L13 How Drugs Control the Brain Flashcards
describe and state the Two main families of GABA receptor:
1) GABA(A) ionotropic receptors
Ligand gated Cl- channel
Fast IPSPs
Mainly GABAergic interneurons
2) GABA(B) metabotropic receptors
G protein coupled receptors Indirectly coupled to K+ or Ca2+ channel through 2nd messengers (opens K+ channel, closes Ca2+ channel) Slow IPSPs Both pre- and post- synaptic
describe the structure of GABA (A) receptors
-Heteropentameric structure - 2 a + 3 more subunits
describe what occurs when a GABA(A) receptor is activated
- Cl- channel gated by the binding
of two agonist moleculesCl- potential is near resting potential increasing chloride permeability hyperpolarizes the neuron decreasing the depolarizing effects of an excitatory input
where do indirect and direct antagonists bind to a GABA receptor
- bind at GABA binding site
state and describe a direct agonist
Muscimol – agonist
state and describe a direct antagonist
Bicuculline – antagonist (experimental tool)
state and describe an indirect agonist
Benzodiazepine - binding increases the receptor affinity for GABA - increase frequency of channel opening
- anxiolytic and hypnotic drugs with rapid onset, but less satisfactory in the long term
state and describe an indirect agonist
Barbiturates increase the duration of channel openings (anaesthesia, epilepsy treatment)
state and describe an indirect agonist
Alcohol - agonist
go into more detail about the actions of a benzodiazepine on GABA (A) and give an example
- diazepam (Valium)
- Benzodiazepine binding site on the a subunit of GABA(A) receptor
Indirect agonist - benzodiazepine binds to a subunit, changes conformation of the receptor so GABA activation of receptor is more effective.
Effects of benzodiazepine are to:
- reduce anxiety
- cause sedation
- reduce convulsions
- relax muscles
- cause amnesia
Inverse agonists bind to benzodiazepine site and have opposite effects
– produce anxiety and predisposition to convulsions
describe in more detail the pharmacology of barbiturates and alcohol on GABA(A)
Bind at different sites on the receptor
Both have same effect: 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 and describe an agonist for a GABA(B) receptor
Agonist - Baclofen (used as a muscle relaxant to reduce spasticity e.g. in Huntington’s disease)
Gi coupled - inhibits adenylyl cyclase
Gbg gated K+ channels
increases K+ conductance
decreases Ca2+ conductance (presynaptically)
Slow hyperpolarizing current (late inhibitory postsynaptic potential)
does inhibition of a GABA(B) transmission have the same effect as on a GABA(A) transmission
NO- Inhibition of GABA(B) transmission does not have same behavioural outcome as inhibition of GABA(A) receptors (e.g. seizure)
name some diffuse modulatory systems
Dopaminergic (DA) Serotonergic (5-HT) Noradrenergic (NA/NE) Adrenergic Cholinergic (ACh) Histaminergic
what is a diffuse modulatory system
-Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas.
what are the patterns of communication in the NS
- 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 dopamine neurons found
cell bodies in the midbrain
project into the forebrain
what systems are included in the dopaminergic system
- Nigrostriatal system (75% of brain DA)
(motor control)
Mesolimbic system
Mesocortical system
(behavioural effects)
Tuberohypophyseal system (endocrine control)
describe metabotropic receptors D(1-5)
Dopamine (DA) receptors
Dopamine produces both EPSPs and IPSPs depending on the receptor subtype and coupled G proteins
D1-like (1 & 5) Gs - stimulate adenylyl cyclase
- stimulate phospholipase C
postsynaptic
D2-like (2, 3 & 4) Gi - inhibit adenylyl cyclase - open K+ channels - close Ca2+ channels postsynaptic presynaptic autoreceptors (D3)
Balance of these systems
maintains dopaminergic
tone
describe the Nigrostriatal system
- cell bodies in the substantia nigra project to the striatum (caudate nucleus and putamen)
Important part of the basal ganglia involved in movement.
describe some dysfunctions associated with the nigrostriatal system
Dysfunction:
Parkinson’s disease
destruction of DA projections from SN to basal ganglia
Huntington’s disease
destruction of DA target neurons in striatum
what are some drugs that help with dysfunction in the Nigrostriatal system
Drugs:
L-DOPA, Monoamine oxidase (MAO) inhibitors, Dopamine receptor agonists -treatments for Parkinson’s Disease
describe 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 some dysfunctions associated with the mesolimbic system
Dysfunction:
Addiction - most drugs of abuse lead to enhanced DA release in the NAcc
describe the drugs and their short and long term effects that stimulate the mesolimbic system
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 the Mesocortical system and its role
Mesocortical system – VTA projections to prefrontal cortex
Role in functions such as working memory and planning.
describe the dysfunction in the Mesocortical system and some drugs used to treat them
Dysfunction:
Schizophrenia
Drugs: 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
what dos the serotonergic system function in
mood
sleep pain emotion appetite
describe the metabotropic serotonin receptors
Ionotropic
5-HT3 opens channel that fluxes Na+, K+, Ca2+ (excitatory)
Metabotropic
5-HT1A Gi raphe, hippocampus
5-HT7 Gs thalamus, hypothalamus, amygdala
5-HT2A, B and C Gq cortex, hippocampus
describe the drugs that have an effect on the serotonergic system
1)Selective Serotonin Reuptake Inhibitors e.g.fluoxetine (Prozac)
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.
2)Methylenedioxymethamphetamine (MDMA) - ecstasy
causes serotonin (and norepinephrine) transporters to run in reverse increased release of serotonin and blocked reuptake
describe LSD
LSD – (Lysergic acid diethylamide) hallucinogen
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 cholinergic 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
look at slide 30 for ACh and NA in the PNS
how was it
describe 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
describe the importance of AChesterase inhibitors
-Prolong action of acetylcholine at the synapse
- Treatment for Alzheimer’s disease (e.g. physostigmine)
- Treatment for Myasthenia gravis (neostigmine)
Insecticides & Chemical warfare agents, e.g. “Sarin”
Botox - prevents release of ACh at NMJ
Latrotoxin - permanent release - depletes ACh at NMJ
what are the 2 types of ACh receptor
Two types of acetylcholine receptor
Muscarinic - metabotropic
Nicotinic – ionotropic
Visceral motor system / sympathetic & parasympathetic preganglionic neurons
what is a muscarine
Muscarine (agonist of Muscarinic receptors – metabotropic
) found in poisonous mushroom Amanita muscaria
what is a atropine
Atropine (antagonist of Muscarinic receptors – metabotropic
) belladonna alkaloid extracted from deadly nightshade
describe some common muscarinic receptors and overall effects on neuron & whether on just post or presynaptic
M1
M3 via Gq to phospatidylinositol hydrolysis
M5 (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
hyperpolarization or depolarization (cell type/receptor type dependent)
Pre and postsynaptic receptors
Presynaptic autoreceptors - negative feedback - stop ACh release
describe muscle nicotinic receptor (structure, function, location, antagonist)
-2x a1, b, d and g subunits
(neuromuscular junction NMJ)
(Antagonist - curare (poison darts) - instant paralysis)
describe neuronal Muscle receptor (structure, and location)
Heteromeric combination of a3,4,5 and b2,3,4 or 6
Homomeric receptors a7, 8 or 9
a3b4 on autonomic ganglia a4b2 and a7 most common brain receptors
Vary in their pharmacology, selectivity and kinetics and conductance
Located pre and postsynaptically
Presynaptic receptors - facilitate transmitter release
(Na+ and Ca2+, depolarization and direct transmitter 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
