PSYC 181 Lecture 4
Definition and Scope of Behavioral Pharmacology
Behavioral pharmacology is defined as the study of the relationship between the pharmacodynamics of a drug—its physiological actions and effects—and its subsequent impacts on behavior and psychology.
This field examines how drugs interact with biological systems to alter the behavioral repertoire and psychological state of an organism.
Principles of Behavioral Drug Action
Drugs do not create brand new, novel, or unique behaviors. Instead, they modify the species-typical behavioral repertoire that already exists.
Drugs alter the probability or frequency of behaviors occurring rather than inventing new ones.
Even behaviors considered rare or infrequent, such as hallucinations, are part of a potential behavioral repertoire. Hallucinations can occur naturally under conditions of extreme dehydration, starvation, or high fever, and in medical conditions like schizophrenia. Drugs simply increase the likelihood of these rare behaviors.
Physiological and Environmental Determinants: Set and Setting
The behavioral and psychological effects of a drug are heavily dependent on two primary factors: set and setting.
The Concept of Set
Set refers to the physiological and psychological state of the organism at the time of drug administration. It can be thought of as the "mindset" or "body set" of the individual.
The effect of a drug is determined by the starting point of the organism:
Antihypertensive Drugs: If administered to an individual with high blood pressure, the drug reduces blood pressure to normal levels. However, if administered to someone with normal blood pressure, it will lower the pressure to subnormal levels, potentially causing lightheadedness or fainting.
Anxiolytics: If given to a person in a high-anxiety state, the drug produces relaxation and returns the individual to a normal state. If given to a non-anxious person, it often acts as a sedative and causes sleep.
The Concept of Setting
Setting refers to the environmental circumstances surrounding drug administration. This includes anything beyond the immediate internal physiology of the organism.
Setting factors include:
Time of Day: Alcohol has a more prominent effect when consumed at night compared to the morning, a phenomenon observed in both humans and other animals.
Physical Location: The location (e.g., drinking at home alone in a basement versus at a social bar) significantly influences the drug's impact.
Socio-cultural Implications: The broader environment and social context influence the proclivity to use a drug and its perceived effects.
Conditioning: Organisms can become conditioned to the environment where a drug is administered, which significantly impacts the drug's effects during subsequent administrations.
Methodologies for Behavioral Evaluation
Primary Evaluation
Primary evaluation is the first stage in testing a novel compound to observe its unconditioned effects on behavior.
The goal is often to ensure the drug does not produce unintended side effects. For example, a candidate cancer drug should ideally treat cancer without causing drowsiness, hallucinations, or seizures.
Key areas of assessment in rodents include:
Locomotion/Motor Activity: Checking for changes in how much an animal walks or if it becomes lethargic.
Catalepsy and Balance: Evaluated using tests like the dowel test. A mouse is placed on a thin wooden dowel; failure to stay on or scurry across indicates profound balance disturbances. In humans, who are bipedal, such balance issues are significantly more dangerous.
Strength: Measured by having rats or mice pull on a chain attached to a force meter to check for diminished tension.
Seizures: If a drug causes seizures, even at a rate of in every people, it is usually disqualified from the market unless the condition being treated is terminal (e.g., advanced cancer).
Eating and Drinking: Even a increase in food consumption can lead to significant weight gain over time. Approximately of patients treated with certain antipsychotics eventually develop diabetes due to increased calorie consumption.
Secondary Evaluation
Secondary evaluation involves testing specific functions and behaviors targeted by the drug's intended use.
Analgesia vs. Anesthesia: Analgesia is the reduction of pain sensation, while anesthesia is the loss of all sensation and consciousness.
Tests for Analgesia:
Tail Flick Test: A light source heats a rat's tail until it moves it. Drugs like opioids increase the time before the "flick" occurs because the animal can tolerate more heat.
Hot Plate Test: An animal is placed on a surface that heats up until the animal jumps or walks off. Analgesics increase the temperature threshold at which the animal reacts.
Limitations: These simple tests model momentary pain. Modern research often requires more unpleasant models involving actual injury to better reflect the chronic pain conditions humans seek treatment for.
Learning and Memory Paradigms
Specialized Models
Transgenic Mice: Researchers transplant human genes, such as those associated with familial Alzheimer's, into mice. These mice develop plaques and memory impairments similar to human patients, allowing for the testing of memory-enhancing drugs.
Toxicological Screens: The American Toxicology Society recommends or mandates testing drugs for cognitive side effects (e.g., ensuring a weight loss drug doesn't cause amnesia).
Spatial Radial Maze (Radial Arm Task)
Consists of a central platform with several arms (appending structures) extending outward. Arms are baited with sugar pellets that are coated so the animal cannot smell them.
Performance: Mice must remember which arms they have already visited. An error is defined as revisiting an arm where the treat has already been collected.
Ecologically Valid: The test mimics natural foraging behavior where animals avoid return-visits to depleted resource areas.
Primary Function: It is a test of hippocampal function and delayed memory.
Morris Water Maze
A tank of water is made opaque using non-toxic gray/white paint or milk powder. A platform is hidden just below the surface.
Procedure: The animal swims until it finds the platform by chance. On subsequent trials, the animal uses distal cues in the room (posters, clocks, etc.) to navigate directly to the platform.
Significance: It serves as a classic test for the creation of spatial maps and hippocampal function.
Primate Object Recognition
Delayed Non-Matching to Sample: A monkey displaces a cup to find a treat (e.g., Skittles, M&Ms, or raisins). A screen is lowered for a specific delay, then two objects are presented. The monkey must choose the new (non-matching) object to receive another treat.
Advantage: This task translates directly across species, including human children and rodents.
Fear and Anxiety Models
In pharmacology, unlearned fear is termed "anxiety," while learned fear is termed "pathological fear."
Fear Potentiated Startle
Based on the principle that fear increases the startle reflex. A light is paired with a foot shock. Later, a loud noise is presented. The animal will jump higher if the noise occurs while the light is illuminated because the light signals fear.
Pavlovian Conditioned Freezing
A tone or environment is paired with a light foot shock. The animal displays fear by freezing and tensing up.
Context Dependency: The animal becomes afraid of the specific environment where the shock occurred even without the tone, which acts as a memory and hippocampal test.
Use of "Humanized" Mice: Small mice serve as excellent models because researchers can transplant human receptors to see how they respond to pharmacology.
Anxiety Specific Tasks (Conflict Paradigms)
These tasks create a conflict between the desire to explore and the unlearned fear of heights or open spaces.
Examples: Elevated Plus Maze (cross-shaped platform with two open and two closed arms), Open Field Task, Zero Maze, and Light/Dark Emergence Maze.
Anxiolytics (like Valium) increase the time the animal spends exploring the open or "dangerous" areas.
Behavioral Models of Depression and Other Disorders
Depression Models
Porsolt Forced Swim Test: A mouse is placed in a large glass beaker of water. It will tread water until it eventually gives up (immobility). Antidepressants like Zoloft (sertraline) increase the time the animal struggles before giving up.
Tail Suspension Test: An animal's tail is taped to the ceiling. It struggles to get away until it eventually becomes immobile. SSRIs like Prozac (fluoxetine), Paxil (paroxetine), and Celexa (citalopram) decrease immobility time.
Predictive Validity: While the tasks do not look like human depression, they reliably predict the efficacy of antidepressant drugs in humans.
Complex Disorders
Schizophrenia, Bipolar Disorder, and Autism: These are difficult to model because subjective experiences like hallucinations cannot be easily observed in animals.
Most drugs for bipolar disorder were discovered by accident because of the lack of good behavioral models.
Self-Administration and Operant Procedures
Used to assess the addiction potential of a drug and to determine its scheduling.
Self-Administration Setup: Animals are typically fitted with a catheter into the heart (the safest long-term site) or brain, or placed in vapor chambers. They can press a lever to receive a drug infusion.
Reinforcement and Punishment
Positive Reinforcement: Presentation of a stimulus (drug high) increases the probability of behavior.
Negative Reinforcement: Removal of an aversive stimulus (withdrawal symptoms or anxiety) increases the probability of behavior.
Punishment: Providing an aversive stimulus to decrease the probability of a behavior.
Schedules of Reinforcement
Ratio Schedules: Based on the number of responses.
Fixed Ratio (): Reinforcement after a set number of responses (e.g., means every lever presses earn a drug dose).
Variable Ratio (): Reinforcement after an average number of responses (e.g., averages but varies trial to trial).
Interval Schedules: Based on the amount of time elapsed.
Fixed Interval (): Reinforcement for the first response after a set time (e.g., minute).
Variable Interval (): Reinforcement after an average amount of time has passed.
DRL (Differential Reinforcement of Low Rates): Reinforcing the animal for low rates of responding. If the animal responds too quickly or too often, the clock resets.
Drug Discrimination and Interoceptive Cues
Drugs act as discriminative stimuli (). They provide interoceptive cues that animals can learn to categorize.
Procedure: An animal is trained to press a left lever when on morphine and a right lever when on saline. Then, a new drug is introduced. If the animal pushes the left lever, it indicates the new drug "feels" like morphine.
Significance: Animal categorization of drugs into classes (stimulants, opiates, etc.) very closely matches human clinical and pharmacological classifications.
Quantifying Drug Reward and Addiction
Progressive Ratio Schedule
Designed to overcome the limitations of Fixed Ratio () schedules. In schedules, a decrease in responses could mean the drug is less rewarding or that the animal is too incapacitated to move.
Progressive Ratio: The requirements for a dose increase with each trial (e.g., , , , , etc.).
Breakpoint (Final Ratio): The highest ratio completed before the animal gives up. This is an unambiguous measure of drug reward. Animals will work much harder ( lever pushes) for cocaine () than for food or sex ( of pushes).
Conditioned Place Preference (CPP)
Measures compulsive drug seeking (Pavlovian) vs. self-administration, which measures drug taking.
Procedure: One environment (e.g., red side) is paired with the drug; another (e.g., blue side) is paired with saline. Animals that find the drug rewarding will spend more time in the drug-associated environment even when drug-free.
Questions & Discussion
Side Effect Acceptance: How does the FDA or DEA determine acceptable side effects? Generally, if a treatment for a condition already exists, new drugs must have fewer or milder side effects. For life-threatening conditions like advanced cancer, there is a higher tolerance for severe side effects like nausea or immune suppression.
Mirror Therapy and Phantom Limb Pain: Does mirror therapy work? It works for some patients as a temporary treatment by using visual cues to alleviate pain in a missing limb, but it is not a standing cure and its effectiveness often diminishes over time.
Mouse Utility: Why are mice preferred over rats for some tasks? Mice are used extensively because of the availability of transgenic lines. While they are a different species and smaller than rats, they allow for the modeling of specific human receptors and genetics.
Progressive Ratio Issues: What are the drawbacks? Although it is the best measure of reward, it only provides one data point (the breakpoint), and the animal develops tolerance or sensitization during the long process of reaching that breakpoint.
Dopamine Loss: What happens if the dopamine system is destroyed? Using (six-hydroxydopamine), which kills dopamine neurons, significantly decreases the rate of responding for rewards, confirming that dopamine is central to the rewarding effects of drugs.