Neuropsychiatric Disorders and Psychoactive Drugs

Imaging techniques and other methods can be applied to both human patients and animal models (e.g., primates, rodents, etc.).
Importance of clarifying whether discussing data from humans or broader applications in animals.

The human brain is often inaccessible for direct study, limiting the understanding of disorders.
Patient groups exhibit significant diversity, leading to heterogeneous manifestations of disorders.
Challenges arise in defining appropriate control groups due to factors such as genetics, metabolism, age, sex, and life experiences.

Cellular models (e.g., in vitro) and animal models (e.g., rodents and primates) help to simplify the underlying conditions of neuropsychiatric disorders.
Cellular models can be human, providing advantages; however, they function in vitro, which presents limitations.
Animal models present controlled genetic environments, allowing for the investigation of specific factors affecting neuropsychiatric disorders.
The relationship between cellular models, animal models, and human studies contributes valuable knowledge.

Primarily used in human patients; they are noninvasive and can track changes longitudinally.
Major imaging techniques include:
- CT scans (Computed Tomography)
  - Often initial imaging for psychotic episodes, mainly to rule out alternatives like tumors.
- MRI (Magnetic Resonance Imaging)
  - Provides highly detailed brain images, measuring contrast between oxyhemoglobin and deoxyhemoglobin.
  - Features improved spatial resolution (under 1 mm) compared to CT (several mm).
- DTI (Diffusion Tensor Imaging)
  - Assesses water movement to map white matter tracts in the brain.
- PET (Positron Emission Tomography)
  - Partially invasive involving radioactive tracers, measuring gamma rays.
  - Useful for estimating receptor levels and monitoring brain activity via radiolabeled tracers.
  - Especially relevant in addiction research.
- SPECT (Single Photon Emission Computed Tomography)
  - More economical than PET but less spatial resolution.

EEG (Electroencephalography) records summed electrical activity in the brain; efficient for surface-level signal observation but offers poor spatial resolution.
MEG (Magnetoencephalography) measures magnetic fields generated by electrical brain activity, providing better spatial resolution than EEG.

Paired auditory stimulation illustrates concepts of paired pulse inhibition;
- Normal control responses show dampened responses to repeated stimuli (S1 and S2).
- Schizophrenic patients exhibit less inhibition, indicating disrupted neural processing.

Neuroimaging and genetic meta-analysis consortia collect and analyze data worldwide, allowing for better analysis due to large cohort sizes.

Changes in neurotransmitter levels in human studies are typically indirect, necessitating care when analyzing cerebrospinal fluid or applying invasive procedures like lumbar punctures.
Alternative indirect measures include plasma and urine sampling; however, urine analysis is more historical now, e.g., for Parkinson's disease.

Platelets express similar receptors to those in the brain (e.g., 5-HT2A receptors).
Analyzing binding affinity on platelets may reflect brain receptor functionality;
- Example shows increased binding affinity for spiroperidone in patients with schizophrenia compared to controls.

Valuable for quantifying receptors and proteins in human tissue, using techniques like Western blot, mass spectrometry, and RNA sequencing.
Allow for sectioning and staining brains to observe the distribution of proteins and cell types, with some constraints (e.g., medication status, cause of death).
Tissue viability post-mortem is crucial; delays in freezing tissue can lead to degradation.

Culturing human tissue is improving studies in neuropsychiatric diseases; tissues collected during surgeries (e.g., for epilepsy) can be kept alive in vitro for real-time measurements.
Enables direct interaction with neurons to test responses to various treatments.

Crucial to identify genetic changes that elevate the risk of developing neuropsychiatric disorders.
A dedicated lecture is forthcoming to address complexities of genetic studies in this field.

Use of transformed cancer lines and increasingly, iPS cells derived from patients allows the modeling of diseases with specific genetic mutations.
iPS cells can be differentiated into various cell types, including neurons, providing important insights into neuropsychiatric disorders.
They can also be used for drug screening, which could influence regulatory policies to reduce animal testing requirements.

The gene Set D1A has been linked to schizophrenia via genetic studies; manipulation of this gene in iPS cells shows a distinct phenotype affecting neuronal morphology and firing patterns.
Downstream changes in pathways often stem from such studies may reveal new therapeutic targets.

Rodents and primates are the primary focus for understanding neuropsychiatric disorders through controlled experiments.
Allows intervention and timed experiments; however, they are not perfect analogs for human conditions.

Psychotomimetic drugs mimic psychosis and could serve as models for studying neuropsychiatric conditions.
- Their use highlights the biological basis underlying perceptions and behavioral changes associated with these disorders.

Naturally occurring hallucinogens have been utilized in various cultures for thousands of years; e.g.,
- Ayahuasca (active compound: harmine).
- Peyote (active compound: mescaline).
- Magic mushrooms (active compound: psilocybin).

LSD (lysergic acid diethylamide) was initially synthesized for treating postpartum hemorrhage; discovered its psychoactive effects accidentally.
Its association with psychosis was observed, presenting it as a potential experimental model for studying schizophrenia.

Cross-tolerance among hallucinogens suggests they may share pharmacological action pathways, particularly involving serotonin receptors (5-HT2A and 5-HT2C).
LSD exerts its effects via serotonin receptor agonism, particularly in specific regions of the brain (e.g., locus coeruleus).

Studies in rats and drug discrimination models reveal that LSD changes firing rates in important neuronal areas (e.g., locus coeruleus neurons).
Evidence from brain imaging studies shows LSD increases functional connectivity across brain regions, correlating to subjective experiences of users.

The interactions between hallucinogens, brain activation patterns, and neuropsychiatric disorders illuminate potential therapeutic avenues and highlight the interface of neurology and psychiatry.