Drug Tolerance, Sensitization, and Expectation PDF

**How we adapt to drugs---tolerance, sensitization and expectation** *Tolerance defined:* Two definitions we can use: "The decreased effectiveness (or potency) of a drug that results from repeated administrations" "The necessity of increasing the dose of a drug in order to maintain its effective...

**How we adapt to drugs---tolerance, sensitization and expectation** *Tolerance defined:* Two definitions we can use: "The decreased effectiveness (or potency) of a drug that results from repeated administrations" "The necessity of increasing the dose of a drug in order to maintain its effectiveness after repeated administrations." Some effects of a drug may develop tolerance quickly, some other may show tolerance slowly, and some effects may not show tolerance at all. (E.g. morphine: tolerance to nausea develops very quickly; no tolerance to the ability of morphine to constrict the pupils of the eyes) Because tolerance to different effects of a drug develops at different rates, it is apparent that many mechanisms must be responsible for tolerance Note: it is often more useful to think of developing tolerance to drug effects rather than to themselves. ***Mechanisms of Tolerance:*** *Pharmacokinetic Tolerance:* "Arises from an increase in the rate or ability of the body to metabolise a drug, resulting in fewer drug molecules reaching their sites of action: Generally, this is the result of enzyme induction. All effects of the drug will be diminished. Will create cross tolerance with other drugs metabolised by the same enzyme. *Pharmacodynamic Tolerance (Physiological or Cellular Tolerance):* "Arises from adjustments made by the body to compensate for an effect of the continued presence of a drug...such adjustments are believed to be the result of a process called homeostasis." Homeostasis: The ability or tendency of a living organism, cell, or group to keep the conditions inside it the same despite any changes in the conditions around it: e.g. Warm-blooded animals are able to achieve temperature homeostasis. Human body will use vasodilation or vasoconstriction to control body temperature Most of the body's physiological processes are controlled by feedback loops Homeostasis provides a flexible system for maintaining a set point in circumstances in which environmental condition changes. If a drug is repeatedly administered, the body gets better and better at restoring normal function and diminishing the disruptive effect of the drug. Stimulus disrupts homeostasis--- (increasing or decreasing a) controlled condition that is monitored by---receptors that send (Input, nerve impulses or chemical signals to a)---control centre that receives the input and provides (output, nerve impulses or chemical signals to)---effectors that bring about a change or---response that alters the controlled condition. There is a return to homeostasis when the response brings the controlled condition back to normal. One example of pharmacodynamic tolerance is upregulation and downregulation of receptors. The concentration of postsynaptic receptors is dynamic and changing depending on the activity in the synapse. Higher activity = less receptors, lower activity = more receptors. In general, repeated activation of receptors leads to receptor down-regulation in an attempt to restore the normal level of information flow through the synapse. Decreased receptor activation induces the opposite homeostatic response: receptor up-regulation. *Behaviour tolerance:* "Through experience with a drug, an organism can learn to decrease the effect that the drug is having." (p.38) This learning can involve both operant and classical conditions and will be addressed under the subsection *Conditioning of Drug Effects* (P.41-45). **Other relevant considerations:** *Functional disturbances:* "Disruptions of physiology alone are not always sufficient to cause tolerance. The drug-induce change usually needs to be of some significance to the animal." Ex. Amphetamine will cause anorexia (appetite suppression) in rats; this effect will show tolerance when the drug is repeatedly administered to hungry rats in the presence of food. The rats will develop a tolerance to the effect of the drug if there is food present when the drug is administered. If no food is present when the drug is administered, then it doesn't have a change to interfere with the functioning of the organism; thus tolerance to the anorexic effects of amphetamine do not develop. The rat that had food present will eat even if given the drug, the rat that did not have food present will not eat when given the drug. *Cross tolerance:* When tolerance to one drug diminishes the effect of another drug (often happens between two drugs with similar functions or effects---for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. E.g. alcohol and sedatives) Mechanistically, may be pharmacokinetic and/or pharmacodynamic (and/or behavioral) Ex. If you took a lot of one drug, it may cause another drug with a similar effect to not work as well since you've already built-up tolerance for that drug type. *Acute tolerance:* With some drugs and depending on the effect being measured, the drug effect can be greater at a specific blood level during absorption than it is at the same blood level during elimination. Note that: Drug effect at Time A \> Time B, even though drug level is the same. **Withdrawal:** Withdrawal symptoms are physiological changes that occur when the use of a drug is stopped or the dosage is decreased. Different drugs produce different withdrawal symptoms, but drugs of the same family usually produce similar withdrawal. Withdrawal symptoms may vary in intensity from one drug to another. Can be stopped almost instantly by giving the drug that has been discontinued. Often another drug of the same family will also stop withdrawal (phenomenon known as cross dependence). e.g. benzodiazepines (e.g. diazepam \[valium\]) are considered the drugs of choice for the management of all stages of alcohol withdrawal syndrome, including DTs They act on the benzodiazepine-GABA chloride receptor complex, having a similar GABA-potentiating effect as alcohol. **Dependence:** A state in which withdrawal symptom occurs when the drug use stops *Dependence does not imply anything about compulsive drug use, abuse, or addiction* Drug dependence is not addiction---and it matters. Dependence is when the body physically relies on a substance. Addiction involves compulsive, harmful substances use or behaviours. Opponent process theory (3.2 and 3.3, p. 39-40): "The affective (hedonic or emotional) response to a stimulus (a drug in this case) is the underlying a-process, which in turn elicits the opponent b-process. The underlying processes add together to cause the initial pleasant A-state, which is actually experienced, followed by an opponent unpleasant B-state. Initially, the pleasant A-state is large, followed by a small B-state. With repeated drug use and in addiction, however, the opponent b-process increases in magnitude and duration, leading to an experience dominated by the unpleasant symptoms associated with withdrawal." a-state is euphoria, b-state is dysphoria. Withdrawal occurs when we no longer have the drug but we still have the b-state processes working. This is after *physical dependence* has developed. As you take a drug more, it will cause a lesser positive effect, and will often cause a greater negative effect. You need to take the drug to counteract the B-processes. 1. Withdrawal symptoms are usually thought of as expressions of the compensatory adjustments that homeostatic mechanisms have made to the effects of a drug after repeated exposure. 2. With repeated administrations of the drug the body changes it's functioning, and through homeostatic feedback, it compensates for the physiological changes the drug produces. 3. When the drug is discontinued and its effects disappear, it takes some time for the body to readjust to the drug's absence. Environmental stimuli Drug effects on brain Compensatory reaction to drug associated with drug administration Subsequent reactions Environmental stimuli associated with drug administration Compensatory reaction to drug Even without the presence of the drug, the environment can trigger a reaction as if you had taken the drug, making you need to take more drug to feel the effect. When you then take it in a new place without that environmental reaction, there is no conditioned compensatory response, causing an overdose. Environmental stimuli facilitated a tolerance to heroin When environmental stimuli were removed, the rats demonstrated a weaker tolerance for heroin. Repeated administration of a dose causing only behavioral activation will eventually cause stereotyped behaviour. *Brain Mechanisms Responsible for Sensitisation* No single neuronal effect can be responsible, but sensitisation does involve the brains general motivation control system The part of the system that becomes sensitized is the mesocoricolimbic dopamine system (also reinforcing the effects of drugs) **Expectancy and context** *The Placebo Effect:* "Placebo effect: also called the placebo response. A remarkable phenomenon in which a placebo---a fake treatment, an inactive substance like sugar, distilled water, or saline solution---can sometimes improve a patients condition simply because the person has the expectation that it will be helpful. Expectation to plays a potent role in the placebo effect. The more a person believes they are going to benefit from a treatment, the more likely it is that they will experience a benefit." Much of the work on placebo effect has been done studying placebo analgesia (Pain relief response to an inactive substance.) Pain is a complex, multidimensional experience, which causes activity in many brain regions involved with things like attention, feeling emotions such as fear, etc. **Top-Down** processing involves voluntarily engaged higher, global, abstract levels of analysis. Emphasises the observer's prior knowledge, experience, meaning, ad interpretation, as well as expectations in shaping perception. **Bottom-Up** processing is based on the stimuli reaching the receptors. *The placebo effect in medical treatment:*  *Psychosocial context*: The things like past experiences, knowing and trusting the people, knowledge from others you trust, etc. Ex: Hidden vs open application In the hidden application, the medicine is administered by a machine (unbeknownst to the patient). In the open application, the medicine is administered by a physician. The results show that in the open application, the pharmacological effect (level of pain relief) is almost double the amount of the hidden application due to expectancy related (placebo) effect. This is because the patient expects to get pain relief when they know they are being administered pain relief medication, while if they don't know they are receiving pain relief medication, they don't have the expectation that they should be feeling pain relief, so the effect of the medication is not as profound. The placebo effect might result from learning, or it may be the case that expectation alone can result in a placebo effect. Physiologically, the simple answer is that expectations (of pain relief for ex) can cause the body to release natural painkillers, which will then help supress our feelings of pain. In the hidden vs open ex, we can look at how classical conditioning impacts the effects as well. By giving a neutral stimulus like a sugar pill (no response) with an active drug (response) an unconditioned response will occur. After the brain has been trained to associate the sugar pill with the response from the drug, and then the sugar pill will cause the drug response *Expectation:* Ulrike Bingel and coworkers (2011) demonstrated the effect of expectation on painful heat stimulation presented by an electrode on the calf of a persons leg. The heat was adjusted so the subject reported a pain rating of 70, where 0 corresponds to "no pain", and 100 to "unbearable pain". Subjects then rated the pain under four conditions: 1. Baseline, in which a saline solution was presented by infusion 2. No expectation, in which the analgesic drug remifentanil (i.e. short acting synthetic opioid) was presented, but the subject thought they were still receiving saline solution 3. Positive expectation, in which the subjects were told that the drug was being presented 4. Negative expectation, in which the subjects were told that the drug was going to be discontinued in order to investigate the possible increase in pain that would occur. The results: Baseline: Drug (no) pain rating (66) No expectations: Drug (yes) pain rating (55) Positive expectation: Drug (yes) pain rating (39) Negative expectation: Drug (yes) pain rating (64) *The Nocebo Effect:* Phenomenon in which inert substances or mere suggestions of substances actually bring about negative effects in a patient or research participant (presumably psychogenic, but they can induce measurable changes in the body and the brain). For some, being informed of a pill or procedure's potential side effects is enough to bring on real-life symptoms Like the placebo effect, it is still poorly understood and thought to be brough about by a combination of Pavlovian conditioning and a reaction to expectations.