l13 Flashcards
what do epileptic treatments look to enhance
GABA transmission to treat convulsions and seizures
what are the main neuronal types
Projection neurons-for GLU
Local interneurons-GABA
LOOK AT SLIDE 7
LOOK AT IT
2 main families of GABA receptor
GABA (A) ionotropic receptors
fast IPSPs
GABAergic
GABA (B) metabotropic receptors
G protein coupled receptors
indirectly coupled to K+ or ca2+
Both pre and post synaptic
Describe GABA (A) receptors structure
2 a + 3 more subunits
Heteropentameric
Describe GABA (A) receptors function
Cl- channel gated by the binding of 2 agonist molecules
Cl- potential is near RMP
Increasing chloride permeability
Hyperpolarizes the neuron
Decreasing depolarising effect of excitatory neuron
Give an example of a direct agonist and antagonist of GABA(A)
Muscimol- agonist
Bicuculline-antagonist
Give an example of an indirect agonist of GABA(A) channel
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
Barbiturates increase the duration of channel openings (anaesthesia, epilepsy treatment)
Alcohol - agonist
GABA(A) Receptor- benzodiazepine action: where does it bind
a subunit
GABA(A) Receptor- benzodiazepine action: function
Indirect agonist - benzodiazepine binds to a subunit, changes conformation of the receptor so GABA activation of receptor is more effective.
What are the effects of benzodiazepine
reduce anxiety cause sedation reduce convulsions relax muscles cause amnesia
what do inverse agonists that bind to benzodiazepine site do?
– produce anxiety and predisposition to convulsions
GABA(A) Rs - barbiturates and alcohol- effect?
Both have same effect: to enhance GABA(A) activity and effects are additive - combining the two can be fatal
What does alcohol also interact with
NMDA, glycine, nicotinic and serotonin
what do low doses of alcohol as well as high doses do
Low doses of alcohol - mild euphoria and anxiolytic effects
Higher doses - incoordination, amnesia
what is an agonist for GABA(B) receptor -metabotropic
Baclofen
What is baclofen used to treat
GABA(B) receptor -metabotropic
used as a muscle relaxant to reduce spasticity e.g. in Huntington’s disease
When activated what does the Gi subunit do
GABA(B) receptor -metabotropic
Inhibits adenylyl cyclase
when activated what does the Gby gated K+ channels do
Increase K+ conductance
decreases ca2+ conductance-presynaptically
What is another phrase for Slow hyperpolarizing current
(late inhibitory postsynaptic potential)
IPSP’s
What are the main overall function of glutamate neurons
primary route of sensory and motor information and relay neurons between brain areas
Overall main function of GABA neurons
interneurons, maintain balance between excitation and inhibition
In a neuron there are Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas, what are they called
Diffuse modulatory systems
Give an example of some diffuse modulatory systems
Dopaminergic (DA) Serotonergic (5-HT) Noradrenergic (NA/NE) Adrenergic Cholinergic (ACh) Histaminergic
what are the 4 types of 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)
In the dopaminergic system, where are the cell bodies and where do they project to?
Cell bodies in the midbrain
Project into the forebrain
what is the Nigrostriatal system responsible for
motor control
what is the Mesocortical system
responsible for
behavioural effects
what is the Tuberohypophyseal system responsible for
endocrine control
Dopamine (DA) receptors
Dopamine produces both EPSP’s and IPSPS depending on what factor, and after which have been activated
Depending on receptor sub type 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)
Dopamine (DA) receptors
where do the cell bodies of neurons in the Nigrostriatial system reside in and project to
cell bodies in the substantia nigra project to the striatum (caudate nucleus
what is a dysfunction of the dopaminergic system
Parkinson’s disease
destruction of DA projections from SN to basal ganglia
Huntington’s disease
destruction of DA target neurons in striatum
what drugs are used to treat such dopaminergic dysfunctions
L-DOPA, Monoamine oxidase (MAO) inhibitors, Dopamine receptor agonists -treatments for Parkinson’s Disease
dopaminergic system
where do the cell bodies of the Mesolimbic system reside in and to where do they project
cell bodies in ventral tegmental area (VTA) project to the limbic system, nucleus accumbens
what is the role of the Mesolimbic system
It has a role in reinforcement (reward) of several categories of stimuli, including drugs of abuse
what is a dysfunction of the mesolimbic system
Addiction - most drugs of abuse lead to enhanced DA release in the NAcc
Give an example of drugs that affect the Mesolimbic system
The dopaminergic system
Cocaine and Amphetamine
ST effects of Cocaine and Amphetamine
- 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
LT effects of Cocaine and Amphetamine
- 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
The dopaminergic system
Where do cell bodies of the mesocortical system lie and to where do they project
VTA projections to prefrontal cortex
What is the function of the mesocortical system
Role in functions such as working memory and planning
what is a dysfunction of the mesocortical system
Schizophrenia
what drugs can be used to treat Schizophrenia & effects
Typical antipsychotics (e.g. chlorpromazine and haloperidol)
- DA receptors antagonists (pre and postsynaptic)
- Increase DA turnover - lose autoreceptor inhibiton
- Blockade of postsynaptic receptors - upregulation
what are the Extrapyramidal side effects of the Antipsychotic drugs
tardive dyskinesia etc.
(chronic blockade causes system to become supersensitive
give an example of an atypical antipsychotic & effects
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
serotonergic system
has an ascending?
Reticular activating system
serotonergic system
Dorsal and medial raphe projects to where?
through-out the cerebral cortex
when do raphe neurons fire
They fire tonically during wakefulness
and are quiet during sleep
where are raphe neurons
they lie to either side of the midline of the brain stem.
what is the main functions of the Serotonergic system
mood
sleep pain emotion appetite
what are the drugs with general effects on serotonergic system
Selective Serotonin Reuptake inhibitors-Fluoxetine (Prozac)
-which 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
LSD- hallucinogen
Causes a dreamlike state with altered sensory perceptions- potent agonist at 5HT1A receptors in raphe nucleusnsory perceptions-
serotonergic system
what does MDMA (Ecstasy do )
causes serotonin (and norepinephrine) transporters to run in reverse increased release of serotonin and blocked reuptake
Noradrenergic System
where do they project to
Projections form the Locus Coeruleus throughout the brain
what is the function of the Noradrenergic System
Role in arousal and attention
what type of receptors are in the Noradrenergic system
Metabotropic receptors
what subunits do the alpha and beta adrenergic receptors correspond to
a1 Gq
a2 Gi
b1, 2 and 3 Gs
Adrenergic system
and project towards
Primarily in lateral tegmental
area, projecting to thalamus
and hypothalamus.
Cholinergic system
from where do the cell bodies lie and synapse with…
Acetylcholine at NMJ and
synapses in the autonomic ganglia
In the Basal Forebrain complex where is cholinergic innerv
Hippocampus and the neocortex
Cholinergic system
In the brain stem complex, where is cholinergic innerv
innervates the dorsal thalamus and telencephalon
Cholinergic system
what is the 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
4 functions of ACH
Skeletal NMJ
Neuromuscular synapse between the vagus nerve and cardiac muscle fibers
Synapses in the ganglia of the visceral motor system
Look at slide 30
LOOK AT IT!!!!!!!!!!
Disorders of the cholinergic system -peripheral
Myasthenia gravis
Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity
Disorders of the cholinergic system -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
ACHesterase inhibitors treat what diseases and give examples
Alzheimers disease-physostigmine
Myasthenia gravis-neostigmine
what does botox do
Prevents release of ACH at NMJ
What does latrotoxin do
Permanent rlease-depletes ACh at NMJ
what are the 2 types of ACH receptor:
Muscarinic
Nicotinic
What types of receptors are muscarinic and nicotinic
Metabotropic
Ionotropic
what pathway do M3 receptors use
Via Gq to phosphatidylinositol
where are M5 receptors found
Smooth muscles and glands
what pathway do M4 receptors use
Via Gi to inhibit cAMP
Where are M4 receptors used
Smooth muscles and cardiac muscles
what is the result of the activation of M-type receptors
Hyperpolarisation or depolarisation due to opening or closing of K+, ca2+ or cl- channels
what is the function of the histaminergic system
Arousal & attention
Reactivity of vestibular system
Mediation of allergic responses
Influence of brain blood flow
what type of receptors are in the Histaminergic system
3 G-protein-coupled Rs
