Lecture 34 - Pathophysiology of CNS Disorders Flashcards
Hindbrain consists of
medulla, pons, cerebellum
Midbrain consists of
substantia nigra
Forebrain consists of
cerebral cortex
basal ganglia: striatum (caudate and putamen), globus pallidus, subthalamic nucleus
limbic system: hippocampus, amygdala diencephalon: thalamus, hypothalamus
Medulla
autonomic functions - control of involuntary functions
includes centers for controlling respiration, cardiac function,
vasomotor responses, reflexes (e.g. coughing)
Pons
“bridge” to cerebellum and forebrain
relays signals from the forebrain to the cerebellum
Cerebellum
“little brain”
governs motor coordination for producing smooth movements undergoes neurodegeneration in spinocerebellar ataxias (uncontrolled disjointed/jerky movement)
Substantia nigra
consists of 2 sub-structures
SN pars compacta
=> provides input to the basal ganglia, supplies
dopamine to the striatum
=> involved in voluntary motor control
(‘movement with intention’) and some
cognitive functions (e.g. spatial learning)
=> undergoes neurodegeneration in PD
SN pars reticulata has an output function, relays signals from the basal ganglia to the thalamus
Forebrain
- cortex (cerebrum)
→ involved in processing and interpreting information - basal ganglia: striatum (caudate & putamen), globus pallidus, subthalamic nucleus
→ voluntary motor control, some cognitive functions - limbic system
→ emotions (amygdala), memory (hippocampus) - diencephalon:
→ thalamus: ‘relay station’ to and from the cortex (voluntary motor function)
→ hypothalamus:
=> regulates internal homeostasis, emotions
=> hormonal control (through the pituitary
gland) and direct neural regulation (involuntary motor function)
The cortex is involved in
decision making, higher level functions
- our senses receive information about the environment, which is passed through the thalamus, to the cortex, and back.
- ‘decisions’ are made in these cortico-thalamic loops about how to interpret and act on the incoming sensory information.
- damage to the cortex can affect movement, speech, personality.
- schizophrenia is considered a disease of the frontal cortex
Which of the following brain structures is directly involved in controlling involuntary functions?
hypothalamus
medulla oblongata
The CNS consists of
neurons and glial cells
Glial cells
astrocytes
oligodendrocytes
microglia
Astrocytes
- provide neurons with growth
factors, antioxidants - remove excess glutamate
(excitotoxic neurotransmitter) - support the blood-brain barrier
Oligodendrocytes
- produce myelin sheath that
insulates axons
Microglia
- provide growth factors
- clear debris (e.g. myelin debris)
by phagocytosis - role in neuroinflammation (in CNS diseases, microglia are overactive and can harm others)
Blood-brain-barrier is stabilized by
tight junctions in the endothelial cell layer of blood vessels in the brain.
drugs have to be small enough or hydrophobic enough to get through the BBB
Neurotransmission involves
a release of synaptic vesicles from boutons into the synaptic gap (cleft).
Neurtransmission is triggered by
electrical depolarization of the neuron (influx of Na+ ions that changes the charge polarity of the membrane).
Action potentials last
0.2-0.5 msec
action potentials for a single neuron are always of the same magnitude (‘all or none’)
Refractory period
period after action potential (hyperpolarized phase) during which a neuron will not fire again.
Current carried by a nerve fiber (bundle of axons) is
greater as a result of summation
Excitatory neurotransmitters induce EPSPs
- definition of EPSP: excitatory postsynaptic potential
(subthreshold depolarization peak) - excitatory neurotransmitter acts on an ionotropic receptor,
allowing Na+ ions to cross the membrane. - an increase in the strength of the stimulus will increase the magnitude of the depolarization, so that the threshold depolarization to trigger an action potential is achieved.
Inhibitory neurotransmitters induce IPSPs
- definition of IPSP: inhibitory postsynaptic potential
- inhibitory neurotransmitter induces hyperpolarization by allowing Cl- ions to cross the membrane.
- an IPSP can decrease the magnitude of a subsequent EPSP.
How do drugs act in the CNS? What are the mechanisms?
- generally drugs act in the CNS by modulating synaptic neuro- transmission:
→ some drugs act as agonists, antagonists, or partial agonists at synaptic receptors
→ other drugs target mechanisms involved in metabolizing (or removing) transmitter from the synaptic cleft.
=> enzymatic metabolism
=> transport into the presynaptic neuron or a neighboring glial cell
→ in many cases the underlying molecular mechanisms aren’t clear – but we do know about effects on neurotransmission.
Common amino acid (aa) neurotransmitters
(1) GABA (gamma aminobutyric acid)
(2) glycine
(3) glutamate
GABA (gamma aminobutyric acid)
throughout the brain
- major inhibitory neurotransmitter in the brain. (hyperpolarization)
- depresses neuronal excitability by increasing the flux
of Cl- ions into the neuron.
- there are GABA-A and GABA-B receptors.
- drugs that interact with GABA pathways are generally
CNS depressants and include:
*Sedative hypnotics (benzodiazepines, barbiturates)
*Anticonvulsants
*Anxiolytics
glycine is similar to GABA but acts in the spinal cord
GABA receptor
GABA(A) - ion channel
GABA(B,C) - GPCR
Glutamate
throughout the brain
- major excitatory aa neurotransmitter in the brain. (depolarizes)
- excess glutamate can cause neuronal damage by allowing excessive Ca2+ influx into the neuron.
- glutamate receptors are metabotropic (GPCRs - metabolic rxns involving phosphorylation) or ionotropic (NMDA and AMPA - receptors that bind glutamate that are activated by glutamate and allow for influx of ions).
Glutamate receptor
AMPA, NMDA - ion channel
mGluR - GPCR
Common non-amino acid neurotransmitters
(1) acetylcholine
(2) dopamine (DA)
(3) norepinephrine
(4) serotonin; 5-hydroxytryptamine (5-HT)
Acetylcholine
basal forebrain, pons, cortex, basal ganglia
- both muscarinic (M1-M5) and nicotinic
receptors (as in the periphery)
- examples of drugs targeting this form of neurotransmission are cholinesterase inhibitors (e.g. Aricept, used to treat Alzheimer’s disease).
ACh receptor
nicotinic - nAChR
muscarinic - mAChR
Dopamine
midbrain
- drug targets include the D1-D5 receptors (GPCRs)
and the dopamine transporter (DAT)
- DA neurons arise from the ventral tegmental area
(VTA) and the SN.
- drugs that block DAT and thus increase extracellular DA (e.g. amphetamine or cocaine) can produce euphoria and lead to addiction.
- excessive dopaminergic signaling may be involved in schizophrenia.
- loss of DA neurons in the SN is responsible for PD.
- drugs that interact with DA pathways include:
*Antipsychotics (D2 receptor antagonists)
*D2/D3 and D1 receptor agonists for PD
Dopamine receptors
D1-like - Gs coupled (increase cAMP)
D2-like Gi coupled (decrease cAMP)
Norepinephrine
- drug targets include the α- and β-adrenergic receptors (GPCRs) and the norepinephrine transporter (NET)
- NE axons arise from the locus coeruleus in the pons region.
- NET inhibitors are used to treat depression.
Norepinephrine adrenergic receptor
alpha1, alpha2 - GPCR
Serotonin; 5-hydroxytryptamine (5-HT)
midbrain/pons
- drug targets are serotonin receptors (14 GPCRs and one gated ion channel) and the serotonin transporter (SERT).
- 5-HT axons arise from a group of cell bodies called the raphe (rah-fay) nuclei.
- serotonin systems are involved in sleep, vigilance, mood, and sexual function.
- drugs that interact with 5-HT receptors include: (prevent excessive serotonin)
*5-HT2A antagonists as atypical antipsychotics
*5-HT1D agonists for migraine
*SERT uptake inhibitors for depression *5-HT2A agonists are hallucinogenic (e.g. LSD)
5-HT receptor
5-HT3 - ion channel
5-HT1,2 - GPCR
