
Describe the histaminergic system
Arousal & attention
Reactivity of vestibular system
Mediation of allergic responses
Influence of brain blood flow
3 G-protein-coupled Rs
