How drugs control the brain Flashcards
GABA(A) ionotropic receptors
Ligand gated Cl- chanell
Fast IPSPs
Mainly GABAergic interneurons
GABA(B) metabotropic receptors
GPCR
Indirectly coupled to K+ or Ca2+ channel through 2nd messenger
Slow IPSPs
Both pre and post synaptic
GABA(A) receptors
Heteropentameric structure
2 alpha and 3 more subunits
Cl- channel gated by the binding of two agonist molecules
Cl- potential near resting potential
GABA(A) and drugs
Muscimol- direct agonist
Micuculline- direct antagonist
Benzodiazepine- indirect agonist
Barbiturtes- indirect agonist
Alcohol- indirect agonist
GABA(A) benzodiazepine action
Bind to alpha subunit
Changes conformation so receptor is more effective
- reduce anxiety
- cause sedation
- reduce convulsions
- relax muscles
- cause amnesia
GABA(A) barbiturates and alcohol
Bind at different sites
Enhance GABA(A) activity
Combining the two can be fatal
Alcohol also interacts with NMDA, glycine, nicotinic and serotonin receptors
Doses of alcohol
Low- mild euphoria and anxiolytic effects
Higher- incoordination, amnesia
GABA(B) receptor
Gi coupled- inhibits adenylyl cyclase
GBy increases K+ conductance, decreases Ca2+
Slow hyperpolarising current
GABA(B) and baclofen
Agonist
Used as a muscle relaxant to reduce spasticity
e.g. in Huntington’s disease
Neurotransmitter system
Glutamate and GABA are main workhorse of the brain
Glutamate neurones- primary route of sensory and motor information and relay neurones between brain areas
GABA neurones- interneurones, maintain balance between excitation and inhibition
The diffuse modulatory systems
Modulate activity of glutamate and GABA
- dopaminergic
- serotonergic
- noradrenergic
- adrenergic
- cholinergic
- histaminergic
Patterns of communication in the NS
Point to point systems
Hormones released by the hypothalamus
ANS neurones activating body tissues
Diffuse modulatory system with divergent axonal projections
Dopamine neurones
Cell bodies in the midbrain
Project into the forebrain
The dopaminergic system
Nigrostriatal system (75%) of brain DA) (motor control)
Mesolimbic system
Mesocortical system (behavioural effects)
Dopamine receptors
Metabotropic receptors
D1 (1-5)
- Gs
- stimulate adenylyl cyclase
- stimulate phospholipase C postsynaptic
Gi
- inhibit adenylyl cyclase
- open K+ channels
- close Ca2+ channels postsynaptic
Nigrostriatal system
Cell bodies in the substantia nigra project to the striatum
Important part of the basal ganglia involved in movement
Dysfunction of nigrostriatal pathways
Parkinson’s disease
- destruction of DA projections from SN to basal ganglia
Huntington’s disease
- destruction of DA target neurons in striatum
Drugs for dysfunction of nigrostriatal
L-DOPA
MAOi
DA receptor agonists
Mesolimbic system
Cell bodies in VTA project to NAcc in limbic system
Role in reinforcement (reward) of several categories of stimuli
Dysfunction of mesolimbic system
Addiction
Most drugs of abuse lead to enhanced DA release in the NAcc
e.g. cocaine and amphetamines
Mesocortical system
VTA projections to prefrontal cortex
Role in functions such as working memory and planning
Dysfunction in mesocortical system
Schizophrenia
Typical antipsychotics
Chlorpromazine and haloperidol
DA receptor antagonists
Increase DA turnover
Blockade of postsynaptic systems
Atypical antipsychotics
Clozapine (D4)
Specific to receptor subtype
Serotonergic system
Nine raphe nuclei in reticular formation with diffuse projections
Descending projections to cerebellum and spinal cord
Ascending reticular activation system
Dorsal and media raphe project throughout the cerebral cortex
Function of serotonergic system
Mood
Sleep
Pain
Emotion
Appetite
Selective serotonin reuptake inhibitors
Fluoxetine (Prozac)
Increases serotonin function by preventing its uptake
Treatment for depression and anxiety disorders
MDMA
Causes serotonin transporters to run un reverse
Increased release of serotonin and blocked reuptake
LSD
Hallucinogen
Causes dreamlike state with altered sensory perceptions
LSD potent agonist at 5HT1A receptor
The noradrenergic system
Projections from the locus coeruleus throughout the brain
Role in arousal and attention
Metabotropic receptors
- alpha1 Gq
- alpha2 Gi
- beta 1,2,3 Gs
The adrenergic system
Primarily in lateral tegmental area, projecting to thalamus and hypothalamus
Acts on alpha and beta adrenergic receptors
The cholinergic system
In the periphery
ACh at NMJ and synapses in the autonomic ganglia
In the basal forebrain complex
- cholinergic innervation of hippocampus and the neocortex
In the brain stem complex
- innervates the dorsal thalamus and telencephalon
- control excitability of sensory relay neurones
Myasthenia gravis
Autoimmune disease
Destroys cholinergic receptors in the muscle
Muscle weakness and eventual loss of muscle activity
Alzheimer’s disease
Loss of cholinergic neurons in the basal ganglia
Possibly underlies deficits in memory associated with disease
Epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy
Associated with mutations in nicotinic receptor genes
Acetylcholinesterase inhibitors
Prolong action of acetylcholine at the synapse
- treat alzheimers (physostigmine)
- treat myasthenia gravis ( neostigmine)
Muscarinic receptors
M1,3,5
- via Gq to phospatidylinositol hydrolysis
- smooth muscle glands
M2,4
- via Gi to inhibit cAMP
- smooth and cardiac muscle
Nicotinic receptors- ionotropic
5 subunits surrounding central pore
Muscle and neuronal receptors different
Histaminergic system
Arousal and attention
Reactivity of vestibular system
Mediation of allergic responses
Influence of brain blood flow
3 GPCRs
