The Basics & The Main Theories

Question 1

Psychosis (schizophrenia) is a syndrome -

Answer 1

1. at a minimum it means delusions and hallucinations (the Positive Symptoms)

      a. delusions- fixed beliefs- often bizarre- inadequate rational basis-rigid
      b. hallucinations- perceptual experiences of any sensory modality
      c. disorganized speech
      d. catatonic behavior
      e. disorganized behavior
      f. language distortions

2. Negative symptoms-
   a. diminished emotional expression
   b. decreased motivation.
   c. blunted affect
   d. emotional withdrawal
   e. passivity, poor rapport
   f. anhedonia (lack of pleasure)
   g. lack of spontaneity
   h. stereotyped thinking
   i. alogia (decreased fluency and productivity of thought and speech
   j. avolition (decreased initiation of goal-directed behavior
3. Psychosis can be paranoid, disorganized, excited, or depressive.

Question 2

Localization of symptom domains ala Stahl, 2021

Answer 2

1. mesolimbic- positive symptoms
2. mesocortical and prefrontal cortex- negative symptoms.
3. nucleus accumbens and reward circuits- negative symptoms.
4. dorsolateral prefrontal cortex- cognitive symptoms.
5. amygdala and orbitofrontal cortex- aggressive symptoms.
6. ventromedial prefrontal cortex- affective symptoms.

Question 3

Schizophrenia stats

Answer 3

1. affects .5 to 1% worldwide and 1.1% 12 month prevalence in the USA
2. In the USA there are great than 300,000 acute episodes annually
3. Mortality rate is 8 times great than the general population
4. Life expectancy is 20-30 years shorter (lifestyle, suicide)
5. 5% commit suicide.
6. is a disturbance that must last six months or longer including at least one month of positive symptoms.

Question 4

Risk factors for schizophrenia

Answer 4

1. Nutritional deficiencies
2. poverty
3. childhood adversity
4. maternal stress (pre, peri, post)
5. immigration status
6. late winter or early spring birth
7. older father
8. adolescents who frequently smoke marijuana (even when cannabis is discontinued, the risk remains higher).

Question 5

Factors in morbidity and mortality in schizophrenia

Answer 5

1. Lifestyle (poor nutrition, lack of exercise, cardiovascular, diabetes
2. socio (decreased access to primary healthcare and poor adherence).
3. Substance use disorders (smoking, alcohol, cannabis).

Question 6

Three types of violence (Stahl p. 147)

Answer 6

1. psychotic (17%)- associated with positive symptoms of psychosis
2. impulsive (54%)- this is the most common; associated with autonomic arousa and often precipitated by stress, anger, or fear
3. organized (29%)= also known as psychopathic violence is planned and is not accompanied by autonomic arousal. Also called predatory, instrumental, proactive, or premeditated aggression.

Question 7

Causes of schizophrenia

Answer 7

1. Polygenetic- 108 genetic markers that increase the risk; shared with other disorders.
   a. Genes code for proteins and epigenetic regulation.
2. Probability of schizophrenia:
   a. 1 parent with schizophrenia and the probability is 7%

     b. 2 parents with schizophrenia and the probability is 27%
     c. 1 twin- 6-14% probability
     d. identical twins- 33-60% probability

3. The classic (dopamine) theory of schizophrenia accounts for the positive and not the negative symptoms of schizophrenia.
   a. classic theory of inherited disease states that a single abnormal gene can cause a mental illness. No such gene has been identified.
   b. new theory- suggests that a portfolio of a few hundred genes may together cause risk of schizophrenia.
4. Synapse formation and development in schizophrenia neurodevelopment is proposed to go awry (synaptogenesis and brain restructuring goes awry). [Stahl pp152-153].
   a. the onset of positive symptoms of psychosis tends to follow the critical neurodevelopmental periods of pubescene and adolescence.
   b. the key susceptability of genes that cause abnormal synaptic genesis (synaptogenesis) then you have very weak connections and that messes up the neurotransmission that needs to occur in these neurons.
5. Course of schizophrenia illness:
   a. prodrome
   b. Ventricles in the first episode are small, larger in the second episode and so forth.
   c. therefore there is a lot of brain tissue loss and response to treatment decreases.
   c. this can lead to chronic relapsing and residual symptoms.

Question 8

Three Major Hypotheses of Psychosis

Answer 8

1. Dopamine Theory
2. Glutamate Theory
3. Serotonin Theory

Question 9

Classic Dopamine Theory

Answer 9

1. Hyperactive dopamine at D2 receptors in the mesolimbic pathway
   a. the mesolimbic emotional part of the brain fires too much (impacts positive symptoms)

      b. the meso cortical pathway is underactive (moves from the midbrain to the cortex; impacts the 
          negative symptoms of psychosis).

Question 10

Dopamine synthesis

Answer 10

1. Tyrosine (precursor to DA) is taken up into the dopamine nerve terminals via tyrosine transporter and converted into DOPA by the enzyme tyrosine hydroxylase.
2. DOPA is then converted into dopamine by the enzyme DOPA decarboxylase.
3. After synthesis, dopamine is packaged into synaptic vesicles via the vesicular monoamine transporter and stored there until its release into the synapse during neurotransmission.
4. Dopamine’s action can be terminated through: a) transported out of the synaptic cleft and back into the presynaptic neuron via DAT; b) can be broken down intracellularly by COMT, MAO-A, or MOA-B.
   c)

Question 11

Presynaptic D2 autoreceptor

Answer 11

1. regulates DA from the presynaptic neuron
2. allows DA release when not occupied.
3. inhibits DA release when DA builds up in synapse and occupies receptor.
4. DA receptors on somatodentritic area or on axon terminal.
5. DAT clears DA from synapse.

Question 12

Dopamine receptors (post-synaptic)

Answer 12

1. D1-like receptors- includes D1 and D5 receptors
   a. D1 receptors are excitatory and positively linked to adenylate cyclase; therefore when DA Blocks these receptors, they are excitatory
2. D2-like receptors- include D2, D3, and D4 receptors.
   a. D2 receptors are inhibitory and negatively linked to adenylate cyclase; therefore, when DA blocks these receptors, they are inhibitory

Therefore DA can be either excitatory or inhibitory.

Question 13

Striatum

Answer 13

1. Are the subcortical areas that communicate with the basal ganglia.
2. Is the input module to the basal ganglia.
3. Is a neuronal circuit necessary for voluntary movement control.
4. Is composed of three nuclei: caudate, putamen and ventral striatum. (the ventral striatum contains the nucleus accumbens).
5. Dorsal striatum is the Habit Hub.
6. Ventral Striatum is the Reward Hub.

Question 14

New Pathway Concept

Answer 14

1. Integrative Hub mesostriatal Hyperdopaminergia
   a. Sensorimotor (substantia nigra lateral)- associated with the dorsal striatum.
   b. Associative (substania nigra medial)- NOW THOUGHT TO BE VERY IMPORTANT; THOUGHT THAT DA HERE COMMUNICATES WITH DA IN LATERAL SUBSTANTIA NIGRA
   c. Ventral (ventral tegmental area)- associated with the ventral striatum.

Question 15

Dopamine Pathways

Answer 15

1. tuberoinfundibular-DA neurons project from the hypothalamus to anterior pituitary gland.
   a. normal function- DA neurons are tonically active and inhibit prolactin; this is “normal” in schizophrenia.
   b. other function- in postpartum these neurons are decreased and prolactin can increase for
   breastfeeding. Lesions or drugs (that block DA) can also increase prolactin levels.
   c. Causes glactorrhea (breast secretions, amenorrhea, and possible sexual dysfunction.
2. thalamic- this pathway arises from the periacqueductal gray matter, the ventral
   mescencephalon, various hypothalamic nuclei, and the lateralparabrachial nucleus.
   a. may be involved in sleep and arousal by gating information passing hrough the thalamus to
   the cortex and other brain areas.
   b. to date there is no evidence of abnormal functioning of this DA pathway in schizophrenia.
3. nigrostriatal- projects from the DA cell bodies in the brainstem substantia nigra via axons
   terminating in the striatum.
   a. controls motor movements via connections with the thalamus and cortex in the cortico-
   striato-thalamo-cortical circuits.
   b. DA deficiency in this pathway can cause movement disorders. No evidence for abnormal
   functioning of this pathway in schizophrenia.
   c. Part of extrapyramidal nervous system.
   d. “Normal” in schizophrenia.
4. mesolimbic- projects from DA cell bodies in the ventral tegmental area to the nucleus accumbens
   a. Function-DA release is thought to impact negative symptoms, emotional behaviors, including motivation, pleasure and reward
   b. DA proposed to be hyperactive and leads to sx of sxhizophrenia.
   c. D2 antagonists block DA from binding.
   d. 80% occupancy needed in the mesolimbic pathway for an antidpsychotic effect.
5. mesocortical- projects from DA cell bodies in the ventral tegmental area to the prefrontal cortex.
   a. Function- regulates cognition and executive functioning (DLPFC) and regulates negative symptoms, emotions
   and affect (VMPFC).

Question 16

Glutamate Hypothesis

Answer 16

1. The NMDA (N-methyl-D-aspartate) subtype of glutamate receptor is hypofunctional at critical synapses in the prefrontal cortex.
   a. NMDA receptor hypofunction hypothesis: theory accounts for negative symptoms and can account for role of DA through downstream consequences of NMDA receptors that hypofunciton.
2. The primary glutamate neuron talks to the GABA interneuron which talks to another (secondary) glutamate neuron. If there is a dysfunction of the GABA interneuron this could effect the GLU secondary neuron and too much DA can be released which can increase positive symptoms.
   a. this dysfunction can be related to neurodevelopmental or neurodegenerative abnormalities.

Question 17

Glutamate

Answer 17

1. The major excitatory neurotransmitter in the CNS; called the master switch of the brain.

Question 18

What role do GABAergic interneurons play in the release of glutamate

Answer 18

1. The GABAergic interneurons help intracortical pyramidal neurons to communicate.

Question 19

Glutamate synthesis

Answer 19

1. Glutamate or glutamic acid is a neurotransmitter that is an amino acid.
2. When used as a neurotransmitter it is synthesized from glutamine in glia.
3. When glutamate is released from synaptic vesicles of glutamate neurons, it interacts with receptors in the synapse and is transported to neighboring glia via a reuptake pump (excitatory amino acid transporter).
4. glutatmate is then converted to glutamine inside the glia by enzyme glutamine synthetase.

Question 20

Glutamate transporters and receptors

Answer 20

1. After release of glutamate from the presynaptic neurong, it is taken up into glial cells via the excitatory amino acid transporter (EAAT).
2. vesicular transporter for glutamate into synaptic vesicles (vGluT)
3. metabotropic glutamate receptors are linked to G-proteins (8 subtypes)
   a. Group 1- mGluR1, mGluR5
   b. Group 2- mGluR2, mGlur3
   c. Group 3- mGluR4, mGluR6, mGluR7, mGluR8

Question 21

Psychosis in Dementia

Answer 21

1. Neurodegeneration of glutamate/GABA connections leads to positive symptoms.

Question 22

Psychosis in Ketamine/PCP

Answer 22

1. NMDA glutamate receptor is blocked by ketamine/PCP

2. this leads to direct innervation so excitatory glutamate causes DA hyperactivity leading to positive symptoms.

Question 23

Key Glutamate Pathways in the Brain

Answer 23

1. cortico-brainstem- projects from cortico pyramidal neurons to brainstem neurtransmitter centers
   (raphe, VTA, and substantia nigra, locus coeruleus)
   a. a key regulator of neurotransmitter release
2. cortico-striatal- projects from cortical pyramidal neurons to the striatal complex.
3. hippocampal-striatal- projects from the hippocampus to the nucleus accumbens
4. thalamo-cortical- brings information from the thalamus back into the cortex, often to process
   sensory information.
5. cortico-thalamic- projects directly back to the thalamus
6. cortico-cortical (direct)-
7. cortico-cortical (indirect)

** NOTE- If the pyramidal neuron hypofunctions then GABA is not inhibitory.

Schizophrenia: NMDA is theorized to hypofunction in schizophrenia. There is direct innervation so excitatory glutamate causes DA hyperactivity leading to positive symptoms.
For the negative, cognitive, and affective symptoms in schizophrenia, the hypofunction of NMDA glutamate synapse is theorized to cause glutamate hyperactivity which causes key GABA interneurons to inhibit DA release.

Question 24

NMDA glutamate hypofunction hypothesis

Answer 24

1. Psychosis may be caused by dysfunction of glutamate synapses at the GABA interneurons in the prefrontal cortex (PFC).
2. Therefore GABA release is inhibited and the cortical brainstem pathway to the VTA will be overactivated, leading to excessive release of glutamate in the VTA.
3. This will lead to excessive stimulation of the mesolimbic dopamine pathway and to excessive dopamine release in the nucleus accumbens.
4. This hyperactivity is thought to be associated with the positive symptoms of psychosis.

Question 25

NMDA glutamate hypofunction hypothesis’s relation to the DA hypothesis of psychosis

Answer 25

Glutamate neurons directly innervate VTA/mesostriatal dopamine neurons, and when they lose their GABA inhibition from any cause they become hyperactive and stimulate too much dopamine release from the mesostriatal projections of those dopamine neurons.

Question 26

Serotonin Hypothesis of Psychosis

Answer 26

1. hyperactivity/imbalance of serotonin, particularly 5HT2a receptors, can result in psychosis.
2. This disruption leads to positive symptoms of psychosis.
3. This disruption can by hypothetically due to neurodevelopmental abnormalities in schizophrenia and neurodegeneration in Parkinson’s hallucinations as those associated with dopamine principally have more auditory hallucinations.

Question 27

5HT interacts in a neuronal network to regulate all major neurotransmitter systems.

Answer 27

1. 5HT circuits arise from discrete brainstem nuclei (raphe) and project to a wide range of cortical and subcortical brain areas, increasing PFC and locus coeruleus for norephinephrine, VTA for dopamine, hypothalamus for histamine and basal forebrain for acetylcholine.
2. through these connections, 5HT might be modulating itself and directly and indirectly influencing all other neurotransmitter networks.
3. therefore the 5HT network is thought to regulate a variety of behaviors, including mood, sleep, and appetite.
4. 5HT1 stimulation indirectly increases release of other neurotransmitters.
5. 5HT1b stimulation decreases release of other neurotransmitters.
6. 5HT2A stimulation both promotes and inhibits glutamate release.
7. 5HT3 stimulation inhibits norephinephrine and acetycholine release.
8. 5HT3 stimulation inhibits serotonin release.
9. 5HT7 stimulation inhibits glutamate release.
10. 5HT7 stimulation inhibits serotonin release.

Question 28

Postsynaptic serotonin receptors

Answer 28

1. Serotonn regulates glutamate release directly and indirectly.
2. Most 5HT receptor subtypes are postsynaptic heteroreceptors and reside on the neurons that release any of a number of neurotransmitters
3. serotonin can regulate downstream release of numerous neurotransmitters.
4. 5HT’s direct influence on glutamate pyramidal neurons can be both excitatory (5HT 2a, 2c, 4,6,7) and inhibitory (5HT 1a,5 and possibly postsynapitc 5HT1b.

Question 29

Presynaptic 5HT receptors

Answer 29

1. 5HT1a- detect serotonin released from dendrites- negative feedback
2. 5HT2b-acts in opposition to the 5HT1a; these receptors activate the serotonin neuron to cause more impulse flow and increased serotonin release from presynaptic nerve terminals; feed forward feedback.
3. 5HT1b/d- negative feedback autoreceptors to detect the presence of 5HT causing shutdown of further 5HT release and 5HT neuronal impulse flow. Also called the terminal autoreceptor.

Question 30

Actions of 5HT1a receptors

Answer 30

1. promotes release of other neurotransmitters
2. always inhibitory
3. frequently localized upon postsynaptic GABA neurons which means that the net downstream effect is excitatory

Question 31

5HT receptors Overview

Answer 31

1. there are more than a dozen serotonin receptors
2. half of them have known clinical relevance
3. only a few 5HT receptors are located on the serotonin neuron itself (5HT1a, 1b, 1d and 2b) and their purpose is to regulate the presynaptic serotonin neuron directly
4. has receptors both on its axon terminals (autoreceptors) and on its dendrites and soma (somatodentritic autoreceptors) and both regulate serotonin release.

Question 32

Serotonin synthesis

Answer 32

1. tryptophan to trypotphan-5-hydroxylase to 5-hydroxytryptophan to aromatic L-amino acid decarboxylase to serotonin (5HT); removal occurs via transports and MAO.

Question 33

How the Serotonin Hypothesis is related to the Dopamine Hypothesis and Psychosis.

Answer 33

1. The consequences to dopamine of the theoretical excessive or imbalance 5HT2a stimulation at the glutamatergic pyramidal neurons:
   a. leads to dopamine hyperactivity
   b. When glutamate neurons that innervate VTA dopamine neurons lose thier serotonin input due to neurodegeneration of serotonin neurons in Parkinson’s Disease OR their GABA inhibition from neurodegeneration of any cause, they become hyperactive and stimulate too much dopamine release from the mesostriatal projections of those dopamine neurons.

Question 34

Serotonin hyperfunction hypothesis of psychosis

Answer 34

1. Suggests that psychosis may be caused by an imbalance in excitatory 5HT2a receptor stimulation of those glutamate pyramidal neurons that directly innervate VTA/mesostriatal integrated hub dopamine neurons and visual cortex neurons.
2. Hallucinogens LSD, mescaline, and psilocybin all are powerful 5HT2a agonists and induce psychosis, dissociative experiences, and especially visual hallucinations by overstimulating prefrontal and visual cortex 5HHT2a receptors.
3. The psychosis symptoms can be blocked by 5HT2a antagonists, demonstrating that hallucinogens cause psychosis by 5HT2a stimulation.
4. In Parkinson’s there is not only a loss of dopamine nerve terminals in the motor striatum of the nigrostriatal pathway BUT ALSO LOSS OF SEROTONIN NERVE TERMINALS IN THE PREFRONTAL AND VISUAL CORTEX. THIS LOSS OF SEROTONIN AND SEROTONIN NERVE TERMINALS leads to upregulation and too many 5HT2a receptors in the cortex. This overabundance leads to imbalance in their excitatory actions on glutamate dendrites and lead to symptoms of psychosis.
5. In dementia psychosis, the accumulation of plaques, tangles, and Lew bodies, hypothetically knocks out cortical neurons and leads to a lack of inhibition of the surviving glutamate neurons. If there is not enough GABA inhibition to counter the normal 5HT2a stimulation this theoretically causes psychosis in dementia.