Methodology & Psychoactive Drugs ppt

Methodology

  • Methods for studying neuropsychiatric disorders:

    • Imaging techniques

    • Electrical signals from the brain

    • Indirect ‘markers’ for changes in neurotransmitter function

    • Post-mortem studies

    • Human genetics

    • Cellular models

    • Animal models

  • These methods can be applied to human patients.

Imaging Techniques

  • Human Imaging Techniques

    • Non-invasive methods

    • Longitudinal studies feasible

    • Limitations:

    • Cannot conduct intervention studies, making it challenging to understand mechanisms

    • Can visualize the effect of drugs and specific types of information, e.g. CT (computed tomography)

    • Literature citations:

    • Tshibanda et al. 2009

    • Svancer & Spaniel 2021 https://doi.org/10.1016/j.neulet.2021.136065

  • Types of Imaging Techniques:

    • DTI (Diffusion Tensor Imaging)

    • MRI (Magnetic Resonance Imaging)/fMRI (functional MRI)

Nuclear Medicine Imaging Techniques

  • Positron Emission Tomography (PET):

    • Used for functional imaging of the brain

  • Single Photon Emission Computed Tomography (SPECT):

    • Main advantage: does not require an on-site cyclotron

  • Production of Isotopes:

    • Unstable positron emission isotopes created in a cyclotron, e.g., O-15 (half-life of 2 minutes).

    • Isotopes are injected and distribute according to the relative activity of different brain regions.

    • Can also be used to estimate receptor levels in the brain.

Electrical Signals from the Brain

  • Techniques:

    • Electroencephalography (EEG)

    • Magnetoencephalography (MEG)

    • Reference: https://doi.org/10.1016/B978-0-12-801829-3.00021-5

Global ENIGMA Initiative

  • Website: https://enigma.ini.usc.edu/

  • Working Groups Included:

    • 22q

    • Addiction

    • ADHD

    • Anorexia

    • Anxiety

    • ADHD (Attention-Deficit/Hyperactivity Disorder)

    • Autism Spectrum Disorder (ASD)

    • Borderline Personality Disorder (BPD)

    • Epilepsy

    • Major Depressive Disorder (MDD)

    • Obsessive-Compulsive Disorder (OCD)

    • Post-Traumatic Stress Disorder (PTSD)

    • Schizophrenia (Scz)

    • Stroke

    • Additional areas reviewed include genetic variability, neuroimaging, etc.

Indirect Markers for Neurotransmitter Function

  • Methods of Measurement:

    • Levels of neurotransmitters/metabolites in:

    • Cerebrospinal fluid

    • Plasma

    • Urine

    • Example: Decreased dopamine (DA) and metabolites (e.g., HVA) in Parkinson's disease.

    • Reference: Govitrapong et al., 2000 https://doi.org/10.1016/S0165-1781(00)00191-8

Post-Mortem Studies

  • Focus Areas:

    • Imaging and biochemical analysis

    • Analysis includes protein (e.g., receptor) levels, RNA levels, protein/RNA localization

  • Limitations:

    • Endpoint analysis only

    • Delay post-death before analysis can introduce variability

    • Cause of death and prior medication affect results.

Genetic Analysis

  • Aim:

    • Identify genetic changes in humans that may contribute to an increased risk of developing neuropsychiatric disorders.

Cellular Models

  • Use of Induced Pluripotent Stem Cells:

    • Process:

    • Reprogramming somatic (unipotent) cells into iPS cells which can then differentiate into specialized cell types.

    • Applications:

    • Disease modelling

    • Drug screening and discovery (including toxicology tests)

    • Potential for cell therapy

    • Reference: Bellin et al. 2012 https://doi.org/10.1038/nrm3448

Animal Models

  • Model Organisms:

    • Drosophila (fruit flies)

    • Caenorhabditis elegans (roundworms)

    • Mice

    • Rats

    • Primates

  • Approach:

    • Knockout/knock-in genes to mimic neurochemical changes observed in human diseases.

  • Advantages:

    • Flexible and adaptable for various studies

  • Disadvantages:

    • May not completely represent human conditions.

Psychotomimetic Drugs

  • Definition:

    • Drugs that induce profound changes in perception, mood, and behavior.

  • Questions raised:

    • What are the biochemical bases and anatomical substrates for these effects?

    • What insight do they provide into brain function and disorders like schizophrenia?

  • Examples of Drug Types:

    • Hallucinogens

    • Cocaine

Hallucinogens

  • Naturally Occurring Examples:

    • Harmaline

    • Mescaline

    • Ayahuasca

    • Peyote

    • Psilocybin (active ingredient in magic mushrooms)

Potency Comparison of Hallucinogens

  • Dosage and Duration:

    • Psilocybin: 250 µg/kg, Duration: 3 hrs

    • Mescaline: 15 mg/kg, Duration: 12 hrs

    • LSD: 3 µg/kg, Duration: 10 hrs

  • Notably, LSD is extremely potent, likely acting at very specific receptor sites in the brain.

Historical Context: LSD Synthesis

  • Origins:

    • Synthesized to treat ergotism (caused by consuming ergot-contaminated rye bread leading to gangrene and psychosis).

  • Ergot Alkaloids:

    • Compounds causing peripheral vasoconstriction; both dangerous and useful.

  • First Synthesis:

    • Albert Hofmann, 1943, at Sandoz Laboratories.

    • Quote describing visual effects:

    • “… Little by little I could begin to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes…"

Effects of LSD

  • Categories:

    • Somatic, perceptual, and psychological effects.

  • Effect Spectrum:

    • Visionary restructuralization

    • Oceanic boundlessness

    • Experience of unity

    • Spiritual and blissful states

    • Includes auditory and visual synesthesia.

  • Data Representation:

  • Findings from Liechti (2017) show a scale for altered perceptions based on dosages.

Mechanisms of Action for LSD

  • Receptor Interaction:

    • Cross-tolerance observed between LSD and mescaline, indicating action at similar receptor sites.

    • LSD's structure and effects suggest it acts as both an agonist and a partial agonist at 5-HT receptors.

  • Early Studies:

    • In vitro studies show LSD interacts with 5-HT receptors, acting as an agonist in the brain, while acting as an antagonist in the peripheral vasculature.

Brain Areas Affected by LSD

  • Key Regions:

    • Thalamus, primary somatosensory cortex, and reticular formation.

  • Symptoms:

    • Include synesthesia resulting from alterations in these pathways.

Perception Alteration by LSD

  • Mechanisms:

    • Decreases firing rate of raphe neurons (5-HT1A receptors)

    • Increases activity in locus coeruleus neurons and subsets in the cortex.

  • Findings:

    • Studies by De Gregorio et al. (2016) support the link between serotonin neural activity and perception.

Unique Observations

  • Cross Tolerance with Mescaline:

    • Mescaline does not affect raphe neuron firing despite LSD showing effects.

  • Noradrenergic Pathways:

    • Increased activity in locus coeruleus neurons leads to modulation of sensory information processing pathways.

Summary of LSD Effects and Sites of Action

  • Decreased firing rates of raphe neurons, increased activity in locus coeruleus neurons, and enhanced connectivity in the primary visual cortex.

  • Studies by Carhart-Harris et al. (2016) illustrate the impacts of LSD on cerebral blood flow and functional connectivity, correlating these changes with subjective experiences of hallucination and ego dissolution.