Lecture 16: Drugs and Synapses Flashcards
What are the 3 main ways of classifying psychoactive drugs?
- pharmacology
- physiology
- sociology
What are psychoactive drugs?
drugs that act on the brain – almost exclusively, at chemical synapses
Psychoactive Drugs Classified by Target
What are the 3 targets?
psychoactive drugs can be classified by their targets (in neurotransmitter signalling cycle) and the actions they exert upon them
- transporters (or any process where a first messenger is recycled by nearby cells)
- enzymes (targeting transmitter synthesis or transmitter breakdown)
- receptors (for neurotransmitters or other signalling molecules – ie. hormones)
Psychoactive Drugs Classified by Target
What kind of transporters (or any process where a first messenger is recycled by nearby cells) can be targets? (2)
- inhibitors (antagonists)
- reversers
Psychoactive Drugs Classified by Target
What kind of enzymes (targeting transmitter synthesis or transmitter breakdown) can be targets? (2)
- inhibitors
- precursor supplements
Psychoactive Drugs Classified by Target
What kind of receptors (for neurotransmitters or other signalling molecules – ie. hormones) can be targets? (3)
- agonists
- antagonists
- inverse agonists
What are inverse agonists?
antagonist drug that acts on a metabotropic receptor to reduce the activity of its signalling transduction cascade to a level BELOW basal (resting) activity of that pathway in an unstimulated cell
What must psychoactive drugs do?
get into CNS, bind target molecules, and resist degradation
Within a particular class (types of drug action), how can we classify various properties of a specific individual drug?
What are the properties?
by how it affects the nervous system (pharmacodynamics vs. pharmacokinetics)
- solubility
- selectivity
- affinity
- longevity (half-life)
What is pharmacodynamics?
how a drug affects the body
What us pharmacokinetics?
how the body affects a drug
What is solubility?
Does it affect pharmacokinetics or pharmacodynamics?
ability to enter the bloodstream, and ability to cross the BBB
pharmacokinetics (how the body affects a drug): affects ‘bioavailability,’ mode of effective administration, and whether CNS effects will occur
What is selectivity?
Does it affect pharmacokinetics or pharmacodynamics?
ability of the drug to also bind and affect other proteins
pharmacodynamics (how a drug affects the body): affects the number of ‘off-target’ side effects that could be experienced
What is affinity?
Does it affect pharmacokinetics or pharmacodynamics?
ability of the drug to bind its target site and activate/inactivate receptors
pharmacodynamics (how a drug affects the body): affects the concentration of a drug needed to see an effect
What is longevity (half-life)?
Does it affect pharmacokinetics or pharmacodynamics?
ability to resist degradation by enzymes, or excretion by liver and kidneys
pharmacokinetics (how the body affects a drug): affects ‘bioavailability,’ and how long the effects of the drug will persist for
What can affinity be measured in terms of? (2)
- one drug acting on different receptors
- different ligands acting on one receptor (more common)
What is affinity reported in terms of?
Kd – the concentration of the drug which will bind half the available receptors
What factors cause drug-receptor interactions to be complex and diverse, and act on multiple systems?
- lack of selectivity
- ubiquity (nervous system)
- ubiquity (non-nervous)
Why might a drug be multi-functional due to lack of selectivity?
it shows promiscuity – can bind to and activate/inactivate more than one type of receptor/transporter/enzyme
Why might a drug be multi-functional due to ubiquity (nervous system)?
the same receptor/transporter enzyme is present on different neurons in distinct brain circuits with distinct functions
Why might a drug be multi-functional due to ubiquity (non-nervous)?
it also targets receptors that lie outside the nervous system (ie. drugs targeting adrenergic receptors – L17)
What are amphetamines?
good examples of drugs that bind to multiple targets (lack of selectivity)
- can interact with multiple different proteins in aminergic neurons – including transporters, degrading enzymes, and vesicular transporters
- BUT they have different relative affinity (binding strength), and therefore different potency with different targets
Which biogenic amine’s (NE, DA, 5-HT) levels will be most affected by amphetamine?
NE – amphetamine will work most effectively at low concentrations of norepinephrine
(a decent amount of amphetamine will have a noticeable effect on dopamine (DA) too)
What are some psychoactive drugs that cause relaxation?
What is the mechanism?
drugs: alcohol, downers (ie. barbiturates), ketamine, Xanax/Ambien
mechanism: enhance GABA signalling
What are some psychoactive drugs that cause reward?
What is the mechanism?
drugs: cocaine, amphetamines, opiates/opioids
mechanism: enhance dopamine and/or norepinephrine signalling
What are some psychoactive drugs that cause euphoria/mood elevation?
What is the mechanism?
drugs: MDMA (ecstasy/molly), amphetamine, SSRIs, SNRIs
mechanism: enhance serotonin and or NE signalling
What are some psychoactive drugs that cause pain relief?
What is the mechanism?
drugs: opiates/opioids, cannabis, gabapentin
mechanism: variable mechanisms
What are some psychoactive drugs that cause concentration/alertness?
What is the mechanism?
drugs: caffeine, tobacco/nicotine, uppers (ie. amphetamines, ritalin/adderall)
mechanism: enhance cholinergic or biogenic amine signalling
What are some psychoactive drugs that cause unusual perceptual experiences?
What is the mechanism?
drugs: LSD, MDMA, cannabis, psilocybin, mezcal, ketamine
mechanism: variable mechanisms (though a number are 5-HT subtype selective agonists)
What do many recreational drugs (drugs of abuse) target?
CNS neuromodulator neurotransmitter systems
What are the similarities in the way aminergic systems (biogenic amines) are organized?
- project widely throughout the brain
- signal principally through metabotropic receptors
- often have modulatory effects
- each system has a different pattern of targets and receptor subtypes
- there is crosstalk between these networks
*within your brain there are also systems of (cholinergic) ACh-releasing neurons based in the brainstem and basal forebrain that are organized in very similar ways – their synapses are the targets of nicotine
What are the three different organizing questions to discuss psychoactive drugs?
How real is the line between medical and recreational psychoactive drugs?
Where and why do we draw distinctions between tolerance, dependence and addiction?
How and when do overdoses occur?
Medical vs. Recreational Drug Use Case Study: Dopaminergic Signalling in Disease
–
What is Parkinson’s disease?
progressive neurological disease characterized by movement-related symptoms (rigidity, tremors), depression, and subtle cognitive deficits
What is Parkinson’s disease caused by? What is the primary treatment?
loss of DA neurons from substantia nigra (in midbrain)
primary treatment is L-DOPA, which increases amount of DA available to be released
What are the side effects of Parkinson’s disease?
more than 50% of people who take L-DOPA experience episodes of drug-induced psychosis
What is schizophrenia?
neurodevelopmental disorder characterized by hallucinations, withdrawal, catatonia, cognitive disruptions, and distortions
What is schizophrenia caused by? What is the treatment?
unclear (probably multiple causes)
however, some symptoms can be treated by antagonists to D2Rs (ie. haloperidol, chlorpromazine)
What are the side effects of schizophrenia?
up to 40% of people taking chlorpromazine develop Parkinsonian-like motor symptoms
How does the amount of dopamine signalling in the brain affect things?
there are negative consequences to either too little OR too much DA signalling in the brain
Medical vs. Recreational Drug Use Case Study: Dopaminergic Signalling in Stimulants
–
Drug-Use and Physiological Processes Over the Long-term – Case Study: Caffeine Addiction
What are the effects of a moderate dose of caffeine in naive subjects?
increases in alertness, cognitive performance, blood pressure, power output in exercise tests, and urine production (diuresis)
Drug-Use and Physiological Processes Over the Long-term – Case Study: Caffeine Addiction
What are the effects of a daily moderate dose (equivalent to 1-2 cups of coffee)?
regular effects of a moderate dose of caffeine diminish or disappear within 1-2 weeks of regular consumption
Drug-Use and Physiological Processes Over the Long-term – Case Study: Caffeine Addiction
When can symptoms of caffeine withdrawal occur? How can these symptoms be ‘cured’?
symptoms of caffeine withdrawal after going >12 hours between caffeine doses (especially the caffeine headache) can occur after only a few days of regular consumption
these symptoms are ‘cured’ (within 30 min) by a dose of caffeine
Do drugs always have the same effect?
no – using almost any drug once, or once in every few months, often has different effects than using it regularly every day
What can long-term effects of psychoactive drugs be, in a rough way, divided between?
dependence and addiction
What is dependence?
physiological/(physical) adaptation to sustained or repeated drug use, which is usually homeostatic in nature, and encompasses tolerance, compensation and physical withdrawal effects if drug use is interrupted
- tolernace
- compensation
- withdrawal
What is tolerance?
ability to take larger doses of a drug without increasing the physiological effect of that drug
What is compensation?
homeostatic adaptation of cells/circuits that induces reliance on continued intake to maintain normal levels of functioning
What is withdrawal?
physiological effects due to compensation-related changes that are observed if drug use is interrupted
What is addiction?
psychological/behavioural changes that can accompany sustained drug use, where the drive to keep taking the drug negatively impacts the rest of the individual’s life
thought to involve learned behaviours driven by synaptic plasticity (L13-15) in brain circuits underlying motivated behaviour
What are some potential mechanisms to explain homeostatic effects on endogenous ligand-receptor signalling due to prolonged drug use?
effects on ligand concentration
- alteration of the amount of endogenous ligand released under normal physiological conditions
- alteration in the rate of breakdown of the drug or the endogenous ligand the body (this is known as pharmacokinetic tolerance)
effects on the receptor
- alteration of the numbers of receptors present at the synapse
- alteration in the receptor subtype or other properties that change the receptor’s affinity for the endogenous ligand or exogenous drug
Potential Mechanism to Explain Homeostatic Effects on Endogenous Ligand-receptor Signalling
In general, how does a higher concentration of ligand affect the response?
lead to larger response until saturation is reached (all available receptors are already bound to and activated by ligand)
What is saturation?
all available receptors are already bound to and activated by ligand
Potential Mechanism to Explain Homeostatic Effects on Endogenous Ligand-receptor Signalling
What effect does more receptors have on the response?
more receptors will mean more potential for ligand-binding, and therefore larger responses, at all ligand concentrations
activity level at the point of response saturation will also be larger
Potential Mechanism to Explain Homeostatic Effects on Endogenous Ligand-receptor Signalling
What effect does higher-affinity receptors have on the response?
higher-affinity receptors will be more likely to bind ligand, so you will have a larger response at low concentrations
if there are the same number of receptors overall, the amount of activity for the saturated (maximal) response will be the same
What does caffeine act as?
antagonist at purinergic receptors, which use adenosine as their main endogenous ligand
Is caffeine selective or non-selective?
non-selective – has nearly equivalent binding to A1 and A2A classes of metabotropic adenosine receptors, and will also bind to other subtypes (see tables in L12)
Why is metabotropic signalling complicated?
A2A receptors act via Gs signalling cascades (ie. stimulates neuronal activity), BUT activation of these receptors actually has the effect of decreasing dopaminergic and excitatory neuron activity in the CNS, and therefore decreasing alertness
this is thought to be because A2A receptors are present at higher levels on inhibitory neurons than on excitatory neurons
How does caffeine affect A1 and A2 binding sites in the brain?
chronic (long-term) consumption of caffeine causes up-regulation of A1 and A2 binding sites
however there is no significant difference in the amount of mRNA for A2 receptors (or A1 – not shown here) present in brain tissue
- remember: mRNA isn’t the same thing as functioning proteins
What is an overdose death?
toxic amount of the drug directly causes the physiological functions of the body (ie. breathing, cardiac function) to be overwhelmed and cease
BUT taking LSD, deciding that you can fly, and then stepping off a tall building is drug-induced death but not an overdose
Consumption of what drugs can cause overdose death?
can occur from consumption of many (though not all) psychoactive drugs
BUT it is generally considered impossible to die from a cannabis overdose
What is an opioid?
any drug that acts as an agonist for opioid receptors, but is often used to refer specifically to drugs that are synthesized by chemists
What is an opiate?
molecules (such as morphine) that are opioid receptor agonists which are directly sourced and purified from nature (ie. plant compounds)
What type of receptors are opioid receptors?
metabotropic neurotransmitter receptors
What are the endogenous ligands for opioid receptors?
small peptide neurotransmitters that come from three different gene families
Are opioid receptors presynaptic or postsynaptic?
are often presynaptic receptors (from axo-axonic synapses)
What acts on opioid receptors?
opioids and endorphins
Are all opioid receptors GPCRs?
all are GPCRs, but they have different distributions, and different affinities for ligands
What subtype of GPCRs are all opioid receptors?
all are Gi/o type GPCRs – therefore endogenous ligands and agonists tend to inhibit neural activity by a variety of mechanisms
What are the three subtypes of opioid receptors?
µ, δ, κ
What do µ-type receptors mostly mediate?
most of the effects of opioid drugs that promote euphoria (and addiction)
Do opioids vary in their binding affinity for the different subtypes of opioid receptors?
yes
Which type of opioid receptor is responsible for the clinical and recreational effects of opioids?
MORs (aka µ-opioid receptors)
What is morphine?
opiate that can be purified from certain varieties of poppies
What is oxycodone?
synthetic opioid, and the active ingredient in OxyContin
What is fentanyl?
synthetic opioid
Which drug (morphine, oxycodone, fentanyl) is likely to be the most potent if injected?
morphine is very effective if injected by IV
in pill form, swallowing is not effective because it does not make it across the gut very well
Which drug (morphine, oxycodone, fentanyl) is likely to be the most potent in a pill?
oxycodone is almost twice as potent as morphine,
oxycodone has higher bioavailability if swallowed in pill form – good at getting into the bloodstream
- in pill form, despite the fact that it is 10x less good at binding to receptors, it has much more bioavailability that it has a lower dose needed to reach analgesia or euphoria
What factors contribute to the potency of a drug at a receptor?
binding affinity AND pharmacokinetics
What are opioid overdoses most often due to?
drug-induced respiratory depression
What are some symptoms of a drug-induced overdose?
varies depending on the drug
overdose symptoms are often side effects (physiological effects that are unrelated to the desired medical or recreational effects of the psychoactive drug)
When opioid drugs cause overdoses, which drugs are potentially deadly and why?
drugs that are consumed for pain relief and the induction of euphoria are potentially deadly due to the fact that they ALSO cause profound depression of respiratory drive
What do opioids affect?
brainstem’s patterned motor output to breathing muscles
Where are opioid receptors found? What does this mean in terms of function?
in neurons in distinct neural circuits in multiple different locations within the CNS
therefore although the receptors all use the same signalling pathway, they participate in very different functions
What do opioid receptors in spinal cord and periaqueductal grey (part of midbrain act on? What does this cause?
act on GABAergic terminals to inhibit GABA release (reducing inhibition)
causes analgesia (reduced pain signals)
What do opioid receptors in VTA (dopaminergic reward center) act on? What does this cause?
act on GABAergic terminals to inhibit GABA release (reducing inhibition)
causes enhanced DA signalling, promoting ‘reward’ and habit formation
What do opioid receptors in the pons (upper hindbrain where there are breathing-related circuits) trigger?
reduce excitation (by acting on excitatory terminals)
triggers respiratory depression (reduced breathing)
What people are more likely to have an opioid overdose?
users with high tolerance for opioid effects
because of the potency of the respiratory depression they induce, opioids/opiates can be fatal to anyone when administered in sufficiently high doses
- however, in the population of people with substance use disorders, opioid overdoses are actually much more likely to occur in experienced than naive users
Why might overdose deaths be more common in experienced users?
some researchers hypothesized that tolerance processes occur at different rates in different brain circuits
as opioids are used repeatedly, the gap between a dose that creates a high and a lethal dose gets smaller and smaller
Is opioid tolerance building up more rapidly in VTA or in the pons?
in VTA – part of brain that controls release of dopamine (feeling of euphoria)
- if that’s adapting really quickly (building up tolerance), whether or not the dose kills you is controlled by the pons that is not adapting (not building up tolerance)
- the more times you take the drug, the more tolerance you build up in VTA – it is not building up as quickly in the pons
- gap between the dose that produces euphoria, and the dose that stops your breathing gets smaller and smaller – eventually will get to the point where there is no gap and you will go over and have an overdose
How can psychoactive drugs be classified?
by their pharmacology (mechanism of action) or by their effects (neuron/circuits targets in physiology and anatomy)
in both classification systems, drugs are diverse (having different routes of actions) and complex (ie. affecting multiple pathways and systems)
What systems do many drugs target?
aminergic neurotransmitter systems, particularly dopaminergic, adrenergic and serotonergic pathways
drugs that do not directly interact with these ligand-receptor systems may still exert indirect influence on the same neurons (ie. opioid actions on GABAergic neurons disinhibit dopamine neurons)
What does repeated use of drugs often induce?
homeostatic or compensatory alterations in neurons and synapses that oppose the effect of the drug
these changes underlie the physiological effects for the drug taker known as tolerance and, if drug taking ceases, withdrawal
What is the potential for fatal overdose is dependent on?
dependent on, and specific to, the particular class of drug being taken, and often is due to drug ‘side effects’
