Drug Tolerance and Addiction Flashcards

• Tolerance to a drug means the drug's effect diminishes with the same dosage; a higher dose is needed for the same effect.

• This is depicted as a rightward shift in the dose-response curve: dose on the x-axis, effect on the y-axis.

• Tolerance is a form of negative feedback, where the body tries to maintain homeostasis.

• Homeostasis involves maintaining certain parameters within acceptable limits.

• The body compensates for drug effects through negative feedback mechanisms.

• These mechanisms can be:

  • Fast (e.g., body temperature, blood pressure regulation).

  • Slow (e.g., changes in drug elimination or receptor characteristics).

• Tolerance is an active response that takes time to develop: repeated or continuous exposure leads to a tolerance response.

• Tolerance mechanisms may involve:

  • Better drug elimination.

  • Changes in the number or type of receptors.

  • Alterations in intracellular processes.

• Tolerance isn't limited to drugs of abuse; common medications like ibuprofen can also lead to tolerance.

• Tolerance mechanisms don't disappear immediately after drug use stops.

• These mechanisms persist, pushing the body away from homeostasis in the opposite direction, leading to withdrawal effects.

Withdrawal Effects

• Withdrawal effects are the body's tolerance mechanisms acting in the absence of the drug.

• These effects are opposite to the drug's original effects (e.g., insomnia from sleeping pill withdrawal, increased pain from pain medication withdrawal).

• Withdrawal symptoms diminish over time as the body returns to homeostasis.

• The duration of withdrawal varies depending on the drug.

• Withdrawal symptoms are indicative of physical dependence on a drug.

• The easiest way to alleviate withdrawal symptoms is to take the drug, reinforcing dependence.

• When discontinuing a drug after long-term use, it should be done slowly and under supervision to minimize withdrawal effects.

• Nicotine patches or gum are examples of methods used to gradually reduce drug intake.

Context-Dependent Tolerance

• Tolerance can be classically conditioned to the context in which the drug is taken.

• Addicts often associate drug-taking with specific places or people.

• The context becomes a conditioned stimulus that triggers the tolerance response.

• Overdose can occur in novel environments where the context doesn't trigger the tolerance response, leading to a greater effect from the same dose.

• Withdrawal symptoms can be triggered by familiar environments associated with drug use, even after detoxification.

• Relapse can occur when returning to these environments due to the triggered withdrawal symptoms.

• Tolerance varies among drugs due to different mechanisms and time frames.

• Tolerance can be triggered by a context, leading to drug-seeking behavior, or can be dangerous in a new context due to the lack of a tolerance response.

Psychological Dependence

• Psychological dependence has a neurobiological basis.

• Instrumental or operant conditioning plays a key role: a stimulus triggers a behavior that leads to a reward, reinforcing the behavior.

• A brain system must reinforce behaviors that lead to evolutionarily important rewards (e.g., food, sex).

• Older and Milner discovered a reinforcement system in the brain by accidently stimulating a rat's brain whilst the rat was in a specific point of the maze.

• They decided to proceed by mapping out the brain by intracranial self-stimulation in rats; the rats would press a lever to receive electrical stimulation.

• Mapping of the brain revealed locations where stimulation would reward a behavior.

Neuroanatomical Terminology

• During brain development, the neural tube forms three primary vesicles: the forebrain, midbrain, and hindbrain.

• The forebrain divides into the telencephalon (cortex, basal ganglia) and diencephalon (thalamus, hypothalamus).

• The midbrain remains the mesencephalon.

• The hindbrain divides into the metencephalon (pons, cerebellum) and myelencephalon (medulla oblongata).

• The cortex in humans is so large that it covers most other structures.

• The brain can be thought of as five major subdivisions: medulla, pons/cerebellum, midbrain, diencephalon, and cortex/basal ganglia.

Reward System

• The nucleus accumbens and ventral tegmental area (VTA) are key components of the reward system.

• These are part of the mesotelencephalic dopamine system, connecting the midbrain to the telencephalon via dopamine.

• The system includes dopamine as a neurotransmitter, and substantia nigra to the striatum connection.

• The VTA contains dopaminergic neurons that project to the nucleus accumbens, forming synapses.

• The medial forebrain bundle is a bundle of axons running from the mesencephalon to the telencephalon, using dopamine as the neurotransmitter.

• Electrical stimulation of the medial forebrain bundle triggers dopamine release.

• Dopamine levels in the nucleus accumbens increase during rewarding activities.

Dopamine and Reward

• Stella, Kelly, and Corbett demonstrated that blocking dopamine receptors in the nucleus accumbens prevents rats from learning to press a lever for stimulation.

• This indicates that dopamine release is crucial for the rewarding effect.

• The VTA-to-nucleus accumbens dopamine release is a key part of the reinforcement system.

• Dopamine also relates to wanting and seeking rather than just pleasure.

• Dopamine is released during both reward and punishment.

• Dopamine release is more related to gathering information and the compulsion to repeat behaviors.

Dopamine and Addiction

• Drug addicts crave drugs even when they no longer enjoy the effects.

• The dopamine system drives animals to do things that increase their fitness, regardless of whether they like it.

• Cocaine and amphetamines increase dopamine levels, making them psychologically addictive.

• Self-injection experiments in rats show that dopamine levels increase with drug use.

• Infusing cocaine directly into the nucleus accumbens leads to self-administration, indicating a direct effect on the mesotelencephalic dopamine system.

• Addictive drugs bypass the brain's assessment systems and directly activate dopamine release in the nucleus accumbens.

• This leads to a compulsion to take the drug again in the future.

Review Questions

• Dopamine release from VTA neurons into the nucleus accumbens is a crucial step in the reinforcement system.

• Dopamine receptor blockers have the potential to prevent the development of addiction but may be less effective once the psychological addiction is established.

• Dopamine also drives exploration and makes the animal do that behaviour more likely again in the future.

Summary

• Pharmacokinetics involves drug absorption, distribution, and elimination, with different drugs having different parameters.

• Physical drug dependence results from drug tolerance and withdrawal symptoms.

• Psychological dependence is due to activation of the VTA and nucleus accumbens connection, involved in the rewarding or seeking system; the drug bypasses other systems to directly get into that pathway.

• Drugs that cross the blood-brain barrier are lipophilic and affect areas with dopamine neurotransmitters.