Drugs on the brain Flashcards
Dopaminergic systems
Neuronal projections from the midbrain into the forebrain.
Originations
- Substantial nigra
- Ventral tegmental area
3 systems:
- Nigrostriatal
- Mesolimbic
- Mesocortical
- Tuberohypophyseal
Nigrostriatal system
- Function
- Projections
Dopaminergic system–> produces 75% of dopamine in the brain.
Projection:
- Cell body in substantial nigra
- Neurones project into the striatum [caudate nucleus and putamen]
Function:
- Motor—.> voluntary movement
Mesolimbic system
Dopaminergic system
Projection:
- Ventral tegmental area—> limbic system [nucleus accumbens]
Function:
- Reinforcement of certain stimuli [incl. drug abuse]
Addicition
Dysfunction of the mesolimbic system [responsible for reinforcement]
Drug abuse enchances dopamine release in the nucleus accumbens of the limbic system/
Also dysfunction of the cholinergic system [nicotine]
Cocaine and amphetamine
- System affected
- Immediate and long-term effects
Affects the dopaminergic, mesolimbic system.
Immediate effects:
- Increased alertness, self confidence
- Europhia
- Decreased appepties
- Large dose= psychosis and stereotypy
- Can mimic SNS activation
Long term:
- Natural rewards increase dopamine transmission
- Down-regulation of DA system= craving
- Drug-taking behaviour reinforced.
Dysfunctions of the nigrostriatal system
Parkinson’s disease
- Destroys projection to basal ganglia
Huntington’s disease
- Destroys target neurones in the striatum
Drugs used to treat Parkinson’s
- SYSTEM AFFECTED
Affects nigrostriatal system
L-DOPA [dopamine precursor]
Monoamine oxidase inhibitors
[prevents DA degradation]
DA receptor agonists
Mesocortical system
- Projections
- Function
- Dysfunction
Dopaminergic system
- Projections from the ventral tegmental area to the prefrontal cortex
Function:
- Influences personality, planning and working memory
Dysfunction:
- Schizophrenia
Typical antipsychotics
- Mechanism
- Effects [system affected]
Dopamine receptor antagonists
- Increases dopamine turnover
- Up-regulation [blocks postsynaptic receptors]
- Loss of auto regulation inhibition [blocks pre-synaptic receptors]
Effects
- Antipsychotic effects by influencing the mesocortical system
- Extrapyramidal side effects
Typical antipsychotics
- Examples
Chlorpromazine
Haloperidol
Atypical antipsychotics
- Mechanism
- Effects
Anti-psychotics that are specific to a receptor subtype
Effects
- Reduces schizophrenic psychosis
- Does not have extrapyramidal side effects
Clozapine
Atypical antipsychotic
Cortical D4 receptor antagonist [mesocortical system]
- Used to treat schizophrenic psychosis
Extrapyramidal side effects of typical antipsychotics
Set of symptoms that arise from the chronic blockade of dopamine receptors
- Makes the mesocortical system hypersensitive
Symptoms:
- Tardive dyskinesia
- Parkinsonism
Inhibitory control of cortical pyramidal neurones
- Cells
- Function
Dendrite targeting cells:
- GABAergic interneurones
- Controls input by impinging the dendrites at different sites.
Basket and axo-axonic cells
- GABAergic interneurones that control outputs
- Basket= soma
- Axo-axonic—> on axon. Greatest influence on AP generation
GABA-alpha receptor structure
5 Subunits:
- 2 alpha
- 3 other units
Channe- ionotrophic
- Chloride
Mechanism of GABA-alpha receptor
Gated by two agonists
- GABA
- Another agonist [i.e benzodiazapine]
Binding of two agonists increases chloride permeability
- Hyperpolarises plasma membrane [Cl- enters cell]
- Decreases excitability of cell
Benzodiazapine
- Drug type
- Mechanism
- Effects
Indirect GABA-alpha agonist
- Binds to alpha subunit
- Increases receptor affinity for GABA
Effects- rapid onset
- Increases frequency of Cl- channel opening
- Rapid onset of Anxiolytic and hypnotic effects [less effective long term]
Muscimol
Direct GABA-alpha agonist
- Binds to GABA site
Bicuculline
Direct GABA-alpha antagonist
- Binds to to GABA site
- Use as experimental tool.
Barbituates
- Drug type
- Mechanism
- Uses
Indirect GABA-alpha agonist
- Increases the duration at which Cl- channel opens
- Combination with alcohol is fatal
Use:
- Anaesthetics
- Epilepsy
Alcohol
GABA-alpha agonist
Also interacts with other receptors
- NMDA
- Glycine
- Nicotinic
- Serotinin
Inverse agonists of GABA-alpha
Bind to benzodiazapine site
- Have opposite effects of benzodiazepine
Effects
- Anxiety
- Predispositions to convulsions
Benzodiazepine effects + uses
- Decreased anxiety
- Amnesia
- Sedation
- Muscle relaxant
- Reduced convulsions
GABA-beta receptor
- Structure
- Function
Metabotrophic receptor- G protein
- Gi= inhibitory of adenylyl cyclase
- G[beta-gamma]= increased K+ conductance and decreased Ca2+ conductance.
Effects:
- Late IPSP
Inhibition
- Does not have same anti-seizure properties like GABA-alpha
Baclofen
- Drug type
- Effect
- Uses
GABA-beta agonist
- Muscle relaxant
Use:
- Reduced spasticity in Huntington’s disease
Noradrenaline system
- Projection
- Function
Projections
- From locus coeruleus to everywhere in the brain
Function
- Arousal + attention
Receptors:
- Metabotrophic
Alpha adrenergic receptors
- Alpha 1, 2
Metabotrophic receptors
Alpha-1
- Gq
Alpha- 2
- Gi
Beta adrenergic receptors
- Beta 1, 2,3
Metabotrophic receptors of noradrenaline system
- All Gs receptors
Adrenaline system
Projections:
- Lateral tegmental area [medulla]—-. thalamus and hypothalamus
Acts on alpha and beta adrenergic receptors
Serotonergic system
- Nuclei
- Projections
- Functions
Composed of 9 Raphe nuclei
- In reticular formation
Projections
- Cerebellum + spinal cord [pain]
- Ascending reticular activating system
- Dorsal and medial raphe—> cortex
Functions:
- Mood
- Sleep
- Appeptite
- Emotion
- Pain
Serotonergic receptors
Mainly metabotrophic, one ionotropic
Fluoxetine
Also known as Prozac
SSRI- selective serotonin reuptake inhibitor—-> serotonergic system
Function
- Makes more serotonin more available
Use:
- Depression
- Anxiety
MDMA
- mechanism
- system
Also known as ecstasy
Mechanism:
- Makes NADR and serotonin reuptake transporters run in reverse.
- Blocks serotonin reuptake
Affects serotonergic and noradrenergic systems
LSD
Drug that affects serotonergic system
- 5HT1A receptor agonist
- Works in Raphe nuclei.
Effects
- Hallucinogen [5HT2A receptor in prefrontal cortex]
- Altered sensory perception
- Dreamlike state
Cholinergic system
Releases acetylcholie
Periphery
- Ach release at neuromuscular junction and autonomic ganglia
Brain
- Basal forebrain complex
- Brain stem complex
Basal forebrain complex
Part of the cholinergic system
- Innervation of hippocampus and neocortex
Brain stem complex
Part of cholinergic system
- Innervation of dorsal thalamus
- Telencephalon
Function
- Links brain stem and basal forebrain complex
- Controls excitability of sensory relay neurones.
Myasthenia gravis
Autoimmune disorder of cholinergic system in the periphery
- Destroys cholinergic receptors in muscle
Effect
- Muscle weakness
- Degeneration—> loss of muscle activity
Alzheimer’s disease
- system
- mechanism
Loss of cholinergic neurones in the basal ganglia
- Could underline memory deficits
Autosomal dominant nocturnal frontal lobe epilepsy
Branch of epilepsy with mutations in nicotinic receptor genes
Physostigmine
- Mechanism
- Use
Acetylcholinesterase inhibitor
- Increases Ach at synapse
Treatment for Alzheimer’s disease
Neostigmine
Acetylcholine inhibitor
- Increases Ach at synapse
Used to treated Myasthenia gravis
Histaminergic system
Involves histamine release with histamine receptors
- 3 G-protein coupled receptors
Function
- Arousal and attention
- Vesitubular reactivity
- Allergic responses
- Brain blood flow
