lecture 21: depressants Flashcards
what is MDMA
= a serotonin releasing agent
does MDMA cause physical dependence
–> there is limited evidence that MDMA causes physical dependence
- MDMA has been found to down regulate serotonin receptors and decrease memory in long term users
- heavy use can cause a down regulation of the serotonin transporter (SERT)
What is the connection between dependence and down regulation
- chronic drug use –> overstimulation of certain receptors
- the brain tries to maintain balance (homeostasis)
- it down-regulates those receptors (reduces their number or sensitivity)
- as a result, the brain adapts to function with the drug present
- now, if the drug is suddenly stopped, the system is out of balance –> withdrawal symptoms
- this physiological adaptation = physical dependence
do serotonin agonists exhibit tolerance
–> serotonin agonists exhibit rapid tolerance
- serotonin receptors are rapidly desensitised/down-regulated
what serotonin agonist exhibits a very low risk of dependence
psychedelics (psilocybin, LSD, DMT, mecaline) exhibit a very low risk of dependence
–> some long term studies found improved cognition in monthly ayahuasca users
down regulation def
a cell decreases the number or sensitivity of receptors in response to prolonged stimulation
MDMA dependence
–> heavy use of MDMA is associated with short term down regulation of SERT
- higher lifetime episodes of MDMA use was not associated with greater SERT down regulation
–> abstinence from MDMA use was correlated with increasing SERT levels approaching baseline
conclusion =repeated use of ecstasy produces short to medium term neurocognitive/neurophysiological changes that are subtle, and are potentially reversible over time
what are hallucinogens
hallucinogens are agonists for the 5-HT2A receptor
–> Gq-coupled GPCR
tolerance within hallucinogens/psychedelics
–> tolerance rapidly develops (can’t use them everyday and get the same effects)
- 5-HT2A receptors down regulate
- lowers desire/ability to redose
physical dependence in hallucinogens/psychedelics
–> physical dependence is uncommon with psychedelic drugs
(one case study of a person presenting with physical dependence to LSD)
- subjective effects do not encourage immediate redosing
- limited effects on dopaminergic neurons in the VTA
- psychological dependence can still occur
- as psychedelic use increases, cases of dependence may also increase
what were the outcomes of testing tolerance of serotonin receptors
- tolerance to psychedelic effects of LSD observed after 4 days of administration
–> 52% decrease in strength of psychedelic effects on the second day of administration
–>after a week of administration, 4x the dose did not produce initial effects
why does tolerance occur but not physical dependence from psychedelic effects
- tolerance appears to be driven by internalisation of receptors into the cell
–> more agonist required to reach the same level of intracellular signalling molecules - serotonin receptors do not cause a phasic release of dopamine into the nucleus accumbens
–> low risk of physical dependence
–> no down regulation of dopamine receptors
depressants overview
- include alcohol and benzodiazepines
- decrease general neural activity (hyperpolarise neurons)
- depressants can still stimulate certain regions of the brain (disinhibition)
–> high doses cause general inhibition (anaesthesia)
–> very high doses cause coma and death
what was the general consensus on the positive health effects of alcohol
- low alcohol consumption may have positive benefits on stress reduction and cardiovascular health
- if you have familial risk of heart disease, but not cancer, alcohol may improve longevity
- public health authorities current recommendation is there is no safe level of alcohol consumption
what is the mechanism of action of alcohol
–> very complicated
–> alcohol acts on both specific and nonspecific sites
–> alcohol is a positive allosteric modulator for GABAA receptors
common dosage of alcohol
- the dose of alcohol reached in the body is 100 times greater than most pharmaceutical drugs
- potency and affinity of alcohol aren’t very high, because we have so much of it in the body, it can do many things without having high affinity
what is the alcohol mechanism of euphoria
–> alcohol increases the firing rate of neurons in the VTA
= results in higher levels of dopamine in the nucleus accumbens
what does alcohol dependence result in
= decrease of dopamine and dopamine metabolites in the mesolimbic pathway
mesolimbic pathway
a major dopamine pathway in the brain, primarily responsible for reward and motivation
how does alcohol relate to opiods
–> alcohol increases the release of opioids in the brain
- opioid antagonists (naloxone) reduce alcohol self-administration in animals
clinical trials of opioid antagonists in patients with alcohol use disorder found reduced :
- alcohol consumption
- relapse
- craving
- decrease in the subjective “high”
alcohol and benzodiazepine tolerance
–> mechanism of alcohol and benzodiazepine tolerance has not been fully determined
- most studies do not see a change in GABA subunit expression (one way we can get tolerance = nucleus of the cell can stop producing as many proteins = less gene expression)
- some studies see increased GABA receptor internalization
–> increased dephosphorylation of amino acids in the gamma subunit can trigger internalisation
impacts of tolerance of GABAA receptors
- fewer GABAA receptors will decrease influx of chloride ions into neurons
- less hyperpolarisation of neurons
- increased excitatory activity
- withdrawal effects after benzodiazepine and alcohol physical dependence include seizures
mechanisms of opioid action
–> opioids reduce activity of inhibitory neurons that release GABA (GABAergic) into the VTA
GABA = inhibitory neurotransmitter that can inhibit dopamine release
- u opioid receptors inhibit the firing of GABA neurons (disinhibition)
- end result is increased activity in the VTA releasing more dopamine into the nucleus accumbens
