NURS 660 Exam 1 Study Guide
Note: Exam 1 will cover content from Weeks 4 and 5.
1. Identify the emerging neurobiological hypothesis of
schizophrenia. Dopamine Theory – D2 receptor hyper/hypo activity of
dopamine
o Hyperactive dopamine at D2 receptors in the mesolimbic pathway = psychosis
o Hypodopaminergic in the mesocortical pathway = negative/cognitive/affective symptoms
• Glutamate Theory
o N-Methyl-D-Aspertate (NMDA) receptor is hypofunctional on GABA interneurons in the prefrontal cortex
Causes for hypofunctionality:
• Neurodevelopment abnormalities – schizophrenia
• Neurodegenerative abnormalities – Alzheimer’s, other dementias
• NMDA receptor blocking – ketamine, PCP
Hypofunctional NMDA synapse on the 1st neuron does not excite GABA interneuron, thus no GABA to inhibit the
3rd neuron, therefore the 3rd neuron is excited and a whole bunch of glutamate comes out. The glutamate then
goes downstream to stimulate dopamine (positive symptoms)
o Hypofunctioning NMDA receptors may be linked to downstream:
Overactivity of dopamine in the mesolimbic pathway (VTA -> striatum/nucleus accumbens) (positive symptoms)
Underactivity of dopamine in the mesocortical pathway (VTA -> PFC) (negative/cognitive/affective symptoms)
Serotonin Theory - 5HT2A receptor
o 5HT2A receptor hyperfunction in the cortex
o Serotonin not only regulates its own release via presynaptic receptor actions, but also regulates all other major NTs
through postsynaptic receptor actions
o Serotonin hyperactivity/imbalance @ 5HT2A receptors on glutamate neurons in cerebral cortex is linked to psychosis o
5HT2A receptor actions (in addition to NMDA receptor actions) can hypothetically lead to hyperactivity dopamine
activity in downstream mesolimbic pathways
2. Identify the different dopamine pathways and what role each pathway plays in relation to schizophrenia/psychosis and
treatment.
• MESOLIMBIC PATHWAY
o Projects from the midbrain ventral tegmental area to the nucleus accumbens in the ventral
striatum (VTA -> NA in the striatum), a part of the limbic system of the brain thought to be
involved in many behaviors such as pleasurable sensations, the powerful euphoria of drugs of
abuse, as well as delusions and hallucinations of psychosis. Predominant pathway regulating
positive symptoms of psychosis. Specifically, hyperactivity of this pathway is believed to account
for delusions and
Mesolimbic overactivity = positive symptoms of schizophrenia hallucinations.
Mesolimbic underactivity = anhedonia, apathy, anergia, negative symptoms of schizophrenia
o
Motivation,
pleasure, and reward
o
Dopamine hyperactivity is possibly caused by the downstream consequence of dysfunction in
prefrontal cortex and hippocampal glutamate activity
o MESOSTRIATAL (mesolimbic and nigrostriatal): VTA -> striatum and SN -> striatum
, Hyperdopaminergic of schizophrenia may be mesostriatal and not solely
mesolimbic
• MESOCORTICAL PATHWAY
o Projects from the midbrain ventral tegmental area but sends its axons to areas of the prefrontal
cortex (VTA -> PFC), where they may have a role in mediating cognitive symptoms (dorsolateral
prefrontal cortex, DLPFC) and affective symptoms (ventromedial prefrontal cortex, VMPFC) of
Mesocortical to DLPFC hypoactivity = negative and cognitive symptoms of schizophrenia
Mesocortical to VMPFC hypoactivity = negative and affective symptoms associated with schizophrenia
schizophrenia
• NIGROSTRIATAL PATHWAY
o Projects from the substantia nigra to the basal ganglia or striatum (SN -> striatum). It is part of the
extrapyramidal nervous system and plays a key role in regulating movements.
When dopamine is deficient, it can cause parkinsonism with tremor, rigidity,
and akinesia/bradykinesia. Chronic blockade of D2 receptors here can lead to tardive
dyskinesia
When dopamine is in excess, it can cause hyperkinetic movements such as
tics and dyskinesias.
In untreated schizophrenia, activation of this pathway is believed to be
“normal” o Dopamine Regulation of Motor Movements
Direct Pathway: Populated with D1 receptors (excitatory) – stimulates
movement – “GO” Pathway
• GABA neurons projecting from striatum to globus pallidus interna is activated ->
• GABA release inhibits activity of another GABA neuron projecting to thalamus ->
• Without GABA release in thalamus, glutamate is released into cortex Movement is STIMULATED
Indirect Pathway: Populated with D2 receptors (inhibitory) – blocks motor movement – “STOP” Pathway
• GABA neuron projecting from striatum to globus pallidus externa is activated ->
• GABA release inhibits activity of another GABA neuron projecting to subthalamic nucleus (STN) ->
• Without GABA release in STN, glutamate neuron is activated ->
• Glutamate released in globus pallidus interna -> Stimulates GABA neuron to release GABA in thalamus ->
GABA binds to glutamate neuron and inhibits glutamate release into cortex
• Movement is INHIBITED
o The nigrostriatal pathway has traditionally been uninvolved in schizophrenia pathophysiology (though impacted by
medications), but new understanding of the connections between the dorsal and ventral striatum suggests a role in
emotional regulation too
• Tuberoinfundibular Pathway
o Projects from the hypothalamus to the anterior pituitary and regulates prolactin secretion into the circulation.
Dopamine inhibits prolactin secretion. In untreated schizophrenia, activation of this pathway is believed to be “normal”
o When dopamine is blocked, prolactin levels rise – symptoms of hyperprolactinemia: Gynecomastia (breast
enlargement or breast development)
Galactorrhea (breast secretions)
Amenorrhea (loss of menstrual periods) Oligomenorrhea (irregular/disrupted menstrual periods)
Sexual dysfunction (hypogonadism, infertility)
, Osteoporosis
o Tuberoinfundibular is unaffected by the pathophysiology of schizophrenia, but is impacted by medications
• Thalamic Pathway
o Projects from multiple sites (periaqueductal gray matter, ventral mesencephalon, various hypothalamic nuclei, and the
lateral parabrachial nucleus). Its function is still under investigation, but it may be involved in sleep and arousal
mechanisms by gating information passing through the thalamus to the cortex and other brain areas. There is no
evidence at this point for abnormal functioning of this dopamine pathway in schizophrenia
3. Know the major neurotransmitters and their roles related to schizophrenia.
• Dopamine o
See above
• Glutamate
o Glutamate is the major excitatory NT in the CNS and sometimes considered to be the “master switch” of the brain o
Glutamate activity at NDMA receptors is hypofunctional d/t abnormalities in the formation of glutamatergic NMDA
synapses during neurodevelopment – “NMDA receptor hypofunction hypothesis of schizophrenia”
• Serotonin o
See above
4. Identify potential medical emergencies associated with antipsychotic medications and how to manage these emergencies.
• Serotonin Syndrome o Causative medications:
serotonergic agents
o Physical exam findings: HYPERreflexia, myoclonus, ocular clonus
o Laboratory findings: More commonly no lab findings
o Course of illness: Symptoms seen within 24 hours of starting/changing therapy & resolves within a few days of Tx
o Treatment: benzodiazepines, cyproheptadine
• Neuroleptic Malignant Syndrome o Causative
o Physical exam findings: Severe rigidity (lead pipe), HYPOreflexia
agents: Dopamine antagonists
o Laboratory findings:
Increased creatine kinase, leukocytosis, low serum iron
o Course of illness: slower onset (1 to 2 weeks after starting/changing therapy) & resolves within 9-14 days of Tx
o Treatment:
Supportive care – reduce fever (cooling blankets), corrective dehydration (IVF), correct electrolyte imbalances,
maintain cardiorespiratory stability, etc
Stop antipsychotic agent
IV benzo – lorazepam or diazepam
IV Dentrolene (skeletal muscle relaxant) reserved for extreme hyperthermia
Bromocriptine (dopamine agonist)
Amantadine (dopamine agonist with anticholinergic effects) Electroconvulsive therapy (ECT)?
5. Know the following medications, including their most common expected side effects, drug interactions, potentially
serious adverse events, FDA indications, and lab work that should be monitored prior to starting and while on the medication:
For all antipsychotics:
o Warning: Increased risk of death and cerebrovascular events in elderly patients with dementia-related psychosis o
Monitor: Weight, BMI, waist circumference, BP, fasting plasma glucose, fasting lipid profile
The pines (peens) [sedating (α1-adrenergic, H1, & M1 antagonism), weight gain (5HT2C & H1 antagonism)]
Note: Exam 1 will cover content from Weeks 4 and 5.
1. Identify the emerging neurobiological hypothesis of
schizophrenia. Dopamine Theory – D2 receptor hyper/hypo activity of
dopamine
o Hyperactive dopamine at D2 receptors in the mesolimbic pathway = psychosis
o Hypodopaminergic in the mesocortical pathway = negative/cognitive/affective symptoms
• Glutamate Theory
o N-Methyl-D-Aspertate (NMDA) receptor is hypofunctional on GABA interneurons in the prefrontal cortex
Causes for hypofunctionality:
• Neurodevelopment abnormalities – schizophrenia
• Neurodegenerative abnormalities – Alzheimer’s, other dementias
• NMDA receptor blocking – ketamine, PCP
Hypofunctional NMDA synapse on the 1st neuron does not excite GABA interneuron, thus no GABA to inhibit the
3rd neuron, therefore the 3rd neuron is excited and a whole bunch of glutamate comes out. The glutamate then
goes downstream to stimulate dopamine (positive symptoms)
o Hypofunctioning NMDA receptors may be linked to downstream:
Overactivity of dopamine in the mesolimbic pathway (VTA -> striatum/nucleus accumbens) (positive symptoms)
Underactivity of dopamine in the mesocortical pathway (VTA -> PFC) (negative/cognitive/affective symptoms)
Serotonin Theory - 5HT2A receptor
o 5HT2A receptor hyperfunction in the cortex
o Serotonin not only regulates its own release via presynaptic receptor actions, but also regulates all other major NTs
through postsynaptic receptor actions
o Serotonin hyperactivity/imbalance @ 5HT2A receptors on glutamate neurons in cerebral cortex is linked to psychosis o
5HT2A receptor actions (in addition to NMDA receptor actions) can hypothetically lead to hyperactivity dopamine
activity in downstream mesolimbic pathways
2. Identify the different dopamine pathways and what role each pathway plays in relation to schizophrenia/psychosis and
treatment.
• MESOLIMBIC PATHWAY
o Projects from the midbrain ventral tegmental area to the nucleus accumbens in the ventral
striatum (VTA -> NA in the striatum), a part of the limbic system of the brain thought to be
involved in many behaviors such as pleasurable sensations, the powerful euphoria of drugs of
abuse, as well as delusions and hallucinations of psychosis. Predominant pathway regulating
positive symptoms of psychosis. Specifically, hyperactivity of this pathway is believed to account
for delusions and
Mesolimbic overactivity = positive symptoms of schizophrenia hallucinations.
Mesolimbic underactivity = anhedonia, apathy, anergia, negative symptoms of schizophrenia
o
Motivation,
pleasure, and reward
o
Dopamine hyperactivity is possibly caused by the downstream consequence of dysfunction in
prefrontal cortex and hippocampal glutamate activity
o MESOSTRIATAL (mesolimbic and nigrostriatal): VTA -> striatum and SN -> striatum
, Hyperdopaminergic of schizophrenia may be mesostriatal and not solely
mesolimbic
• MESOCORTICAL PATHWAY
o Projects from the midbrain ventral tegmental area but sends its axons to areas of the prefrontal
cortex (VTA -> PFC), where they may have a role in mediating cognitive symptoms (dorsolateral
prefrontal cortex, DLPFC) and affective symptoms (ventromedial prefrontal cortex, VMPFC) of
Mesocortical to DLPFC hypoactivity = negative and cognitive symptoms of schizophrenia
Mesocortical to VMPFC hypoactivity = negative and affective symptoms associated with schizophrenia
schizophrenia
• NIGROSTRIATAL PATHWAY
o Projects from the substantia nigra to the basal ganglia or striatum (SN -> striatum). It is part of the
extrapyramidal nervous system and plays a key role in regulating movements.
When dopamine is deficient, it can cause parkinsonism with tremor, rigidity,
and akinesia/bradykinesia. Chronic blockade of D2 receptors here can lead to tardive
dyskinesia
When dopamine is in excess, it can cause hyperkinetic movements such as
tics and dyskinesias.
In untreated schizophrenia, activation of this pathway is believed to be
“normal” o Dopamine Regulation of Motor Movements
Direct Pathway: Populated with D1 receptors (excitatory) – stimulates
movement – “GO” Pathway
• GABA neurons projecting from striatum to globus pallidus interna is activated ->
• GABA release inhibits activity of another GABA neuron projecting to thalamus ->
• Without GABA release in thalamus, glutamate is released into cortex Movement is STIMULATED
Indirect Pathway: Populated with D2 receptors (inhibitory) – blocks motor movement – “STOP” Pathway
• GABA neuron projecting from striatum to globus pallidus externa is activated ->
• GABA release inhibits activity of another GABA neuron projecting to subthalamic nucleus (STN) ->
• Without GABA release in STN, glutamate neuron is activated ->
• Glutamate released in globus pallidus interna -> Stimulates GABA neuron to release GABA in thalamus ->
GABA binds to glutamate neuron and inhibits glutamate release into cortex
• Movement is INHIBITED
o The nigrostriatal pathway has traditionally been uninvolved in schizophrenia pathophysiology (though impacted by
medications), but new understanding of the connections between the dorsal and ventral striatum suggests a role in
emotional regulation too
• Tuberoinfundibular Pathway
o Projects from the hypothalamus to the anterior pituitary and regulates prolactin secretion into the circulation.
Dopamine inhibits prolactin secretion. In untreated schizophrenia, activation of this pathway is believed to be “normal”
o When dopamine is blocked, prolactin levels rise – symptoms of hyperprolactinemia: Gynecomastia (breast
enlargement or breast development)
Galactorrhea (breast secretions)
Amenorrhea (loss of menstrual periods) Oligomenorrhea (irregular/disrupted menstrual periods)
Sexual dysfunction (hypogonadism, infertility)
, Osteoporosis
o Tuberoinfundibular is unaffected by the pathophysiology of schizophrenia, but is impacted by medications
• Thalamic Pathway
o Projects from multiple sites (periaqueductal gray matter, ventral mesencephalon, various hypothalamic nuclei, and the
lateral parabrachial nucleus). Its function is still under investigation, but it may be involved in sleep and arousal
mechanisms by gating information passing through the thalamus to the cortex and other brain areas. There is no
evidence at this point for abnormal functioning of this dopamine pathway in schizophrenia
3. Know the major neurotransmitters and their roles related to schizophrenia.
• Dopamine o
See above
• Glutamate
o Glutamate is the major excitatory NT in the CNS and sometimes considered to be the “master switch” of the brain o
Glutamate activity at NDMA receptors is hypofunctional d/t abnormalities in the formation of glutamatergic NMDA
synapses during neurodevelopment – “NMDA receptor hypofunction hypothesis of schizophrenia”
• Serotonin o
See above
4. Identify potential medical emergencies associated with antipsychotic medications and how to manage these emergencies.
• Serotonin Syndrome o Causative medications:
serotonergic agents
o Physical exam findings: HYPERreflexia, myoclonus, ocular clonus
o Laboratory findings: More commonly no lab findings
o Course of illness: Symptoms seen within 24 hours of starting/changing therapy & resolves within a few days of Tx
o Treatment: benzodiazepines, cyproheptadine
• Neuroleptic Malignant Syndrome o Causative
o Physical exam findings: Severe rigidity (lead pipe), HYPOreflexia
agents: Dopamine antagonists
o Laboratory findings:
Increased creatine kinase, leukocytosis, low serum iron
o Course of illness: slower onset (1 to 2 weeks after starting/changing therapy) & resolves within 9-14 days of Tx
o Treatment:
Supportive care – reduce fever (cooling blankets), corrective dehydration (IVF), correct electrolyte imbalances,
maintain cardiorespiratory stability, etc
Stop antipsychotic agent
IV benzo – lorazepam or diazepam
IV Dentrolene (skeletal muscle relaxant) reserved for extreme hyperthermia
Bromocriptine (dopamine agonist)
Amantadine (dopamine agonist with anticholinergic effects) Electroconvulsive therapy (ECT)?
5. Know the following medications, including their most common expected side effects, drug interactions, potentially
serious adverse events, FDA indications, and lab work that should be monitored prior to starting and while on the medication:
For all antipsychotics:
o Warning: Increased risk of death and cerebrovascular events in elderly patients with dementia-related psychosis o
Monitor: Weight, BMI, waist circumference, BP, fasting plasma glucose, fasting lipid profile
The pines (peens) [sedating (α1-adrenergic, H1, & M1 antagonism), weight gain (5HT2C & H1 antagonism)]
