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
16
Q
Metabotropic Serotonin receptors
A
(1-2,4-7)
- 5-HT1A: Gi raphe, hippocampus
- 5-HT1B, C D and E: Gi substantia nigra, basal ganglia
- 5-HT2A, B and C: Gq cortex, hippocampus
- 5-HT4: Gs hippocampus
- 5-HT5A and B: Gi /Go only the A subtype present in the human brain
- 5-HT6: Gs striatum, accumbens, cortex
- 5-HT7: Gs thalamus, hypothalamus, amygdala
17
Q
Ionotropic Serotonin receptors
A
- 5-HT3: opens channel that fluxes Na+ , K+ , Ca2+ (excitatory)
- when activated it enhances the release of a variety of neurotransmitters, including dopamine
- drugs that target this receptor are the gold standard for treating postoperative nausea and vomiting
18
Q
Drugs that affect the Serotonergic system
A
- Selective Serotonin Reuptake Inhibitors e.g.fluoxetine (Prozac)
- prevents the reuptake of serotonin: increases its function
- used as a treatment for depression and anxiety disorders
- effects not seen for 2-3 weeks
- increased availability triggers downstream pathways: 2nd messenger cascades, gene transcription, long term modulatory effects
- Methylenedioxymethamphetamine (MDMA) - ecstasy
- increased release of serotonin (and NE) and blocks the reuptake, increased firing at neurons
- LSD – (Lysergic acid diethylamide)
- a hallucinogen that causes a dreamlike state with altered sensory perceptions
- LSD potent agonist at 5HT1A receptors in the raphe nucleus
- Hallucinogenic properties at 5HT2A receptors in prefrontal cortex
19
Q
The Noradrenergic system
A
- Projects from the Locus Coeruleus superior to the Pons
- plays a role in arousal and attention
- uses Metabtorpic receptors
- alpha-1 Gq
- alpha-2 Gi
- Beta -1,2 and 3 Gs
20
Q
The Adrenergic system
A
- Effect primarily in the lateral tegmental area, projecting to the thalamus and hypothalamus
- Acts an alpha and beta-adrenergic receptors
(epinephrine in the US)
21
Q
The Cholinergic system in
- the Periphery
- the Brain
- the Brainstem complex
A
The Periphery
- Acetycholine at NMJ and synapses in the autonomic ganglia
The Brain
- In the basal forebrain complex
- Cholinergic innervation of the hippocampus and the neocortex
Brain stem complex
- innervates the dorsal thalamus and telencephalon
- control the excitability of sensory relay neurons and provide a cholinergic link between the brain stem and basal forebrain complex
22
Q
Disorders of the cholinergic system
A
in the Peripheral: Myasthenia gravis
- Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity
in the Brain:
Alzheimer’s disease
- Loss of cholinergic neurons in the basal ganglia - possibly underlies deficits in memory associated with the disease.
Addiction
Epilepsy
- Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with mutations in nicotinic receptor genes.
others: comorbidities with smoking
23
Q
Action and examples of Acetylcholinesterase Inhibitors
A
- prolong the action of acetylcholine at the synapse
- treatment for Alxheimets: physostigmine
- treatment for Myasthenia gravis: neostigmine
Botox: prevents the release of ACh at NMJ
Latrotoxin: permanent release, depleting the ACh at the NMJ
24
Q
What are the two types of acetylcholine receptors?
A
Muscarinic- Metabotropic
Nicotinic: Ionotropic
25
Q
Metabotropic
ACh Muscarinic receptors
A
Muscarine (agonist): Aminta muscaria a poisonous mushroom
Atropine (antagonist): belladonna alkaloid from the nightshade
- M1, M3, M5
- via Gq channels to phosphatidylinositol hydrolysis
- found on smooth muscles and glands
- M2, M4
- via Gi to inhibit cAMP
- found on smooth and cardiac muscle
- Leads to the opening or closing of K, Ca or cl channels –> hyperpolarization or depolarization
- are pre and postsynaptic receptors, can also be presynaptic autoreceptors (negative feedback)
26
Q
Ionotropic
Structure of ACh Nicotinic Receptors
A
Nicotine (agonist): 5 subunits surrounding a central pore
-
Muscle receptor
- 2x alpha-1, beta, delta and gamma subunits
- neuromuscular junction NMJ
- Antagonist - curare (poison darts) - instant paralysis
-
Neuronal receptors
- Heteromeric combination of alpha-3,4,5 and beta-2,3,4 or 6
- Homomeric receptors alpha7, 8 or 9
- alpha-3-beta-4 on autonomic ganglia
- alpha-4-beta-2 and alpha-7 most common brain receptors
27
Q
The Histarminergic system
A
- Centered in the Tuberomammillary nucleus of the hypothalamus
- 3 G-protein-coupled receptors
- players roles in arousal and attention
- Reactivity of vestibular system
- Mediation of allergic responses
- Influence of brain blood flow
