Identify/ outline DA pathway, origins and areas it innervate
DA Pathways projects from VTA (brainstem) ----hypothalamus----PFC---BF----striatum---Nucleus accumbens---amygdala----hippocampus ( all brain regions except cerebellum)
Outline NE pathway
NE projects from (ascending and descending) locus coeruleus (brainstem)----C---thalamus---hypothalamus---amygdala---hippocampus---BF---PFC( Ascending), descending---down the Spinal cord (regulates pain)
outline 5HT pathway
(ascending) originates in brainstem----C---T---Hy----A-----H-----NA----S----BF----PFC (ALL regions of brain). (descending) down the spinal cord and may regulate pain
Outline Acetylcholine pathway
Originates in brainstem---T---Hy----A---H----BF---PFC, from BF----PFC----A----H
Outline Histamine pathway
from hypothalamus to all regions and down the spinal cord except the Cerebellum and nucleus accumbens
Outline the CSTC loops for executive functions
Outline the CSTC loop for Attention
Dorsal ACC---->bottom of striatum----->thalamus------.ACC
The DA transporter DAT and the vesicular transporter VMAT2 pg 267 (also DA 1, 2, 3, 4 receptors)
Outline the function of DA-2 presynaptic autoreceptors
Act as gatekeepers, either allowing DA release when they are not occupied by DA, or inhibiting DA release when DA builds up in the synapse and occupies the receptor
Describe the function of somatodendritic DA-2 receptors
Occupancy of these DA2 receptors provide negative feedback or a braking action on the relapse of DA from the neuron
Name the 5 DA pathways
Mesolimbic DA pathway
Mesocortical DA pathway
Nigrostriatal DA pathway
tuberoinfundibular DA pathway
Thalamic DA pathway pg 272
what is the origin and terminations of the Mesolimbic pathway and its relationship to the symptoms of schizophrenia
This pathway is thought to be involved with the positive symptoms of psychosis (delusions and hallucinations). It originates from the VTA to the nucleus accumbens.
Outline the mesocortical DA pathway, origins and termination sites, and its relationship to schizophrenia
From the VTA to the areas of the PFC (DLPFC), this system is thought to be involved with the cognitive, negative and affective symptoms of schizophrenia due to its hypoactivity
Describe the Nigrostriatal DA pathway and its relationship with schizophrenia
From the brainstem (substantia nigra) to the basal ganglia or striatum. This system control motor movements and it is thought to be relatively preserved in untreated patients. In treated pts this system can produce tardive dyskinesia (EPS)
Outline the tuberoinfundibular DA pathway and its relationship with schizophrenia
It projects from the hypothalamus to the anterior pituitary. This system in untreated pts may be preserved, but in treated pts it may raise the prolactin levels causing galactorrhea, amenorrhea, sexual dysfunction
Outline the Thalamic DA pathway and its relationship to schizophrenia
arises from multiple sites, no evidence of abnormal functioning as related to schizophrenia
Outline/describe all four parts of the manner in which glutamate is recycled and regenerated
1 After release of glutamate from the presynaptic neuron, it is taken up into glial cells via EAAT or excitatory amino acid transporter
2- Once inside the glial cell, glutamate is converted into glutamine by the enzyme glutamine synthetase
3- Glutamine is released from glial cells by a specific neutral amino acid transporter (glial SNAT), through the process of reverse transport, then taken up by
SNATs on glutamate neurons
4- Glutamine is converted into glutamate within the presynaptic glutamine neuron by the enzyme glutaminase and taken up into the synaptic vesicles by the
vesicular glutamate transporter (cGluT),where it is stored for future use.
How is d-serine produced and what is its importance
D-serine can be produced from glycine or from l-serine Glycine is converted to l-serine by the enzyme SHMT and l-serine is converted into d-serine by the enzyme d-serine racemase, this is done inside the glial cells. Glutamate requires the presence of glycine or d-serine at NMDA receptors to exert its effects
2- the vesicular transporter (vGluT), presynaptic as well
3- (postsynaptically) Metabotropic glutamate receptors(8 of them divided in 3 groups)
group 1 -mGluR1
group 2 -mGluR2
group 3 -mGluR4, 6, 7, 8
Ionotropic class : AMPA, Kainate, NMDA
Outline the circuitry in the receptor regulation of the Mesolimbic DA pathway and its relationship to pt symptoms
The mesolimbic DA pathway projects from the VTA to the nucleus accumbens. This pathway has an important role in the positive symptoms of psychosis, such as hallucinations and delusions. This system is also important for motivation, pleasure, and reward. Hyperactivity of this system may account for the positive symptoms.
Outline/describe the mesocortical DA pathway and its relationship to pts symptoms
The mesocortical DA pathway projects from the VTA area to the areas of the PFC (DLPFC). This system may regulate cognition and executive functions, emotions and affect symptoms of schizophrenia. Hypoactivity of this system is theorized to cause the cognitive, affective and negative symptoms of schizophrenia.
-block histamine block receptors ( causes weight gain and drowsiness)
-block alpha-1-adrenergic receptors (causes dizziness, decreased blood pressure and drowsiness)
What makes an antipsychotic atypical
"good for negative symptoms"
from pharmacological perspective 4 ways:
Serotonin dopamine antagonists (SDA)
D2 antagonist with rapid dissociation
D2 partial agonists (DPA)
Serotonin partial agonist (SPA) at 5HT1A receptors
Explain the DA hypothesis of the symptoms of untreated schizophrenia and the relationship to the various symptoms.
In untreated schizophrenic pts DA output is high in the mesolimbic pathway, causing posittive symptoms; low in the mesocortical pathway to the DLPFC causing cognitive and negative symptoms; low in the mesocortical pathway to the VMPFC causing affective and negative symptoms; it is normal in the tuberoinfundibular and nigrostriatal pathways
What are the anticholinergic effects of the antipsychotic drugs
When the conventional antipsychotic act on the D2 receptors they reduce the production of DA. DA normally suppresses acetylcholine activity but with D2 receptors blocking the DA production acetylcholine becomes overly active, this is associated with the production of extrapyramidal symptoms (EPS). Thus deficiency in DA =. a an excess of acetylcholine = EPS.. An antipsychotic with anticholinergic properties has a tendency to lower the EPS but these may cause dry mouth, blurred vision, constipation, etc and still cause tardive dyskinesia.
What are the antihistaminergic antagonist effects of the antipsychotic drugs?
Conventional antipsychotic with H1 receptor antagonism causes weight gain and drowsiness
What are the alpha NE-1-antagonist effect of the antipsychotic drugs?
Conventional antipsychotic with alpha-1 receptor antagonism causes dizziness, decreased blood pressure and drowsiness
Describe the relationship between DA and ACh in the striatum and why it gives rise to EPS?
DA and ACh have a reciprocal relationship. Conventional antipsychotic block D2 receptors which decrease the DA output. DA usually suppresses ACh activity but with a reduced DA output ACh activity, this increases the release of ACh which is associated with EPS.
what are the mechanism of termination of activity of the catecholamines?
DA is terminated by presynaptic transporter called DAT, within the neurons DA is terminated by MAO A or B or outside the cell by COMT
NE is terminated by two principal catabolic enzymes that turn NE into inactive metabolites. The first is monoamine oxydase (MAO) A or B, the second is catechol-O-methyl-transferase (COMT) Also by a reuptake pump called NE transporter (NET)
What are the mechanism of termination for 5HT
The action of 5HT is terminated by enzymes MAO and converted into inactive metabolite and by a presynaptic transport pump called the serotonin transporter (SERT)
These autoreceptors are located in the presynaptic axon terminal, when 5HT occupies these receptors causes a blockade of 5HT, drugs that block 5HT1B/D promote 5HT release.
Explain the functions of the 5HT1A receptor
These autoreceptors are located in the cell body and dendrites , when 5HT binds to these receptors t causes a reduction of 5HT therefore 5HT1A act as an accelerator for DA release
Outline/ explain the effects of the 5HT2A receptor effects on DA release
Many atypical antipsychotics are antagonists at the 5HT2A receptors. When 5HT binds to 5HT2A receptors on postsynaptic DA neurons this inhibits DA release. Similarly 5HT binding to 5HT2A receptors on GABA interneurons causes GABA release, which in turn inhibits DA release.
Whats the impact of 5HT2A antagonists
5HT2A antagonists stimulate DA release, these can explain the properties of atypical antipsychotics namely "low EPS" and "good for negative symptoms"
5HT2A antagonists reduce EPS in the striatum by disinhibiting the DA neuron which causes DA release . The result of this increase in DA is that DA now competes with drug at D2 receptors and reduces binding there enough to eliminate EPS
How is DA release inhibited or enhanced in the nigrostriatal and mesocortical pathways by 5HT receptors and their antagonists
5HT inhibits DA release via stimulation of 5HT2A receptors, when this action is blocked by 5HT2A antagonists this leads to an increase in DA release in the nigrostriatal pathways, which in turn cause DA to knock enough drugs off D2 receptors and the occupancy drops below the threshold needed to produce EPS. Same process in the mesocortical system where 5HT2A antagonists may increase DA release in the hypoactive mesocortical pathway which should improve affective, cognitive and negative symptoms.
How do 5HT2A and 5HT1A receptors impact pyramidal neurons that release glutamate?-
5HT2A and 5HT1A receptors have opposite actions on glutamate release in cortical pyramidal neurons. 5HT2A receptors act as glutamate accelerator, stimulating Glu release when 5HT binds to them. 5HT1A receptors act as brakes (inhibits) Glu release when 5HT binds to them . This is the opposite of DA release.
how do 5HT2A antagonist effects impact the positive and negative symptoms of schizophrenia , as well as Parkinson's side effect and the release of prolactin?
1 5HT2A antagonists knocks off enough drug in the striatal 5HT2A receptor to allow the release of DA which in turn competes with drugs at D2 receptors and
reduces binding there enough to eliminate EPS.
2 Atypical antipsychotic with their 5HT2A antagonists properties may increase DA release in hypoactive mesolimbic pleasure centers enough to reduce
negative symptoms but not as robust to increase the positive symptoms
3 5HT2A antagonists act in the tuberoinfundibular pathway by releasing DA which in turn inhibits prolactin. whereas 5HT promotes prolactin release by
stimulating 5HT2A receptors.
4 The positive symptoms of schizophrenia decrease when 5HT2A antagonists block the serotonergic excitation of cortical pyramidal cell, their Glu release is
reduced this lowers the hyperactive drive on the mesolimbic DA pathway downstream thus reducing hallucinations and positive symptoms.
List the SDA antipsychotics and the new ones just released on the market
Outline/Describe the "hit and run" theory of atypical antipsychotics
Atypical antipsychotics have the ability to rapidly disassociate from D2 receptors or "hit and run" binding. The antipsychotic binds to the D2 receptor "hit" long enough to exert an antipsychotic action but then leaves prior to producing an extrapyramidal side effect, elevation of prolactin or worsening of negative symptoms
Which antipsychotics are SDAs
SDAs = Serotonin-dopamine antagonists
They have dual properties of D2 antagonism and Serotonin 2A antagonism
Which antipsychotics are DPAs
Dopamine Partial agonists
Which antipsychotics are SPAs
Serotonin 1A Partial agonists
-Ziprasidone, quetiapine and clozapine
list the first step along the cardiometabolic highway, identify which mechanism of action are thought to mediate these activities and how they do that
Weight gain and increased appetite, receptors associated with weight gain are H1 histamine and 5HT2C serotonin receptors. When these receptors are blocked weight gain occurs by enhancing appetite in hypothalamic eating centers
List the second step in the cardiometabolic highway, identify mechanisms of actions and how they do that
Increased TG and insulin resistance, they may be present prior to significant weight gain or independent of it, mediated by unknown receptors
List the third step in the cardiometabolic highway, identify the mechanism of action and how they do that
Antipsychotic with M3 antagonism can reduce insulin by binding to pancreatic beta cells causing failure, which could lead to prediabetes, diabetes and diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS)
list the steps in the cardiometabolic highway
1- Increase appetite
2- Weight gain
3- increased TG
4- insulin resistance
7- beta cell failure
10- cardiovascular events
11- premature death
what can/ should a psychopharmacologist do when his client is on an atypical antipsychotic with respect to monitoring and what interventions should be made?
First monitor weight and body mass index and fasting TGs family history 1st step
Management if TG and weight increase consider switching antipsychotics 2nd step
Management --vigilance for DKA/HHS, consider avoiding or switching from high-risk antipsychotics.
what are the symptoms of depression
1- Depressed mood/apathy, loss of interest (one of these)
(four or more of next)
2- weight/ appetite gain
3- sleep disturbance
7- executive dysfunction
8- suicidal ideation
What are the symptoms of mania
1- Elevated/ expansive mood----irritability (one of these)
(4 of these)
2- inflated self esteem/grandiosity
3- agitation/ increased goal-directed activity
5- decreased need for sleep (insomnia, hypersomnia)
6- distractible/ concentration
7- more talkative/ pressured speech
8- flight of ideas/ racing thoughts
Outline the symptoms of depression and identify each of the hypothetical under active pathways involved in these symptoms
1- Depressed mood--linked to inefficient information processing in the amygdala and VMPFC, all 3 NTs innervates these areas and may be under active
2- Apathy/ loss of interest---they may involve the VMPFC , DLPFC as well as the nucleus accumbens, and a deficiency of DA and NE may regulate these areas
3- - Sleep disturbances-- may be localized to hypothalamus, thalamus, basal forebrain, and throughout the PFC with NE, DA and 5HT deficiencies
4- Fatigue is linked to the PFC as well as the striatum and a deficiency of NE and DA for mental and physical fatigue.
5- Executive dysfunction ---linked to DLPFC and being regulated mostly by DA and NE
6- Psychomotor---linked to striatum, cerebellum and PFC, and its regulated by DA, NE and 5HT
7- changes in weight and appetite---linked to hypothalamus and 5HT deficiencies
8- suicidal ideation/ guilt ---linked to VMPFC and its connections to 5HT.
Outline the symptoms of mania and identify each of the hypothetical underactive pathways involved in the mediation of these symptoms
1- Elevated/expansive mood / irritable----hyperactivity of amygdala, VMPFC OFC,-------- all 3 pathways , DA, NE, and 5HT
2- inflated self-esteem/grandiosity/risk taking/more talkative/ flight of ideas/ racing thoughts---linked to nucleus accumbens OFC, DLPFC, VMPFC ---all 3 DA, NE, and 5HT pathways but the nucleus accumbens ---- DA and 5HT only
3- Decreased need for sleep--linked to inefficient hypothalamus, thalamus, BF, -------all 3, DA, NE and 5HT
4- distractible/ concentration ---linked to DLPFC----NE and DA
5-- increased goal activity/ agitation----linked to striatum-----DA and 5HT