Psy 133 Lecture 6 Methods of Research in Psychopharmacology – Flashcards

Behavior, mood, and cognitive processes derived from brain function -Most neuropsychopharmacology is based on behavior

*Brain* *Behavior* Ideally: Neuron Activity Chemical (transmitter,drug) Psychological process/Behavior

-Self-reports are hard to interpret -We typically use *behavior* as a proxy for psyche -There is difficulty tapping into psychological processes -In animals models, hard to understand psychological processes except on behavior

-Screening newly designed drugs -Understanding the neurochemical basis of behavior, and drug-induced changes in that behavior -Developing understanding of psychiatric disorders -Have to be careful when decided what behavior you are analyzing -Important to understand the neurochemical effects of the drugs -Depression is usually linked to serotonin -Have to be careful with therapeutics and actual causal cycles (explanations) -Want to look at cause/effect relations **Science requires determination of cause-effect relationships from controlled manipulations

-Simple observation of tremors, ptosis (drooping eyelids), salivation, catalepsy (e.g. from motor side effects), etc. -Measures of motor activity: identify drugs that produce/inhibit sleep, sedation, loss of coordination, or drugs that stimulate activity -Look at immediate responses, or more complex things -Also look at longer term effects of the drugs -Should be looking at long-term effects, because only after long-term exposure do we see effects emerge

For assessing human condition, allow subjective reports, behavior

-Nuremberg Code -NIH Policy for Protection of Human Subjects *Drugs are screened through animals before they are put into a person

Brains (including chemistry) and behaviors of nonhuman mammals and humans are similar enough to allow *generalization across species* -Used ubiquitously -All therapeutics are marketed having undergone multiple phases of animal testing -Minimal requirement is at least 2 species -Efficacy is similar in human and nonhuman species -As more further away species-wise, more deviations in neurotransmission

*Can determine causal relations* -Rigorous control of living conditions, food, social interactions, etc. is possible -Histories and genetic backgrounds are well known -Many research methods are unethical with human subjects *Validate correlational relationships* with results from controlled animal studies *Drug development and evaluation* -Less limitations on animals vs humans -Can have animal enriched environment vs. deprived -Genetic backgrounds can be manipulated in animal model -Environments are highly controlled -Cannot get cause and effect information from studying people

The *Health Extension Act* (1985) guidelines animal care -Goals: Humane animal maintenance and experimentation that limits the use of animals and animals distress (also improves science!) Research institutions have animal care committees that review protocols: -Relevant to human or animal health, advance knowledge -Alternate methods must be considered -Avoid or minimize discomfort, distress, and pain

1. *Reliability*: stability and consistency with which the phenomenon is readily reproduced under similar circumstances 2. *Predictive Validity*: ability to lead to accurate predictions about the human phenomenon and/or identify therapeutic (i.e. lab vs. clinic) -Ex. Behavioral drug screens -Most important for psychotherapeutics 3. *Construct Validity*: pathophysiological equivalence (common mechanism between model and condition) -Ex. Drinking alcohol by animal causes liver and brain damage -Similarity between model and actual condition 4. *Face Validity*: the model resembles the human condition -Ex. Animals self-administer drugs that are self-administered by humans

**KEY -Across situations -Want something can do in own lab, and someone can do in their lab -Idea that every time the same manipulations are done, will get the same effect

*Rebliability* and *Predictive Validity*

*Predictive* -Does not resemble the disease in terms of etiology or symptomatology, but is predictive of clinical outcome -High: reliable, predictive validity, usually not face, maybe construct *Isomorphic* -Resembles the disease in terms of symptoms and predictive outcome, but is artificially produced in lab -High: Reliable, usually predictive and face validity, limited/partial construct *Homologous* -Resembles the disease in terms of etiology, symptomataology, and predictive outcome -High: reliable, predictive, face, construct -Need human condition -Have clues, but do not understand etiology to produce in animal model **DO NOT EXIST FOR PSYCHIATRIC CONDITIONS (often use partial homologous models) *Evaluating "validity" and deciding where a model "falls" is controversial... -Validating criterion is subjective

-Have *predictive* validity -Be *specific* for the class of drug being screened -Be *sensitive* to a normal therapeutic range of dose and show a dose-response relationship -Demonstrate the same *rank order of potency* in the animal test as the order of potency of the therapeutic action of the drugs -Have high *reliability*- the same results will be recorded each time the test is used

D2-induced yawning -Give an agonist of DA D2 receptors to induce yawning (behavior) -The yawning can be inhibited by known antipsychotics and *screen* for potential antipsychotics--> i.e. it can be used to *predict* therapeutic efficacy -Using yawning behavior to screen for psychotics -Caveat is that there are D2 receptors in a lot of brain regions; the ones associated with yawning probably do not have to do with hallucinations

A mouse model for Huntington's disease has been created by insertion of pathological human gene -Motor functioning of the transgenic mice was evaluated with beam walking, rotorods, swimming ability, gait, and other measures -Comparison with wild-type mice showed progressive (age-dependent) loss of motor ability in transgenic mice -Behavioral impairment associated with neurological pathology -By increasing repeats, causes pathological phases where the cells die -Lot of relation from human condition in terms of CAG repeat -Still correlational, only causative if can directly manipulate -Mice experience motor and some cognitive deficits -In models, a lot of the same symptoms we see in human conditions -Being utilized as the therapeutic screen for this disease -Screen for therapeutic--> just need a predictive model Note: even for neurological conditions, the genetics for HD are simple; there are no known equalivalents in psychiatry

Drug Discrimination Testing!

With conditioning, the animal learns to discriminate between drug and saline treatment based on internal cues produced by the drug -Novel drugs can be tested based on the similarity of internal cues for known drugs -Training AND THEN testing with novel drug -Massively overtrain the animal based on what drug it is on -On different days, inject with saline and then test on saline lever -Take novel drug--> inject animal--> ask which lever it thinks it should pull -If drug is similar, tend to hit drug lever -Thought to tap into subject of experience in unique way -Use psychoactive drug and novel compound

The process of discoveries of new drugs is immense with very low changes of success -Reflects our relatively poor understanding of brain (healthy and pathological) and drug action

Drug discovery--> Preclinical (6.5 years)--> Clinical Trials(7 years)--> FDA Review (1.5 years) -A lot of drugs are lost in clinical trials -Massive number of compounds screened do not even make it to clinical trials Preclinical Research -Discovery and early in vitro screening of compound -Large-scale synthesis -Animal testing -At least 5 years -(Investigational new drug application sent to FDA)-> Clinical Studies -3 phases -7 years -Phase 3 is humans -Thousands of subjects -Drug companies have huge motivation to improve clinical to make sure it is accurate -(New drug application sent to FDA)-> Review by FDA -1.5 years -(Approval)-> Postmarketing Surveillance -Monitor adverse reactions, product defects, long term side effects, drug interactions

-Random Screening -Molecular Manipulation -Molecular Design -Drug Metabolites -Serendipity

Food and Drug Administration (FDA) -Must be demonstrated to be both effective and safe -About 20% of new drugs being tested reach final approval... 80% are eliminated

-Cost of developing new drugs has increased greatly, driven mostly by expenses associated with the phase III human clinical trials -Drug is tested in large trials involving thousands of patients at multiple testing sites around the country -Improving predictability of therapeutic effects would reduce the cost of drug development -Improving understanding of conditions and pharmacology is needed to increase success rate (and decrease costs to industry and consumers)

*Structural (anatomical) approach* -Defines and classifies based on *where* neurons are --> Histology --> Computed tomography (CT or CAT) --> MRI *Functional approach* -Defines and classified based on *what* neurons do --> Neuropsychology (disease/damage/surgery) --> Brain Imaging (Electroencephalogram, Positron Emission Tomography, & Functional MRI) --> Model Systems (behavioral neuroscience & In vitro preparations) **Functional approaches are the most important in drug action

*Histological Analyses* -Manipulation of tissue --> Direct cellular and molecular analyses --> Can only be done post-morten *Static Brain Imaging Techniques* -CT or CAT-series of x-rays --> Scan living brain --> Low resolution; exposure to radiation -Magnetic Resonance Imaging (MRI) -->Use magnetic fields to image density --> Scan living brain; High resolution --> Expensive

*Clinical Neuropsychology* -Analyses of psychological changes after spontaneous brain damage/disease --> Determines critical brain regions --> No control (type or limit) to brain damage *Clinical Neurosurgery* -Analyses of psychological changes after brain tissue removal --> Determines critical brain regions --> Limited control of brain damage --> Preceding pathology

*Electroencephalogram* (EEG) -Measure electrical potentials from scalp --> Activity in living brain; high temporal resolution *PET* -Detect radioative substance (glucose) --> activity in living brain; metabolic/chemical changes --> low resolution; radioactivity; correlational *Functional MRI* (fMRI) -MRI to image blood flow (hemoglobin) --> Activity in living brain; detect metabolic changes; high resolution --> Expensive; correlational

*Behavioral Neuroscience/Animal Models* -Directly *manipulate* brain and detect behavioral changes --> Variety of manipulations (brain damage, drug applications, recording, etc) --> Also extensive control of genetics, development, etc. --> Not human brain; ethical/immoral *In vitro or Artificial preparations* -Isolated cells from brain or molecular components --> Highly flexible extremely accurate, very detrailed molecular analyses --> Highly artificial, limited complexity, starting cells vary in experimental response

The study of chemical in the brain, particularly the *extracellular fluid*, that impact neuronal activity A variety of approaches are used in both animals (more established but could be improved) and humans (This is increasing in utility)

(Animals) *Microdialysis* can measure neurotransmitters and drugs actively engaged in behavior -Extracellular fluid is collected via a cannula/probe from within the brain and analyzed by various methods Note: MD is occasionally used in humans

Measures neurotransmitter using special (ionized) microelectrodes -Changes in current flow at the electrode tip reflect changes in concentration of neurotransmitters (or their metabolites) -Measurements are made continuously

Neurotransmitters, drugs, and receptors are studied outside the brain by several methods: -"Slice" method uses intact piece or slice of tissue; allows localization -"Soup" method- tissue sample is isolated and group to form a homogenate, which can be analyzed; higher accuracy and flexibility

*"Pharmacological" MRI (phMRI)*: analyzez changes in brain function following drug administration, location and time course of drug action using fMRI *Positron Emission Tomography (PET)*: maps glucose metabolism (~brain activity) following drug administration

*PET* with specific labeled-tracers (few available) -Labeled precursors (Dopa) to see monoamine activity -Labeled drugs (raclopride) to see receptor binding --> Can be used with "competing" drugs