Lecture 30-33 Flashcards
Hallucinogens
substances whose primary effect is to cause perceptual and cognitive distortions without producing a state of toxic delirium.
Most hallucinogenic drugs have either a —— or a ——- structure.
- serotonin-like
- catecholamine-like
Mechanism of serotonergic psychedelics:
- Act on 5-HT2A receptor
LSD (7)
what + psycholytic therapy + psychedelic therapy + absorbed within + peak pahse + total duration + metabolite/excretion
- a synthetic compound, its structure is based on a family of fungal alkaloids
- One way of using LSD was in psycholytic therapy. This therapeutic method was based on the concept of drug-induced “psycholysis”, meaning psychic loosening or opening. It involved giving LSD in low but gradually increasing doses, greater frequency to promote the release of repressed memories and to enhance communication with the analyst.
- Psychedelic therapy, in which the patient was typically given a single high dose of LSD with the hope of gaining insight into his problems through a drug-induced spiritual experience.
- absorbed orally within 60 mins
- The peak phase generally begins after about 3 hours and lasts for another 2 or 3 hours. During this phase, the user feels as if she’s in another world in which time has been suspended.
- Total duration of 8-12 hours
- Metabolized in the liver to 2-oxo-3-hydroxy LSD and excreted via urine.
Physilogical and psychological effects of LSD (3)
3 phases
Somatic phase
- absorption of drug
- CNS stimulation, automomic changes
- Increase in body temp, dilation of pupil, increase heart rate, dizziness
Sensory (perceptual) phase
- Altered perceptions/sensory disortion
- synesthesia: intermingling of senses
Psychic phase
- Changes in mood
- depersonalization
- Potential “bad trip” (distressing thoughts, memories, anxiety)
Hallucinogens (LSD) lack the high degree of abuse potential seen with most other recreational drugs, such as opoids, psychostimulants, cannabis, alcohol, and nicotine. They do not produce —– after chronic use, and they are not effective reinforcers in animal tests such as the ——-.
- physical withdrawal symptoms
- self-administration paradigm
Hallucinogen persisting per- ception disorder (HPPD) (2)
The 2 types
more serious disturbance in which severe perceptual symptoms persist for a long period of time following drug use and are experienced sufficiently frequently to cause significant distress or impairment to the indi- vidua
MDMA (5)
catecholamine-like psychedelic
developed by + mechanism of action + results in + absorbed within + total duration
- developed by the pharmaceutical company E. Merck
- releases/reuptake inhibitor of 5-HT, DA and NE acting on SERT so more 5-HT
- This surge in serotonin contributes to:
Enhanced mood and emotional connectivity.
Increased empathy (often called an “empathogen”).
Euphoria. - Absorbed within 30-45 min
- Total duration of 3-6 hours
MDMA assited therapy for PTSD
Psilocybin (5)
structure + pro + onset of action + peaks around + total duration
- Alkaloid from several mushroom species (magic mushroom)
- The major ingredients of these mushrooms are psilocybin (prodrug) and the related compound psilocin. After ingestion, the psilocybin is enzymatically converted to psilocin, which is the actual psychoactive agent
- Onset of action is 20-45 mins
- Peaks around 2 hours
- Total duration: 6-8 hours
Caffeine (5)
absorption + blood levels + absrobed within + solubility + placenta
- rapidly, completely absorbed (oral)
- 15-20 mins, blood levels are significant
- 99% absorbed within 45 min
- Soluble in water and oil lesds to equal distribution throughout the body and brain
- Freely crosses the placenta
Caffeine metabolism (3)
enzyme + similar + nonsimilar
- By enzyme CYP-1A2 enzyme
- two metabolites behave similarily to caffeine (theophylline, paraxanthine)
- the third theobromine does not
Benefits
Pharmacological effects of caffeine
PD (1) + AD (2)
Protective against Parkinson’s Disease
- Men and women, decaf ineffective
Decreased risk of Alzheimer’s Disease
- Daily coffee/caffeine intake during middle and old age.
- High plasmic levels of ceffein prevents progression from mild cognitive impairment to dementia
Caffeine experiment with bees (3)
enhances what + what happened + results
- Caffeine in floral nector enhances a pollinator’s memory of reward.
- Train honey bees to associate floral scents with sucrose (prescence or abscence of caffeine)
- Results: Caffeine significantly increased LT memory for floral scents. In studies, bees trained with caffeinated sucrose solutions were shown to retain the memory of the associated floral scent for longer periods. For example:
After 24 hours, they were much more likely to revisit a flower with the same scent.
Even after 72 hours, their memory of the scent remained stronger than for nectar without caffeine.
Caffeine experiment in young adult memory performance
- Caffeine enhances memory performce in young adults during their non-optimal time of day (Participants were tested in the morning, a time considered suboptimal for cognitive performance in many young adults)
- The experiment tested word recall in students (explicit memory) and found that caffeine increased cognition in the morning.
Lethal dose of caffeine:
10 grams oral
Woman who drinks 2-4 cups of coffee have:
a 15-20% decreased risk for depression
Effect of caffeine on sleep:
- Impairs duration and quality of sleep, cause awakenings throughout the night
Caffeine tolerance and dependence (3)
tolerance + withdrawal symp + onset
- Daily doses are associated with habituation/tolerance
- Withdrawal is associated with: headache, drowsiness, lack of concentration, irritability
- Onset of symptoms 12-24 hours after cessation, peaks at 24-48 hours, cease after a few days
Explain the experiment of caffeine and the 7 scientist-colleagues
- Subjects blind to condition (caffeine vs placebo pills)
- Everyone rated themselves in headache, energy/active, lethargy, concentration
What does adenosine do (4)?
name + promotes + supresses + levels
- Neuromodulator: Substance other than a neurotransmitter that can alter the activites of a neuron
- Promotes sleep
- Suppresses arousal
- Adenosine levels increase duriing the day due to breakdown of ATP. This increases binding to adenosine receptors and produce drowsiness.
Caffeine mechanism of action:
- There is now overwhelming evidence that blockade of adenosine receptors, particularly the A2A subtype underlies caffeine-induced behavioral stimulation. ATP is released from inside cells by pannexin channels. Once it reaches the extracellular space, ATP can directly activate its own receptors (P2X and P2Y). ATP can also be enzymatically converted directly to adenosine or sequentially metabolized
to ADP, AMP, and then adenosine. - Extracellular adenosine activates metabotropic adenosine receptors (AR) in the cell membrane.
- Four different adenosine receptor subtypes have
been identified: A1, A2A, A2B, and A3. - Striatal A2A receptors form heteromers (complexes containing more than one type of molecule) with D2 receptors. Current evidence suggests that the structure is a heterotetramer consisting of two A2A and two D2 receptors.
- Occupancy of the A2A receptor by adenosine exerts an allosteric influence on the D2 receptor, reducing its affinity for DA and, therefore, decreasing the arousing and behaviorally activating effects of DA. Consequently, under conditions when extracellular adenosine levels are higher, , adenosine inhibition of D2-mediated signaling leads to lower levels of arousal and psychomotor activation.
- Consumption of caffeine releases this inhibition by blocking the adenosine receptors and enhancing D2 signaling, thus leading to mild arousal and psychomotor activation.
- This finding makes clear why caffeine blockade of adenosine receptors is especially beneficial for promoting wakefulness in drowsy individuals.
Smoking increase ——
CYP1A2 (caffeine metabolism)
Genectic variability in the nicotinic receptor increases —– which drives —–
- cigaratte consumption
- caffeine consumption
Nicotine is capable of —- motor recovery after focal stroke and —— dendritic growth in remaining cortical regions.
- enhancing
- stimulating
E- cigarettes
invented by + 2018
- Invented by chinese pharmacist Hon Lik
- 2018: Canada enacts the Tobacco and Vaping products Act (TVPA) : how products are sold, labelled, produced and promoted
Nicotine
Pharmacokinetics (tobacco smoking) (5)
absorption + contains how much of nicotine + BS + lungs + brain
- readily absorbed at all sites: lungs, buccal and nasal mucosa, skin
- Average tobacco cigarette contains 6-11 mg of nicotine
- 1-3mg of nicotine reach bloodstream
- Enter lungs on tar
alters taste and smell of cigarette smoke = reinforcing effect - Nicotine reach brain within 7 seconds
Nicotine
Pharmacokinetics (E-cigarette smoking) (2)
nicotine location + brain
- Nicotine dissolved in glycerin and heated
- Still reaches brain within 7 seconds.
Nicotine metabolism
- 70-80% by the CYP-2A6 enzyme
Mechanism of action for Nicotine:
Activation of cholinergic receptors:
1. Nicotinic receptors (ionotropic, five protein subunits)
2. Muscarinic receptors (metabotropic)
At low doses nicotine —- the receptor. At high doses, nicotine can —– the receptor by ——.
- stimulate
- block
- inducing a conformational change in the receptor resulting in a desensitized state
Nicotine
Prolonged exposure may result in a ——-
depolarization block
Tolerance develops during the day, lost at night
There is a wide distribution of nicotinic receptors throughout the CNS, on presynaptic nerve terminals of DA, ACh and Glu neurons. Nicotine increases DA in reward pathway by (3):
- Nicotinic receptors on VTA dopamine neurons (DA release onto the NAcc)
- Release of GLU from frontal cortex onto the VTA neuron (induces release of DA from VTA neuron)
- Desensitizes nicotinic receptors on GABA neurons (inhibits release of GABA on VTA neurons)
Explain Nicotine experiment (transdermal patches):
- 61 Non-smoking college students.
- Split into high attention or low attention
- Administered 7mg of nicotine or placebo
- Connor’s Continous performance test (CPT) to asses attention (press space bar as quick as posible for certain words)
- Results: Enhanced student stimulus detection in low attention group. Nicotine might only be able to help to a certain level, after that it doesnt help with attention.
The five-choice serial reaction time task (5-CSRTT) of attention experiment:
- A typical 5-CSRTT apparatus consists of an operant chamber equipped with a food pellet dispenser, a food magazine where the pellets can be obtained, and a curved front containing five apertures, each of which can be illuminated with a signal light.
- During training and testing, one of the signal lights is illuminated for a brief period such as 1 second or less. The rat must sustain its attention sufficiently to detect the stimulus, which it signifies by poking its nose into the correct aperture. This permits the animal to receive a reinforcement (food pellet) in the food magazine. Computer software enables researchers to obtain data on variables such as accuracy (percentage of trials with a correct response), errors of omission (failure to respond to the signal, suggesting a lapse in attention), premature responses (responding before the signal was displayed), and response latency (time to respond after the signal was presented). The results showed that nicotine has a positive effect on attention.
Acute tolerance in Nicotine:
- Builds throughout the day (receptor desensitization) temporary
- Overnigh abstinence (resensitization)
- First cig of the day is the most rewarding
Chronic tolerance of nicotine (4)
- Superimposed on acute tolerance
- subjective effects of nicotine (reward and aversion are susceptible to tolerance
- receptor desensitization
- Chronic smoker may have up regulation of receptor in brain due to desensitization (homeostatic mechanism)
Partial nicotinic agonist
mechanism of action + reduction + enjoy? + DA
- binds to nicotine Ach receptors
- Partial stimulation of receptor, reduction of withdrawal symptoms
- Blocks access of nicotine to receptor- smoking is less enjoyable
- Low level release of DA: the effect is less satisfying
Non
Nicotine repacement therapies (4)
reduce + safer way to + example + cigs comparison?
- reduce cravings
- safer way to obtain nicotine
- nicotine gum, patches, nasal spray
- More gradual and less nicotine release then cigarettes
Vaccine therapy for nicotine (4)
Mechanism of action + Ex + drawbacks (2)
- Stimulation of immune system to produce antibodies that bind to nicotine. When bound to nicotine they prevent it from crossing the BBB
- NicVAX, NIC002
- Requires repeated doses to remain effective
- Doesnt reduce drug cravings
