Final review Flashcards
*Broadly describe some of the neuropsychological consequences of chronic cannabis use (Q30)
- Tolerance: typically pharmacodynamic (involving a combo of desensitization and down-regulation of CB1 receptors), evidence that desensitization can be reversed
- Dependence: 10% of cannabis users become dependent
- Withdrawal: absence of withdrawal symptoms in studies may have been due to the long elimination half-life of THC; involves lower dopamine VTA firing and increased CRF and cortisol release
What % of cannabis users become dependent? (Q30)
10%
Describe cannabinoid tolerance (Q30)
- Typically pharmacodynamic; involves a combination of desensitization and down-regulation of CB1 receptors
- There is evidence that it can be reversed
What are some withdrawal symptoms of cannabinoid? (Q30)
- Irritability
- Increased anxiety
- Depressed mood
- Sleep disturbances
- Heightened aggressiveness
- Decreased appetite
In some studies, researchers reported a lack of cannabinoid withdrawal symptoms. Why? (Q30)
Might have been due to the long elimination half-life of THC
What does cannabis withdrawal involve? (Q30)
- Lower dopamine VTA firing
- Increased CRF and cortical release
*Identify five acute psychological effects associated with typical recreational doses of inhaled cannabis (Q27)
- Pain perception: reduced unpleasantness of pain, but intensity of pain remains the same
- Visual selective attention: increase in reaction times, decrease in accuracy, reduced binocular depth inversion
- Auditory effects: improved rhythm perception
- Memory: all aspects of memory impaired but especially working memory
- Euphoria: dependent on the THC content
Explain the role of cannabis in pain perception (Q27)
- Reduced unpleasantness of pain
- Intensity of pain remains the same
Explain the role of cannabis in visual selective attention (Q27)
- Increase in reaction times
- Decrease in accuracy
- Reduced binocular depth inversion
Explain the role of cannabis in audition (Q27)
- Improved rhythm perception
Explain the role of cannabis in memory (Q27)
- All aspects of memory impaired, but especially working memory
Explain the role of cannabis in euphoria (Q27)
- Dependent on the THC content
- May be related to pain perception effects
*Identify some of the behavioural and physiological atypicalities observed in both CB1 and CB2 knockout mice (Q29)
- CB1 knockout mice lack four characteristic THC-induced effects: reduced locomotion, hypothermia, catalepsy, hypoalgesia
- CB1 knockouts do not show extinction of fear conditioned responses to auditory cues
- CB2 knockout mice exhibit hyperalgesia
Describe CB1 knockout mice (Q29)
- CB1 knockout mice lack four characteristic THC-induced effects: reduced locomotion, hypothermia, catalepsy, hypoalgesia
- CB1 knockouts do not show extinction of fear conditioned responses to auditory cues
CB2 knockout mice exhibit what? (Q29)
Hyperalgesia
*Describe some of the unique features of endocannabinoid neurotransmission compared to other neurotransmitter systems (Q26)
- Too lipid soluble to be stored in vesicles because they would pass right through the vesicle membrane
- Instead of being stored in vesicles, they are made and released when needed
- Endocannabinoids are retrograde messengers at specific synapses in some brain regions (ie. hippocampus, cerebellum)
- After they are released, endocannabinoids are removed from the extracellular fluid by an uptake mechanism
- They can be metabolized by several different enzymes (ie. FAAH, MAGL)
What enzymes can metabolize endocannabinoids? (Q26)
- FAAH
- MAGL
Why can’t endocannabinoids be stored in vesicles? (Q26)
They are too lipid soluble and would pass right through the vesicle membrane
*Cannabis is becoming increasingly common in the treatment of some chronic pain disorders. Explain how the underlying neural circuitry for pain is modulated by the use of cannabis (Q28)
- CB1 receptor agonists directly decrease the firing rate of peripheral nociceptive neurons
- Spinal and thalamic neurons in the pain pathway are similarly affected by agonists
- Distinct central sites of anti-nociceptive action: PAG, RVM, A5 NE cells
What do CB1 receptor agonists do (pain + cannabis)? (Q28)
Directly decrease the firing rate of peripheral nociceptive neurons
What other neurons in the pain pathway are similarly affected by CB1 receptor agonists? (Q28)
Spinal and thalamic neurons
What are the distinct central sites of anti-nociceptive action? (Q28)
- PAG
- RVM
- A5 NE cells
*Provide an account of the mechanisms of action for the psychoactive effects of cocaine (Q1)
- Different routes of administration produce different effects due to the time course of distribution
- Crosses the BBB because it is lipophilic
- Quickly broken down by blood and liver enzymes
- Half-life is typically 0.5-1.5 hours
- High affinity for SERT > DAT > NAT
- Low affinity for voltage-gated Na+ channels
Why does cocaine cross the BBB? (Q1)
It is lipophilic
Cocaine is quickly broken down by what enzymes? (Q1)
Blood and liver enzymes
What is the half-life of cocaine? (Q1)
0.5-1.5 hours
Cocaine has a high affinity for what? (Q1)
SERT > DAT > NAT
Cocaine has a low affinity for what? (Q1)
Voltage-gated Na+ channels
*Provide an account of the mechanisms of action for the psychoactive effects of amphetamines (Q2)
- Half-lives range from 7-30 hours
- Metabolites mostly excreted in urine
- Amphetamines and methamphetamines are indirect agonists of the catecholaminergic systems
- At very high doses, amphetamines can act as MAO antagonists
- Reversal of DAT function is caused by phosphorylation through PKC
- Release of NE happens in both the brain and the sympathetic nervous system
What is the half-life range for amphetamines? (Q2)
7-30 hours
Amphetamine metabolites are mostly excreted how? (Q2)
In urine
Amphetamines and methamphetamines are indirect agonists of what systems? (Q2)
Catecholaminergic systems
At very high doses, amphetamines can act as what? (Q2)
MAO antagonists
Reversal of DAT function is caused by what? (Q2)
Phosphorylation through PKC
*Explain why amphetamines and other psychostimulants are used in the treatment of attention deficit disorders (Q3)
- Low doses of amphetamines produce calming effects in more than half of ADHD sufferers
- Abnormal prefrontal cortex activity is restored to near normal
- α2A and DA1 receptors are most implicated
- Enhancing catecholaminergic activity in the PFC has been suggested to be a crucial component in ADHD, and psychostimulants are capable of stimulating the release of and blocking the reuptake of catecholamines
Low doses of amphetamines can produce what kind of effects in almost half of ADHD sufferers? (Q3)
Calming effects
Amphetamines can restore what brain activity to near normal in those with ADHD? (Q3)
Abnormal prefrontal cortex activity
What receptors are most implicated in amphetamine treatment for ADHD? (Q3)
α2A and DA1
*Provide an account of the mechanisms of action for the psychoactive effects of nicotine (Q4)
- Typical cigarette contains between 6-11mg but only about one third of it reaches the bloodstream
- Enters the lungs on particles of hydrocarbon mixtures
- Smoking is the fastest and most efficient was of getting nicotine into the brain
- Half life is ~2 hours
- 70-80% metabolized to cotinine by CYP2A6 in the liver
- Mainly activates nAChRs in the CNS, PNS, muscle junction
- High dose can lead to biphasic response
What is the half life of nicotine? (Q4)
~2 hours
High doses of nicotine can lead to what? (Q4)
Biphasic response
Nicotine mainly activates what and where? (Q4)
nAChRs in the CNS, PNS, muscle junction
70-80% of nicotine is metabolized how? (Q4)
To cotinine by CYP2A6 in the liver
What is the fastest and most efficient way to get nicotine to the brain? (Q4)
Smoking
How does nicotine enter the lungs? (Q4)
On particles of hydrocarbon mixtures
A typical cigarette contains how much nicotine? (Q4)
6-11mg
How much of the nicotine in a cigarette enters the bloodstream? (Q4)
One third
*Provide an account of the mechanisms of action for the psychoactive effects of caffeine (Q5)
- Absorbed by the gastrointestinal tract within 30-60 minutes after consumption
- Absorption begins in the stomach but takes place mainly in the small intestine
- Plasma half-life is about 4 hours
- Converted in the liver to multiple metabolites
- Mostly excreted through urine
How is caffeine absorbed? (Q5)
- In the gastrointestinal tract within 30-60 minutes after consumption
- Starts in the stomach but mainly occurs in the small intestine
What is the plasma half life of caffeine? (Q5)
About 4 hours
How is caffeine metabolized? (Q5)
In the liver to multiple metabolites
How is caffeine excreted? (Q5)
95% excreted in urine
*Broadly outline (or list) the neurophysiological components of anxiety and match each CNS component with a behavioural or physiological correlate (Q6)
- Lateral hypothalamus: sympathetic activation
- Dorsal motor nucleus of Vagus: parasympathetic activation
- Parabrachial nucleus: increased respiration
- VTA, LC, PPN: activation of DA, NE, and ACh
- Nucleus reticularis: increased reflexes
- Periaqueductal grey: cessation of behaviour
- Trigeminal and facial nuclei: mouth open and jaw movements
- Paraventricular nucleus of hypothalamus: ACTH release
In anxiety, what is the physiological effect in the lateral hypothalamus? (Q6)
Sympathetic activation
In anxiety, what is the physiological effect in the dorsal motor nucleus of Vagus? (Q6)
Parasympathetic activation
In anxiety, what is the physiological effect in the parabrachial nucleus? (Q6)
Increased respiration
In anxiety, what is the physiological effect in the VTA, LC, PPN? (Q6)
Activation of DA, NE, and ACh
In anxiety, what is the physiological effect in the nucleus reticularis? (Q6)
Increased reflexes
In anxiety, what is the physiological effect in the periaqueductal grey? (Q6)
Cessation of behaviour
In anxiety, what is the physiological effect in the trigeminal and facial nuclei? (Q6)
Mouth open and jaw movements
In anxiety, what is the physiological effect in the paraventricular nucleus of hypothalamus? (Q6)
ACTH release
In anxiety, what is the biological component related to sympathetic activation? (Q6)
Lateral hypothalamus
In anxiety, what is the biological component related to parasympathetic activation? (Q6)
Dorsal motor nucleus of Vagus
In anxiety, what is the biological component related to increased respiration? (Q6)
Parabrachial nucleus
In anxiety, what is the biological component related to activation of DA, NE, ACh? (Q6)
VTA, LC, PPN
In anxiety, what is the biological component related to increased reflexes? (Q6)
Nucleus reticularis
In anxiety, what is the biological component related to cessation of behaviour? (Q6)
Periaqueductal grey
In anxiety, what is the biological component related to mouth open and jaw movements? (Q6)
Trigeminal and facial nuclei
In anxiety, what is the biological component related to ACTH release? (Q6)
Paraventricular nucleus of hypothalamus
*Several neurotransmitters are thought to contribute to the experience of anxiety. Identify the ones discussed in lecture and for each one provide a one sentence summary about its contribution (Q7)
- CRF: initiates HPA axis functions, modulates autonomic response, and involves widespread cognitive modulation
- Norepinephrine: involved in arousal and response to threats/novel situations, also improves memory formation for emotional events
- GABA: relevant to benzodiazepine because many GABAaRs have a binding site for it
- Serotonin: particularly complex (5HT) but anxiolytic effects are demonstrated through SSRIs
- Dopamine: involved in fear and avoidance behaviour
Summarize the role of CRF in anxiety (Q7)
Initiates HPA axis functions, modulates autonomic response, and involves widespread cognitive modulation
Summarize the role of norepinephrine in anxiety (Q7)
Involved in arousal and response to threats/novel situations, also improves memory formation for emotional events
Summarize the role of GABA in anxiety (Q7)
Relevant to benzodiazepine because many GABAaRs have a binding site for it
Summarize the role of serotonin in anxiety (Q7)
Particularly complex (5HT) but anxiolytic effects are demonstrated through SSRIs
Summarize the role of dopamine in anxiety (Q7)
Involved in fear and avoidance behaviour
*Provide an account of how benzodiazepines function to treat anxiety (Q8)
- Differences in effect duration are largely dependent on method of biotransformation and depot binding
- Long-acting benzodiazepines can have half-lives of 60+ hours and/or have multi-step metabolism with bioactive metabolites
- Short-acting benzodiazepines are metabolized in a single step
- Benzodiazepines can have sedative-hypnotic and memory impairing effects
- Clinically useful for relief of worry and physiological signs of anxiety with little to no tolerance for anxiolytic effects
- They are advantageous because they have a high therapeutic index, lethal overdose is rare, no liver enzyme increases, and lower dependence/abuse
Differences in the effect duration of benzodiazepines are largely dependent on what? (Q8)
Method of biotransformation and depot binding
What is the half-life for a long-acting benzodiazepine? (Q8)
60+ hours
Describe the metabolism of long-acting benzodiazepines (Q8)
Multi-step metabolism with bioactive metabolites
Describe the metabolism of short-acting benzodiazepines (Q8)
Metabolized in a single step
What kind of effects can benzodiazepines have? (Q8)
Sedative-hypnotic and memory impairing effects
Benzodiazepines are clinically useful for what? (Q8)
- Relief of worry
- Physiological signs of anxiety
What are the advantages of benzodiazepines in treating anxiety? (Q8)
- High therapeutic index
- Lethal overdose very rare
- No liver enzyme increases
- Lower dependence/abuse
*List five treatment options available for major depression and for each one provide a one sentence summary about how that option is supposed to work (Q10)
- MAOI: involves many side effects, but has an immediate effect on DA, NE, and 5HT synapses; antidepressant effects are the result of receptor regulation over time
- Tricyclic antidepressants: non-selective monoamine reuptake inhibitors, antidepressant effects are likely due to long term regulation, also block ACh, histamine, and α2 NE receptors
- Second generation antidepressants: not more effective than MAOIs or tricyclics but have less side effects, 5HT is complex and some side effects come from SSRIs
- IV ketamine: NMDA antagonist and dissociative anesthetic, increases plasticity, some antidepressant effects can be blocked by AMPA antagonists
- Galanin: widely distributed neuropeptide that is colocalized with 5HT and NE
MAOIs (Q10)
Involve many side effects, but have an immediate effect on DA, NE, and 5HT synapses
- Antidepressant effects are the result of receptor regulation over time
Tricyclic antidepressants (Q10)
Non-selective monoamine reuptake inhibitors
- Antidepressant effects are likely due to long term regulation
- Also block ACh, histamine, and α2 NE receptors
SSRIs (Q10)
- Not more effective than MAOIs or tricyclics but have less side effects
- 5HT is complex and some side effects come from SSRIs
IV Ketamine (Q10)
- NMDA antagonist and dissociative anesthetic
- Increases plasticity
- Some antidepressant effects can be blocked by AMPA antagonists
Galanin (Q10)
- Widely distributed neuropeptide that is colocalized with 5HT and NE
*There are five families of endogenous opioids (endorphins). For each, name either the family itself or the propeptide from which they are derived (Q12)
- Endorphins: derived from POMC
- Enkephalin: derived from proenkephalin
- Dynorphins: derived from prodynorphin
- Nociceptin/orphanin FQ: derived from pronociceptin/orphanin FQ
- endomorphin: unknown
Endorphins are derived from what? (Q12)
POMC
Enkephalin is derived from what? (Q12)
Proenkephalin
Dynorphins are derived from what? (Q12)
Prodynorphin
Nociceptin/orphanin FQ is derived from what? (Q12)
Pronociceptin/orphanin FQ
Endomorphins are derived from what? (Q12)
Unknown
*Explain the role of endorphins and other opioids in the neurocircuitry of pain (Q13)
- Two distinct components: early pain and late pain
- Early pain is sensory and highly informative
- Late pain is an emotional and autonomic response
- Early pain activates contralateral primary somatosensory and bilateral secondary somatosensory cortices
- Late pain activates bilateral secondary somatosensory and anterior cingulate cortices
- Three ways opioids inhibit pain: through descending inhibition of spinal projection neurons, inhibition of excitatory interneurons, and modulation of inhibitory and excitatory opioid interneurons
What are the three ways opioids inhibit pain? (Q13)
- Through descending inhibition of spinal projection neurons
- Through inhibition of excitatory interneurons
- Through modulation of inhibitory and excitatory opioid interneurons
Early pain activates what? (Q13)
Contralateral primary somatosensory and bilateral secondary somatosensory cortices
Late pain activates what? (Q13)
Bilateral secondary somatosensory and anterior cingulate cortices
*Explain the pharmacological basis and rationale for the methadone maintenance program in treating opioid addiction (Q15)
- It is the best way to wean addicts off of opioids
- Produces a relief from the craving
- It’s the substitution of a strong short-lasting opioid for a weak long-lasting opioid
- Reduces withdrawal symptoms at a comfortable level
*Describe some of the abnormalities of brain structure typically observed in individuals with schizophrenia (Q16)
- Reduction in grey matter volume
- Enlargement of lateral ventricles
- More disorganized hippocampal cells
- Connectivity failures resulting from shrunken dendritic “trees”
- Some cortical layers are atrophied
- Many changes seem to be symptoms rather than causes
*Briefly describe some of the evidence that implicates dopamine and glutamate dysregulation in the etiology of schizophrenia (Q17)
- Dopamine agonists can induce schizophrenia-like symptoms and amplify them in schizophrenics
- D2 antagonists are used as an effective treatment
- Low levels of glutamate may both increase mesolimbic and decrease mesocortical DA activity
*Describe what is meant by “broad-spectrum” antipsychotics and explain the rationale for their development in the treatment of schizophrenia (Q18)
- Molecules with complex receptor binding affinities
- Designed to target symptoms and side effects
- They block a wide range of receptors in addition to the D2 receptor
- Clozapine is an example of this
*Describe the characteristic biological dysfunctions and treatment options associated with Alzheimer’s disease (Q19)
- Preceded by mild cognitive impairment
- Amyloid plaques of three forms: surrounded by axons/dendrites, diffuse depot of amyloid, dense core of amyloid
- Neurofibrillary tangles: tau proteins that make up microtubules can become abnormally phosphorylated and cause these tangles
- Two categories of treatment: cholinesterase inhibitors and NMDA antagonists
What are the two categories of treatment for Alzheimer’s disease? (Q19)
- Cholinesterase inhibitors
- NMDA antagonists
*Describe the characteristic biological dysfunctions and treatment options associated with Parkinson’s disease (Q20)
- Mostly presents as a 4-6Hz resting tremor
- Most commonly observed as a loss of DA cells in the substantial nigra
- Later degeneration occurs in basal forebrain nucleus, amygdala, parahippocampal, etc.
- Treatment options include L-DOPA, MAOIs, DA agonists, Amantadine, Statin drugs
What are treatment options for Parkinson’s disease? (Q20)
- L-DOPA
- MAOIs
- DA agonists
- Amantadine
- Statin drugs
Parkinson’s disease normally presents as what? (Q20)
4-6Hz resting tremor
*Describe the neurochemical underpinnings of the effects of psychedelic drugs (Q21)
- All psychedelic drugs act as agonists for the 5HT2A receptor, which is necessary but not sufficient for the psychedelic experience
- The mGlu2 receptor must be coactivated with 5HT2A in order to generate the psychedelic response
- 5HT21 and mGlu2 form a functional heterodimer in the cortex
All psychedelic drugs act as agonists for what? (Q21)
5HT2A receptor
What other receptor must be coactivated with the 5HT2A receptor in order to generate a psychedelic response? (Q21)
mGlu2 receptor
*Outline some of the psychological effects that are typically reported to be occasioned by the use of psychedelic drugs (Q22)
- Not linked to mental health problems or suicide
- Many subjective effects involve altered and/or mystical states of consciousness
- Frequently associated with ecstatic states
- Can devolve into states of anxiety and despair
- Visual perception: binocular rivalry, reduced tracking performance, reduced object completion, colour enhancement
- Increase in wakefulness
- Time distortion
- Enhanced suggestibility
- Enhanced emotional responses
- Reduced psychological distress
*Provide an account of the mechanisms of action for the psychoactive effects of ketamine (Q25)
- Stimulates DA release especially in the mesocortical pathway
- Antagonistic at the NMDA receptor but has affinities at several other receptors
- Induces catecholamine release
- Neurotoxic at high doses
*Identify some of the changes in brain activity that have been described from imaging studies of subjects under the influence of psilocybin. Relate these changes to one of the psychological effects of the drug (Q23)
- MEG study: decrease in frequency in differential brain areas
- Decrease in phase synchronization (ACC, PCC, parahippocampal)
- Decreases in anterior and posterior cingulate cortices
- Anterior cingulate cortex related to cognitive hierarchical goal setting and planning
- Posterior cingulate cortex related to default mode network (network of activity involved when you are not doing a task, i.e. daydreaming)
- Decreases in the thalamus and medial prefrontal cortex
