T1 L10: How do drugs control the brain? Flashcards
What are the effects of too much GABA?
Loss of consciousness and coma
What are the effects of too little GABA?
Convulsions and seizures
What are the 2 main neuronal types?
Projection neurons and local interneurons
Describe the properties of GABA (A) ionotropic receptors
- Ligand gated Cl- channel
- Fast IPSP’s
Describe the properties of GABA (B) metabotropic receptors
- G-protein coupled receptors
- Indirectly coupled to K+ or Ca2+ channels through 2nd messengers
- Slow IPSP’s
- Both pre- and post-synaptic
Describe the structure of GABA (A) receptors
Heteropentameric structure (2-alpha + 3 more subunits)
Describe the structure of GABA (B) receptors
Complex receptor with multiple binding sites
What are some direct agonists and antagonists of GABA (A) receptors?
Muscimol (agonist)
Bicuclline (antagonist)
What are some indirect agonists of GABA (A) receptors?
Benzodiazapine
Barbiturates
Alcohol
What effect does Benzodiazepine have on GABA (A)?
- It increases the receptor affinity for GABA
- Increases frequency of channel opening
- Anxiolytic and hypnotic effects in the short term, less satisfactory in the long term
Can be addictive
What effect do Barbiturates have on GABA (A)?
They increase duration of channel openings.
This is why they can be used for anaesthesia and epilepsy treatment
Where on the GABA (A) receptor does Benzodiazepine bind?
On the alpha subunit
How does Benzodiazepine indirectly agonise GABA (A) receptors?
It binds to the alpha subunit, changes conformation of the receptor so GABA activation of the receptor is more effective
What are the effects of Benzodiazapine?
Reduce anxiety Cause sedation Reduce convulsions Relax muscles Cause amnesia
Which receptors does alcohol interact with?
GABA (A) NMDA glycine nicotinic serotonin
Which type of GABA receptor does Baclofen agonise?
GABA (B)
What is Baclofen used for?
Used as a muscle relaxant to reduce spasticity Eg, Huntington’s disease
When can GABA be excitatory?
If the Cl- electrochemical gradient allows this during development
What does the Gi part of a G-protein do?
It inhibits adenylyl cyclase
Where is dopamine produced?
In the substantia nigra and the ventral tegmental area of the midbrain
Which dopamine receptor is found on the Gs part of a G-protein?
D1
What does the Gs part of a G-protein do?
It stimulates adenylyl cyclase - cAMP - PKA
Which dopamine receptor is found on the Gi part of a G-protein?
D2
Which disease is caused by destruction of DA projections from the SN to the basal ganglia?
Parkinson’s
Which disease is caused by destruction of DA target neurones in the stratum?
Huntington’s
What is the mesolimbic system?
The reward pathway, is a dopaminergic pathway in the brain.
Cell bodies from the ventral tegmental area (VTA) project to the nucleus accumbens in the limbic system
What are some immediate effects of psychomotor stimulants?
- Feeling of increased alertness and self confidence
- decreased appetite
- Euphoria
- Large doses can cause stereotypy and psychosis
- Increased heart rate, increased blood pressure, dilated pupils
Give examples of psychomotor stimulants
Cocaine, Amphetamine
What is Stereotypy?
Repetitive movements or sounds
What are some long-term effects of psychomotor stimulants?
-Natural rewards increase DA transmission and lead to reinforcement of associated behaviours
They cause increased DA so taking drugs is reinforced
-Downregulation of endogenous DA causes craving
What is the Mesocortical system?
A dopaminergic system that connects the Central Tegmental area (VTA) to the prefrontal cortex
Functions as part of the working memory and planning
Which disease is caused by dysfunction of the Mesocortical dopaminergic system?
Schizophrenia
Where in the brain is Serotonin produced?
In the Raphe nucleus
What is the serotonergic system involved in?
Mood, sleep, pain, emotion, appetite
What type of drug is Fluoxetine (Prozac)?
An SSRI
What effect does MNDA have on serotonin?
Causes serotonin transporters to run in reverse so there is increased release and reduced reuptake of serotonin
What effect does LSD have on Serotonin?
It’s a potent agonist of 5HT1A receptors in the raphe nucleus.
It causes a dreamlike state with altered sensory perceptions
What is the Noradrenergic system?
A neuronal system that is responsible for the synthesis, storage, and release of the neurotransmitter norepinephrine
It has a role in arousal and attention
Which G-protein part do alpha-1 adrenergic receptors interact with?
Gq
Which G-protein part do alpha-2 adrenergic receptors interact with?
Gi
Which G-protein part do beta-1, 2, and 3 adrenergic receptors interact with?
Gs
Where is the adrenergic system of the brain located?
Primarily in the lateral tegmental area, projecting to the thalamus and hypothalamus
Where is the cholinergic system of the brain located?
In the basal forebrain complex
What is Myasthenia gravis in terms of the cholinergic system?
A peripheral disorder of the cholinergic system. It an autoimmune disease that causes destruction of cholinergic receptors in the muscles (weak NMJ’s)
Symptoms: Muscle weakness, eventual moss of muscle activity
What is Alzheimer’s disease in terms of the cholinergic system?
A brain disorder of the cholinergic system causing loss of cholinergic neurones in the basal ganglia
Which system is a Nicotine addiction associated with?
The cholinergic system
What causes Epilespy?
Caused by mutations in the nicotinic receptor genes.
What are Acetylcholinesterase’s inhibitors used to treat?
Alzheimer’s and Myasthenia gravis
How does Botox work?
It prevents release of ACh at the NMJ
How does Latrotoxin work?
It causes permanent release of ACH so there is depletion of ACh at the NMJ
What are the 2 types of ACh receptor?
Muscarinic - Metabotropic
Nicotinic - Ionotropic
What is curare?
a bitter resinous substance obtained from the bark and stems of some South American plants used to cause muscle paralysis
It antagonises nicotinic receptors
Describe the structure of nicotinic receptors
Heterometric combination of alpha-3,4,5 and beta-2,3,4,6
Homomeric receptors: alpha-7, 8, 9
alpha-3 beta-4 on autonomic ganglia
alpha-4 beta-2 and alpha-7 most common brain receptors
Where is the Histaminergic system found in the brain?
The Tuberomammillary nucleus of the hypothalamus
What is the Histaminergic system for?
- Arousal and attention
- Reactivity of vestibular system
- Mediation of allergic responses
- Influence of brain blood flow
