Summary 3.6C – The Brain (part 2)
Table of Contents
Theme 3: When Things Go Wrong in the Brain .................................................................................... 2
Stahl (2000) - Part of Chapter 4: How synaptic neurotransmission mediates emotional disorders (pg.
105 – 130) ...................................................................................................................................... 2
Stahl (2008) - Chapter 7: Circuits in Psychopharmacology (pg. 195 – 222) ........................................ 10
Stahl (2008) - Part of Chapter 8: From circuits to symptoms in Psychopharmacology (pg. 223 – 238) . 25
Breedlove & Watson (2013) - First part of Chapter 4, The chemistry of behaviour, pg. 91-107 ............ 35
Stahl (2000) - Part of chapter 3: Agonists and Antagonists, Allosteric modulation, Co-transmission
versus allosteric modulation, (pg 82-98) ........................................................................................ 46
Stahl (2013) - Part of Chapter 2: G-protein-linked receptors and G-protein-linked receptors as targets
of psychotropic drugs, (pg 34-43) .................................................................................................. 53
Stahl (2008) - Part of Chapter 5: Enzymes as sites of pharmacological drug action (pg. 167-170) ....... 58
Theme 4: Brain & Cognition ........................................................................................................... 61
Dresler et al. (2013). Non-pharmacological cognitive enhancement. ............................................... 61
Ilieva et val. (2013). Objective and subjective cognitive enhancing effects of mixed amphetamine salts
in healthy people. ......................................................................................................................... 68
Smith & Farah (2011). Are prescription stimulants “smart pills”? The epidemiology and cognitive
neuroscience of prescription stimulant use by normal healthy individuals. ...................................... 76
Battleday & Brem (2015). Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived
subjects: A systematic review. ...................................................................................................... 85
,Theme 3: When Things Go Wrong in the Brain
Stahl (2000) - Part of Chapter 4: How synaptic neurotransmission
mediates emotional disorders (pg. 105 – 130)
General concepts relating to how psychiatric disorders are thought to be associated with
modifications in synaptic neurotransmission.
Molecular neurobiology and psychiatric disorders
4 elements of psychiatric disorders:
• Genetic vulnerability
Vulnerability arises from abnormally functioning genes, which can be inherited. It is poorly
understood but still very important; a few important principles of genetic vulnerability have
been established:
Ratio of illness between monozygotic vs. dizygotic twins (especially in bipolar disorder and
schizophrenia). No specific genes or single abnormality is found for these diseases but it is
thought that multiple sites in DNA within the genome interacts to produce a psychiatric illness,
see figure 4-2 (this is in contrast to for example Huntington where a single gene has a large
effect, see figure 4-1) --> they may act individually/additively/synergistically and must act
during critical periods of development. Also, different genes may be abnormal in different
families with the same psychiatric disorder: heterogeneity.
The biochemical expression of vulnerability occurs when many different genes make
important proteins in the wrong amounts, wrong places or at the wrong times, causing
abnormal structures and functions of neurons. This creates risk, but still doesn't mean
expression unless nongenetic factors (from the environment) interact to convert latent
vulnerability into manifest disease.
• Life events and the Two-Hit hypothesis of psychiatric disorders
Two two-hit hypothesis tries to explain the combination of the genetic vulnerabilities and
environmental factors as the basis of many psychiatric disorders. The first hit in this would be
all the critical vulnerabilities and the second hit is some type from the environment. This
supports the concept that one does not inherit a mental disorder per se, but one inherits the
vulnerability factors for the mental disorder (genetic first hit) - the chance of actually
manifesting the illness depends also on other factors (the second hits). Some mental disorders
such as bipolar disorder and schizophrenia have higher chances of being expressed in
vulnerable individuals (figure 4-5).
,• Childhood development, personality, coping skills and social support as factors in
psychiatric illnesses
Several environmental interactions are hypothesised to affect the expression of information
present in the genome and therefore may dictate whether a disorder expresses itself. These
include early life experiences, causing a person to develop learned patterns of coping that
could influence a personality disorder. Additionally there are adult life experiences, like
certain stressful events. Personality traits themselves may be genetically influences or
environmentally determined by childhood developmental experiences. Traits generate coping
skills which can have an impact on the adult life events - the ability to buffer stressors may be
the product of which life events occur and how much coping skills and social support exists
prior to being layered onto a genome.
According to this model, the biologically determined disorder with more vulnerable genomes
would require only minor stressors for a person to develop a mental illness. However,
stressors could be so severe that even a normal robust genome might break down to cause a
mental disorder (like PTSD) - figure 4-5
, • Other environmental influences on individuals and their genomes
The environment provides numerous potential biochemical influence on the genome, such as
exposure to viruses, toxins or diseases - these could contribute to the probability that genetic
vulnerabilities for a psychiatric illness will become manifest.
Neuronal plasticity and psychiatric disorders
• Neurodevelopmental disorders
Neurons and synapses must develop properly and then be adequately maintained or else a
disorder could result.
First, the correct neurons must be selected in the utero, then they must migrate to their
predesignated locations for the brain to function properly. Abnormal migration could result in
epilepsy, mental retardation of even schizophrenia and dyslexia. It could be caused by genes
giving the wrong direction, either inherited or acquired in the utero after mother takes cocaine
or alcohol.
Wrong genetic information or toxins could cause abnormal neuronal selections through a
'grim reaper' growth factor to be inappropriately turned on instead of a 'bodyguard' growth
factor --> this could cause the wrong cell to turn on its apoptotic suicide system. What may be
left are puny cells with bad molecular Velcro, which is why they cannot crawl along glia/fibres
to get where they need to go. In this way, a neuronal migration disorder is begun by improper
selection of neurons in the first place.
Abnormal synaptogenesis could lead to other neurodevelopmental problems. Synapses are
dynamic and constantly changing. If a neuron receives the wrong semaphore signal, it may sail
its axonal growth tip into the wrong postsynaptic targets, leading to incorrect information
transfer. If this is done correctly, the next step is to maintain the synapse by branching,
pruning, growing or dying of neuronal axons and dendrites. If the process is interrupted early
in development the brain may not reach its full potential (leading to mental retardation,
autism and maybe schizophrenia). Drug treatments may not only modify neurotransmission
acutely but could potentially interact with neuronal plasticity --> certain growth factors may
provoke the neuron to sprout new axonal or dendritic branches and to establish new synaptic
connections. If applied early enough in development, such treatments might compensate for
problems in cell selection/migration or synapse formation. The problems are however very
anatomically discrete and so hard to program right place right time.
Table of Contents
Theme 3: When Things Go Wrong in the Brain .................................................................................... 2
Stahl (2000) - Part of Chapter 4: How synaptic neurotransmission mediates emotional disorders (pg.
105 – 130) ...................................................................................................................................... 2
Stahl (2008) - Chapter 7: Circuits in Psychopharmacology (pg. 195 – 222) ........................................ 10
Stahl (2008) - Part of Chapter 8: From circuits to symptoms in Psychopharmacology (pg. 223 – 238) . 25
Breedlove & Watson (2013) - First part of Chapter 4, The chemistry of behaviour, pg. 91-107 ............ 35
Stahl (2000) - Part of chapter 3: Agonists and Antagonists, Allosteric modulation, Co-transmission
versus allosteric modulation, (pg 82-98) ........................................................................................ 46
Stahl (2013) - Part of Chapter 2: G-protein-linked receptors and G-protein-linked receptors as targets
of psychotropic drugs, (pg 34-43) .................................................................................................. 53
Stahl (2008) - Part of Chapter 5: Enzymes as sites of pharmacological drug action (pg. 167-170) ....... 58
Theme 4: Brain & Cognition ........................................................................................................... 61
Dresler et al. (2013). Non-pharmacological cognitive enhancement. ............................................... 61
Ilieva et val. (2013). Objective and subjective cognitive enhancing effects of mixed amphetamine salts
in healthy people. ......................................................................................................................... 68
Smith & Farah (2011). Are prescription stimulants “smart pills”? The epidemiology and cognitive
neuroscience of prescription stimulant use by normal healthy individuals. ...................................... 76
Battleday & Brem (2015). Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived
subjects: A systematic review. ...................................................................................................... 85
,Theme 3: When Things Go Wrong in the Brain
Stahl (2000) - Part of Chapter 4: How synaptic neurotransmission
mediates emotional disorders (pg. 105 – 130)
General concepts relating to how psychiatric disorders are thought to be associated with
modifications in synaptic neurotransmission.
Molecular neurobiology and psychiatric disorders
4 elements of psychiatric disorders:
• Genetic vulnerability
Vulnerability arises from abnormally functioning genes, which can be inherited. It is poorly
understood but still very important; a few important principles of genetic vulnerability have
been established:
Ratio of illness between monozygotic vs. dizygotic twins (especially in bipolar disorder and
schizophrenia). No specific genes or single abnormality is found for these diseases but it is
thought that multiple sites in DNA within the genome interacts to produce a psychiatric illness,
see figure 4-2 (this is in contrast to for example Huntington where a single gene has a large
effect, see figure 4-1) --> they may act individually/additively/synergistically and must act
during critical periods of development. Also, different genes may be abnormal in different
families with the same psychiatric disorder: heterogeneity.
The biochemical expression of vulnerability occurs when many different genes make
important proteins in the wrong amounts, wrong places or at the wrong times, causing
abnormal structures and functions of neurons. This creates risk, but still doesn't mean
expression unless nongenetic factors (from the environment) interact to convert latent
vulnerability into manifest disease.
• Life events and the Two-Hit hypothesis of psychiatric disorders
Two two-hit hypothesis tries to explain the combination of the genetic vulnerabilities and
environmental factors as the basis of many psychiatric disorders. The first hit in this would be
all the critical vulnerabilities and the second hit is some type from the environment. This
supports the concept that one does not inherit a mental disorder per se, but one inherits the
vulnerability factors for the mental disorder (genetic first hit) - the chance of actually
manifesting the illness depends also on other factors (the second hits). Some mental disorders
such as bipolar disorder and schizophrenia have higher chances of being expressed in
vulnerable individuals (figure 4-5).
,• Childhood development, personality, coping skills and social support as factors in
psychiatric illnesses
Several environmental interactions are hypothesised to affect the expression of information
present in the genome and therefore may dictate whether a disorder expresses itself. These
include early life experiences, causing a person to develop learned patterns of coping that
could influence a personality disorder. Additionally there are adult life experiences, like
certain stressful events. Personality traits themselves may be genetically influences or
environmentally determined by childhood developmental experiences. Traits generate coping
skills which can have an impact on the adult life events - the ability to buffer stressors may be
the product of which life events occur and how much coping skills and social support exists
prior to being layered onto a genome.
According to this model, the biologically determined disorder with more vulnerable genomes
would require only minor stressors for a person to develop a mental illness. However,
stressors could be so severe that even a normal robust genome might break down to cause a
mental disorder (like PTSD) - figure 4-5
, • Other environmental influences on individuals and their genomes
The environment provides numerous potential biochemical influence on the genome, such as
exposure to viruses, toxins or diseases - these could contribute to the probability that genetic
vulnerabilities for a psychiatric illness will become manifest.
Neuronal plasticity and psychiatric disorders
• Neurodevelopmental disorders
Neurons and synapses must develop properly and then be adequately maintained or else a
disorder could result.
First, the correct neurons must be selected in the utero, then they must migrate to their
predesignated locations for the brain to function properly. Abnormal migration could result in
epilepsy, mental retardation of even schizophrenia and dyslexia. It could be caused by genes
giving the wrong direction, either inherited or acquired in the utero after mother takes cocaine
or alcohol.
Wrong genetic information or toxins could cause abnormal neuronal selections through a
'grim reaper' growth factor to be inappropriately turned on instead of a 'bodyguard' growth
factor --> this could cause the wrong cell to turn on its apoptotic suicide system. What may be
left are puny cells with bad molecular Velcro, which is why they cannot crawl along glia/fibres
to get where they need to go. In this way, a neuronal migration disorder is begun by improper
selection of neurons in the first place.
Abnormal synaptogenesis could lead to other neurodevelopmental problems. Synapses are
dynamic and constantly changing. If a neuron receives the wrong semaphore signal, it may sail
its axonal growth tip into the wrong postsynaptic targets, leading to incorrect information
transfer. If this is done correctly, the next step is to maintain the synapse by branching,
pruning, growing or dying of neuronal axons and dendrites. If the process is interrupted early
in development the brain may not reach its full potential (leading to mental retardation,
autism and maybe schizophrenia). Drug treatments may not only modify neurotransmission
acutely but could potentially interact with neuronal plasticity --> certain growth factors may
provoke the neuron to sprout new axonal or dendritic branches and to establish new synaptic
connections. If applied early enough in development, such treatments might compensate for
problems in cell selection/migration or synapse formation. The problems are however very
anatomically discrete and so hard to program right place right time.
