Exam 3 Flashcards
What happens at the synapse when an agonist binds to an opioid receptor (i.e. which ion channel(s) are opened/closed and is the effect inhibitory or excitatory?)
- when an agonist binds to an opioid receptor G-Protein subunits break away, opening K+ ion channels and allowing flow of positively charged K+ ions out of the cell which is inhibitory
- Voltage sensitive Ca2+ channels close and don’t allow ions in the cell which are inhibitory; leaving the cell hyperpolarized
Provide two effects of opioids on the body?
- Nausea and vomiting
- Vasodilation
- Pinpoint pupils
What are two withdrawal symptoms from opioids?
- Cramps, vomiting, diarrhea
- twitching
Describe how activation of mu and kappa opioid receptors alter dopamine release in the “reward” system (i.e. the projection from the ventral tegmental area to the nucleus accumbens)
Mu (µ) – MOR on GABA interneurons in the VTA cause stimulation of dopamine release from the VTA to the nucleus accumbens (inhibition if GABA = excitatory).
Kappa (𝜅) – KOR are dysphoric as they decrease the dopamine transmission to the nucleus accumbens which is found to be more adverse than rewarding.
Name and provide the mechanism of action for one “maintenance” therapy and one “antagonist” therapy for heroin addiction
Maintenance Therapy = Methadone
* Is a partial Mu (µ) receptor agonist that blocks the effects of heroin and withdrawal by binding tightly without producing a strong effect
Antagonist Therapy = Naltrexone
* Is a pure Mu (µ) receptor agonist given to detoxed patients that binds to receptors, not allowing heroin to bind to them and completely blocks the effects of opioids.
List one positive symptom (1 point) and one negative symptom (1 point) of schizophrenia
A positive symptom is hallucinations, and a negative symptom is attention deficits.
How do typical and atypical antipsychotics differ with respect to receptor affinities (2 points) and effects on behavioral or mental performance (e.g. side effect profile) (2 points)?
Typical antipsychotics have a high affinity for dopamine D2 receptors and atypical antipsychotics have a high affinity to D3 and D4 and low affinity to D2 receptors.
Typical antipsychotics produce adverse extrapyramidal signs and symptoms (EPS) and atypical antipsychotic drugs are more effective in treating negative symptoms of schizophrenia and do not produce debilitating extrapyramidal signs and symptoms (EPS)
- Briefly describe procedure used in the neonatal ventral hippocampal lesion model of schizophrenia (2 points) and two brain changes (i.e., neurotransmission) that result later in development (2 points).
In the NVHL model consists of infusion of a high dose of MK-801, an NMDA receptor antagonist into the hippocampus during the first postnatal week.
Two Brain Changes Later in life that Result in Later Development:
* Dysregulated Dopaminergic Transmission
* Enhanced sensitivity to NMDA antagonists
Briefly describe the “diathesis-stress” model of schizophrenia (2 points).
The diathesis-stress model proposes genetic predisposition combined with prenatal or early neonatal insult produces schizophrenia.
- Briefly describe the mechanism of action for tricyclic antidepressants and MAOIs
Tricyclic Antidepressants – prevents the reuptake of a lot of monoamines but have anticholinergic effects, decreasing the effects of cholinergic receptors.
MAOIs – are monoamine agonists that blocks the enzyme that breaks down monoamines so that monoamines are built up in the synapse.
Describe the results of a study that demonstrates a depression-like behavioral change resulting from exposure to chronic stress
This study mimics the types of stressors that are common in everyday people. Tested on rats by tilting their cage, leaving their lights on, taking away water briefly and leaving cage soiled for an extra day inconsistently to ensure they did not have time to adapt or begin coping. In doing this their sucrose levels should come down when they are stressed. Showing that imipramine does work in bringing levels to normal when stressed and decreasing depression.
effect on that behavior of administering a tricyclic antidepressant alone (1 point) or co-administering a tricyclic antidepressant with a dopamine D1 receptor antagonist (1 point).
Administering tricyclic antidepressants alone leads to and increased monoamine levels in stressed animals indicating of their pharmacological action. Co-administering of a dopamine D1 receptor antagonist would likely lead to alterations in the balance of neurotransmitter systems in the brain that are involved in various cognitive and emotional processes, and their antagonism can affect dopamine neurotransmission.
- Describe the monoamine theory of depression
Theory states that mood is controlled by the level of monoamine activity in the brain. The monoamine fibers of the midbrain and brainstem project to limbic and cortical regions. Decreased levels of monoamines lead to decreased brain activity in which mood is controlled. If monoamines are boosted, then the depression alleviates because depression is decreased cortical functions due to lack of monoamines.
How does prolonged use of SSRI’s alter neural development
Prolonged use of SSRIs can alter neuroplasticity, altering the formation and strength of synaptic connections. It can also alter neural development during pregnancy causing an increased risk of major fetal malformation, cardiac defects, and pulmonary hypertension in newborns.
List one withdrawal symptom of SSRIs and one withdrawal symptom of tricyclic antidepressants
Withdrawal Symptoms:
* SSRIs = fatigue and anxiety
* Tricyclic Antidepressants = restlessness and anxiety
- Describe the phenomena of depolarization-induced suppression of inhibition as it pertains to cannabinoids (2 points).
Depolarization-induced suppression of inhibition represents an important mechanism by which cannabinoids regulate synaptic transmission and neuronal excitability in the brain. Low-frequency stimulation of GABAergic terminals synapsing onto pyramidal cells producing an eIPSC until depolarization is applied to the pyramidal cell and suppressing of presynaptic terminals by voltage -gated calcium channels. By modulating inhibitory neurotransmission, cannabinoids can influence a wide range of physiological and behavioral processes, including pain perception, mood regulation, and motor control.
). List two harmful effects of cannabis
Harmful Effects:
* Mental Disturbance (marijuana psychosis)
* Freak Outs (panic, hallucinations, perceptual distortions)
two withdrawal symptoms of cannabis
Withdrawal Symptoms:
* Anxiety and Irritability
* Decreased food intake
- Briefly describe three medically useful effects of cannabidiol or cannabis
Glaucoma – reduces pressure of fluid in the eyeball but also reduces blood pressure which can compromise blood flow to the optic nerve.
Antiemetic – useful in chemotherapy patients to stop nausea and vomiting.
Antiepileptic/Anticonvulsant – CBD works to reduce seizures without psychoactive side effects.
- Describe the pharmacodynamic mechanisms of action for LSD, MDMA, and ketamine
LSD – Primarily act on 5-HT2A serotonin receptors in the frontal cortex and limbic system to increase receptor activity and is a receptor partial agonist at post-synaptic receptors.
MDMA – Increased serotonin transmission by blocking the serotonin transporter (SERT) and increasing release from terminal buttons and increased dopamine transmission by blocking the dopamine transporter (DAT)
Ketamine – NMDA receptor agonists. NMDA blockade turns down the inhibitory system more than the activating system causing a net increase in dopamine release.
- Name and define three sensory or emotional phenomena that are produced by hallucinogens (1 point for each name, 1 point for each description).
Phantasticants – feelings of emotional significance; induce vivid perceptual experiences.
Psychedelics – Mind manifester that cause surreal sensory experiences.
Psychomimetics – Simulants of psychosis causing delusions and hallucinations.
what is an opiate?
a drug derived from opium
what is an opioid?
drugs with a mechanism of action and affects similar to opiates
what is a narcotic?
abbreviation of narcotic analgesic, causes narcosis (sleep or drowsiness)
what is the source of opiates and opioids?
opium poppy
what are the natural active ingredients in opioids and opiates?
- morphine (10%)
- codeine (0.5 %)
what is an example of a semi-synthetic opioid?
- diacetyl morphine (heroine diamorphine)
- modification of morphine
what are examples of synthetic opioids?
- meperidine or pethidine (demerol)
- methadone
- oxycodone (Percocet (if it is mixed with acetaminophen) oxycontin (high dose, slow release form))
-naltrexone, naloxone (competitive antagonists) - nalorphine (partial agonists)
- mixed (cyclazocine)
Why was heroin created?
attempt to make morphine safer
Absorption and route of administration of morphine
- base that ionizes to a large extent at intestinal pHs
- significant first pass metabolism
- oral administration OK for medicinal uses
Heroin absorption and route of administration
- intranasally
- higher lipid solubility facilitates absorption
- converted to morphine with peak concentration in around 1 hr
-vaporized
opium absorption and route of administration
- inhaled
nalorphine/naloxone absorption and route of administration
poorly absorbed and must be given parenterally (IV)
True or False, Heroin crosses the blood brain barrier faster than morphine?
True, it is > 10 times for lipid soluble, and is converted at the blood brain barrier back to morphine, and 6-MAM
Where is heroin distributed in the brain?
concentrated in the basal ganglia (including VTA), amygdala and periqueductal gray
Excretion of Agonists
- morphine (10% excreted unchanged, rest destroyed in liver, half life = 2 hrs)
- meperidine (demerol) most metabolizes. half life = 3.5 hrs
- methadone (10% excreted unchanged, half life = 10-25 hrs)
excretion of antagonists
- naloxone = half life of 1.5 hrs
- naltrexone = half life of 4 hours
how does lipid solubility relate to addiction?
- increased solubility means that the drug enters the brain faster
- we learn about things that happen closely in time more readily (greater incentive value to cues)
- entering into the brain faster means that the rush is faster and that the effective dose is higher in the brain
types of pain
- thermoceptive pain - pain caused by extreme heat or cold
- mechanical pain - pains due to physical damage to the muscles and skin
- visceral nociception - pain associated with organ damage (often experiences as referred pain)
what kind of main does mu agonists help?
- effective against a broad range of pain, acute types and some chronic
delta agonists are helpful against what kinds of pain?
effective against thermal and mechanical pain but are ineffective against visceral pain
kappa effective against what types of pain?
used against visceral pain but are affective only against low-intensity thermal and mechanical pain
what is pain?
complex phenomena which involves not only sensation but also emotional appraisal of stimuli
how does modification of pain receptors happen?
from changes in external stimulus but also from internal deamnds
what do opioid receptors do?
regulate pain perception and exert top-down control over bottom-up environmental inputs
allodynia
where neuronal alternations or injury make touch that is normally innocuous or pleasant feel unpleasantly painful, caused by decreased effectiveness of opioid receptors
opioid rotation
switching from one opioid to another when OIH (opioid induced hyperalgesia) develops
harmful effects of acute usage of opioids
- Overdose
- sudden loss of tolerance due to change of environment
- mixing with other depressant (benzodiazpines or alcohol) can be lethal
harmful effects of chronic opioid use
- CNS : widespread reductions in cerebral blood flow to frontal parietal and temporal lobes
- needle sharing increases exposure to HIV, AIDS
dopamine hypothesis of schizophrenia
- caused by an excess of dopamine in the brain
- mesolimbic dopamine system from the VTA to the nucleaus accumbent (reward/incentive system - increased activity related to positive symptoms)
- mesocortical dopamine system from the VTA to the prefrontal cortex (cognition - lack of activity related to negative symptoms)
- nigrostriatal dopamine system from the substantial nigra to the dorsal striatum (extrapyramidal motor system, blockade from the typical antipsychotics may product parkinsonian symptoms)
positive symptoms of schizophrenia
- hallucinations (false sensory experiences, seeing or hearing things that didn’t happen)
- delusions (false beliefs, often of persecution or grandeur)
negative symptoms of schizophrenia
- attentional deficits
-flat affect - other cognitive defects related to working memory and executive function
3 theories of schizophrenia from clinical observations
- dopamine theory
- glutamate theory
- serotonin theory
brain alterations from schizophrenia
- overactivity in mesolimbic structures: positive symptoms
- loss of function in prefrontal cortex : negative symptoms (ie. affective flattening)
- altered function of the anterior hippocampus (selective loss in some area)
Development of schizophrenia
- late onset compared to many disorders (typically late teens or early adulthood)
- higher prevalence in males
- more negative symptoms in older individuals
Glutamate Theory of Schizophrenia
- observation that drugs like phencyclidine PCP and ketamine antagonize NMDA receptors and produce effects that resemble both the positive and negative symptoms
- dopaminergic dysregulations according the the glutamatergic theory, results from glutamatergic dysfunction
- NMDA antagonism at does that produce positive symptoms actually increases activity in the prefrontal cortex
Nigrostriatal Effects
parkinsons disease is a result of depletion of DA in the nigrostriatal system
typical antipsychotics
have a high affinity for dopamine D2 receptors
atypical antipsychotics
have a high affinity for dopamine d3 and d4 receptors, low affinity for d2
typical vs atypicals
- atypical antipsychotic drugs are also more effective in treating the negative symptoms of schizophrenia
tardive dyskinesia
presentation of repetitive, involuntary, purposeless movements
how is a major depressive disorder diagnosed?
- five or more of the following symptoms must be present during a discrete period lasting at 2 weeks
- sadness, despair, hopelessness, emptiness, feeling down
- change in appetite, body weight
- sleep disturbance
psychomotor disturbance - tired
How does Excessive Activity in Stress Systems Produces
Depression-like Alterations in the Brain
- stress activates the HPA axis to release CRH, ACTH and cortisol
- the PFC, amygdala and hippocampus receive feedback on cortisol levels and regulate, inhibit, (PFC, hippocampus) or stimulate (amygdala) further activity of the HPA axis
types of antidepressants
first generation antidepressants
- monoamine oxidase inhibitors (MAOIs)
-tricylclic antidepressants
second generation antidepressants
- selective serotonin reuptake inhibitors (SSRIs)
Third generation antidepressants
- norepinephrine reuptake inhibitors and serotonin norepinephrine reuptake inhibitors (NARIs or SNRIs)
- dopamine reuptake inhibitors (e.g. bupropion)
what are the two types of MAO?
- A and B
-A is the enzyme for DA, NE and 5-HT
B is the enzyme for DA - old MAOIs blocked both MAO-A and B, newer drugs preferentially act on MAO-B
Monoamine Theory of Depression
- Mood is controlled by the level of monoamine activity in the brain (serotonin, norepinephrine, and dopamine)
- psychomotor stimulants like cocaine improve mood and drugs like reserpine that block monoamines cause depression
- monoamine fibres from midbrain or brainstem project to limbic and cortical regions
- norepinephrine fibres from the locus coeruleus
- serotonin fibres from the raphe
- dopamine fibres from the VTA
- depression is reflected in decreased cortical function due to lack of monoamine transmission
what do first generation antidepressants do?
MAOIs block monoamine oxidase
tricyclics block reuptake of monoamines
amitriptyline blocks serotonin and norepinephrine reuptake and also is an antagonist at 5-HT2A and 5-HT2c receptors
what do second generation antidepressants
- SSRIs selectively block reuptake of serotonin
What do third generation antidepressants do?
- Reboxetine selectively blocks NE reuptake
- Nefazadone is also a 5-HT2A antagonist and blocks serotonin and norepinephrine reuptake like amitriptyline but has been banned in some places due to live damage
- Bupropion blocks dopamine and norepinephrine reuptake and is a nicontinic receptor antagonist
Pharmacokinetics: Absorption and Distribution
all readily cross barriers (allows for oral administration)
- most reach max concentration in blood in 1-3 hrs, 4-8 hrs for SSRIs
- significant first pass metabolism which is inhibited by alcohol for most antidepressants
Pharamcokeinetics: Excretion
-MAOIs - half life = 2-4hrs, so must be taken several times a day. Older MAOIs have an irreversible effect on MAO and can be taken once a day
- TCAs half life = 24 hrs, daily dose required
- Most SSRIs have half life of 15-20 hrs with no active metabolites, but fluoxetine has a long half life (6 days) and long last metabolites
- considerable invidivual variability in excretion pharmacokinetics of antidepressants
Effects on the body of antidepressants
Tricyclics: Dry mouth, constipation, dizziness, regular heart beat, blurred vision
- excessive sweating, tremours
- confusion and delirium in older patients
- weight gain often reported
antidepressants affects on performance
- tricyclic antidepressants imipramine and amitriptyline can have detrimental effects on vigilance tasks and can cause cognitive memory, and psychomotor impairment that seems to be related to sedation
- no motor impairment with SSRIs
