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Chapter 4: Methods of Research in Psychopharmacology (Animal Behavior),…
Chapter 4: Methods of Research in Psychopharmacology (Animal Behavior)
Operant conditioning
animals learn to respond to OBTAIN REWARDS or AVOID PUNISHMENT
behaviors that are REINFORCED: likely to be repeated
schedule of reinforcement
Fixed-ratio (FR): reinforcement is delivered after a FIXED NUMBER OF RESPONSES
Fixed-interval (FI): reinforcement after a FIXED AMOUNT OF TIME
behaviors that are PUNISHED: not likely to be repeated
Analgesia: reduction of perceived pain WITHOUT loss of consciousness
tail-flick test: measures response of the animal to heat applied to the tail
hot plate test: latency to respond to a thermal stimulus applied to paws (time it takes the mouse to LICK the hind paw, VOCALIZE, or JUMP from the hot plate surface)
measuring pain in HUMANS: 2 rectal balloon distensions, how much researcher can blow up the balloon until it hurt
Learning and Memory
Radical arm maze: hungry rat allowed to explore maze, piece of food at end of each arm
rat learns to visit each arm only once on a given day
must remember which arms were VISITED PREVIOUSLY
use EXTERNAL VISUAL cues as guides
sensitive to hippocampal lesions
Morris Water Maze: circular pool of water, there's a hidden escape platform the rat can get to
external visual cues as guides
sensitive to hippocampal lesions
Barnes Maze: elevated platform with holes (one of the holes has the escape box)
no swimming involved (an unnatural behavior for rodents)
external visual cues
Novel object recognition: animals are given several minutes to explore 2 objects
after a break, one object is replaced with novel object
mouse explores, it will explore the novel object more if he has good recognition memory
Delayed Response Test (for working memory - sensitive to prefrontal cortex lesions)
CUE: monkey has empty dish and food dish
DELAY: put down the screen
RESPONSE: if he remembers, he'll go right to the food
LIMITATIONS FOR ALL TESTS OF LEARNING AND MEMORY
often DO NOT determine whether altered responses are due to drug-induced changes in:
attention/motivation
encoding, consolidation, or retrieval of memory
effects on motor or sensory ability
Anxiety-Like Behaviors: feelings of losing control/going crazy during a panic attack CANNOT be modeled on mice
Tests for anxiety-like behaviors
A natural CONFLICT SITUATION occurs when a rodent is exposed to an unfamiliar environment
open field maze: mouse doesn't like brightly-lit places (should stay by walls)
elevated plus maze: open arms are usually avoided because of HEIGHT/ BRIGHTNESS
light-dark box
elevated zero maze
Fear conditioning (only takes 1 trial to condition mouse)
Conditioned emotional response: presentation of a signal (a light or tone) is followed by an UNAVOIDABLE electric shock
Contextual vs. Cued
contextual: return to SAME BOX 1 day later --> leads to enhanced freezing
cued: 1 day later, put in DIFFERENT BOX and PLAY SIGNAL --> leads to enhanced freezing
OCD-Like Behaviors
Marble-burying test: 20 marbles arrayed along litter
let mouse be
digging behavior to the EXTREME because of CONTAMINATION FEAR is seen as COMPULSIVE behavior
Impulsive Aggression
Resident-Intruder Test: house mouse for 1 month with minimal cleaning
after 1-month isolation, put social "intruder mouse" in the cage
resident mouse is aggressive: tail lashing, attacking
Depressive-Like Behaviors: feelings of worthlessness/thoughts of suicide CANNOT be modeled in mice
Tests for depression
Forced swim test: see if mice struggle or immobile (despair)
antidepressants increase amount of time mice is mobile
Tail suspension test: hang mouse by tail, see if they're struggling vs. freehanging state (depressed)
critique: depression takes a long time to build up, humans require long-term medication
Sucrose preference test: anhedonia (inability to feel pleasure)
give mouse 2 waters to choose from (sugar-flavored vs. plain)
the anhedonic mouse will pick plain water
test is reliant on mouse's ability to sense sugar
Preclinical Models of Depression
Chronic, mild unpredictable stress
expose rodents to a series of PHYSICALLY STRESSFUL EVENTS (not too big) for several weeks
result: cognitive impairments, anxiety-like behaviors, social withdrawal, anhedonia
CHRONIC (not acute) antidepressant treatment required to REVERSE these behaviors
higher VALIDITY to the human condition
Maternal Separation: stimulates EARLY LIFE STRESS
young animals separated from their mothers for BRIEF periods daily during the FIRST FEW WEEKS of life
tested as adults: produces long-term changes in CRF (corticotropin releasing factor) function that may predispose to depression later in life
Schizophrenia Behaviors
Amphetamine-induced hyperkinesia
HIGH DOSES of dopamine (amphetamine) produces symptoms similar to schizophrenia
characteristic STEREOTYPED sniffing, licking, and gnawing and INCREASED locomotor activity
used to screen potential ANTIPSYCHOTIC DRUGS
critique: entirely dependent on the dopamine hypothesis for schizophrenia
Autism Spectrum disorder
Crawley 3-Chamber Box
1st phase: strange mouse in one chamber, other chamber has empty wire cage and no mouse
mouse in center chamber
see how much time they spend with stranger vs. empty cage
mouse with ASD spends EQUAL TIME with stranger and empty case
normal mouse spends MORE TIME with stranger
Drug Rewards and Addiction
Drug Rewards
Self-administration: used to study ABUSE POTENTIAL in humans
BREAKING POINT: point at which effort required EXCEEDS reinforcing value
the higher the breaking point, the higher the abuse potentialo
Intracranial self-stimulation (ICSS): animal SELF-ADMINISTERS a weak electric current to BRAIN REWARD AREAS
THRESHOLD: current value (defined by experimenter) at which animal continually self-administers
Conditioned Place Preference (CPP): conditioned association between drug effect and environment
used to test if drug is rewarding or aversive
Drug Effects
Drug discrimination testing: with conditioning, animal learns to discriminate between drug and saline treatment based on INTERNAL CUES produced by the drug
Techniques for Assessing the CNS
Optogenetics: insertion of genes into neurons that confer light responsiveness to control events within those neurons
Implanted Microelectrodes
implanted into a SINGLE CELL (intracellular recording)
animal must be anesthized
or into the extracellular fluid NEAR a single cell (extracellular recording)
can be done on a mobile animal
In vivo microdialysis: measure NT released in a specific brain region while the subject is ACTIVELY engaged in behavior
Locating and quantifying NTs and receptor
"Soup" method (quantification)
tissue sample is isolated and ground (homogenate)
allows the study of the NUMBER OF RECEPTORS in a brain region and AFFINITY for drugs
"Slice" method (spatial localization)
uses INTACT slice of tissue
visualize DISTRIBUTION of receptors in the brain
PET
maps distribution of an injected RADIOACTIVELY LABELED SUBSTANCE
also locates area of BRAIN ACTIVITY when person is performing COGNITIVE TASKS
fMRI: OXYGENATED hemoglobin has a different magnetic resonance signal than oxygen-depleted hemoglobin
Active brain cells need more oxygen --> blood flow increases
advantage over PET: no radioisotopes are used, no need to wait for washout of ligand
critique: looking at bloodflow, not neural activity
Genetic engineering: DNA of an organism is ALTERED (knockouts or knockins) or a FOREIGN GENE IS ADDED to the DNA of an organism (transgenic)
KO mice: lack gene for making a particular protein
constitutive (germ-line): knowck out gene at point of CONCEPTION
site-specific (cre-lox): knock out in a particular TISSUE
inducible (tet on/off): turn gene on and off
Knock-In Mice
point mutations
targets a SINGLE nucleotide to produce a SINGLE amino acid substitution
may produce a loss or gain of function
allows study of a specific mutation
Transgenic mice: HUMAN genes inserted into mice (models for neurodegerative diseases)
Knockdowns: allows assessment of lowered levels of gene product
may be a MORE VALID representation of the human condition than a KO because most human diseases are caused by a COMBO of different genes
CRISPR: new mutations can be DIRECTLY GENERATED in a genetic background of choice
designer embryos: significant on-target mutagenesis (not as specific as we want --> pathogenic consequences)
Potential problems with genetically modified mice
behaviors are controlled by MULTIPLE GENES
COMPENSATION by other genes
altered gene function occurs in ALL TISSUES AT ALL STAGES OF DEVELOPMENT
environmental factors afffect gene expression: EPIGENETICS
INBRED LINES
Operational Definitions of Independent and Dependent Variables
how the researcher decides to MEASURE the variables in the study
i.e. "cocaine leads to tolerance": measures locomotor activity vs. "cocaine leads to sensitization": measures stereotypy ratings
DIFFERENT operational definitions of the IV and DV may produce PROFOUNDLY DIFFERENT CONCLUSIONS
