Drugs and the Brain Flashcards
1
Q
What are the two main families of GABA receptors?
A
- GABA(A) ionotropic receptors
- Ligand-gated Cl- channel
- Fast IPSPs: mainly GABAergic interneurons
- GABA(B) metabotropic receptors
- G protein-coupled receptors
- Indirectly coupled to K+ or Ca2+ channel through 2nd messengers
- Slow IPSPs
- Both pre and postsynaptic
2
Q
GABA(A) drug agonists and antagonist
A
- Muscimol- directly binds to the GABA binding site
- Bicuculline (antagoinst)
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
- Barbiturates increase the duration of channel openings (anaesthesia, epilepsy treatment)
- Alcohol
3
Q
The action of Benzodiazepine
(diazepam, valium)
A
- acts an indirect agonist binds to the alpha subunit on the GABA(A) receptor changing its confirmation
- increases the affinity of GABA to its receptor
Effects
- reduce anxiety
- cause sedation, relax muscles
- reduce convulsion
- cause amnesia
- inverse agonists bind to benzodiazepine site and have the opposite effect
4
Q
The action of Barbiturates and alcohol on GABA(A) receptors
A
- both bind on different sites on the receptor
- enhance the activity of GABA(A) and their effects are additive
- combining the two can be fatal
- Alcohol interacts with NMDA, glycine, nicotinic and serotonin receptors
Effects
- mild euphoria and anxiolytic effects at low doses
- incoordination, amnesia at higher doses
5
Q
GABA(B) drug agonists and antagonists
A
-
Baclofen: agonist used as a muscle relaxant to reduce spasticity
- Huntington’s disease
- Gi-coupled - inhibits adenylyl cyclase
- Gßŷ-gated K+ channels - increases K+ conductance
- produces a slow hyperpolarizing current (late IPSP)
6
Q
What makes up the Diffuse Modulatory System?
A
Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas.
- Dopaminergic (DA)
- Serotonergic (5-HT)
- Noradrenergic (NA/NE)
- Adrenergic Cholinergic (ACh)
- Histaminergic
7
Q
What are the main distinctions between the functions of the Glutamate and GABA neurons
A
- Glutamate neurons: primary route of sensory and motor information and relay neurons between brain areas
- GABA neurons: interneurons (relay), maintain the balance between excitation and inhibition
8
Q
The Dopaminergic system
A
- involves Dopamine neurons
- cell bodies in the midbrain
- project into the forebrain
- Major dopamine-containing areas are in the Corpus striatum - which receives major input from the Substantia nigra
Plays an major role in:
-
Nigrostriatal system (75% of brain DA) (motor control)
- in Parkinsons, the dopaminergic neurons in the substantia nigra generate resulting in the presenting motor dysfunction
- Mesolimbic system
- Mesocortical system (behavioural effects)
- Tuberohypophyseal system (endocrine control)
9
Q
Types of Dopamine receptors
A
They are Metabotropic receptors D1-5: dopamine produces both EPSPs and IPSPs depending on the receptor subtype and the coupled G proteins
-
D1- like (1 & 5)
- Gs stimulate adenylyl cyclase
- stimulate phospholipase C
- postsynaptic
-
D2- like (2, 3 & 4)
- Gi inhibits adenylyl cyclase
- open K+ channels
- close Ca2+ channels
- postsynaptic
- presynaptic autoreceptors (D3)
- monitors the release of neurotransmitters on the neuron it sits on
10
Q
Dysfunction in the dopaminergic system
A
- Parkinson’s disease: destruction of DA projections from SN to the basal ganglia
- L-DOPA
- MAO inhibitors ( also used as an antidepressant)
- Dopamine receptor agonists
- Huntington’s disease: destruction of DA target neurons in the striatum
11
Q
The Mesolimibic System and Dopamine
A
- this system involves cell bodies in ventral tegmental area (VTA) project to the limbic system, nucleus accumbens (NAcc)
- plays a role in reinforcement (reward) of several categories of stimuli, including drugs of abuse
12
Q
Dysfunction in the Mesolimbic System
A
Addiction: most drugs of abuse lead to enhanced release in the NAcc
- Cocaine and Amphetamine: psychomotor stimulants
13
Q
Immediate effects of Cocaine and Amphetamines
A
- 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 the activation of the sympathetic division of the ANS,
- increased heart rate and blood pressure, dilation of pupils etc.
14
Q
Long-term effects of Cocaine and Amphetamines
A
- 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
15
Q
The Serotonergic System
A
- Found primarily in the groups of neurons found in the Raphe region of the pons and the upper brainstem - have widespread projections to the forebrain
- there are descending projections to the cerebellum and spinal cord
- Ascending reticular activating system
- dorsal and medial raphe project throughout the cerebral cortex
- regulates sleep and wakefulness
- Raphi neurons fire tonically during wakefulness and are quiet during sleep
- other functions in, mood, pain, emotion and appetite
