Topic 7: Withdrawal & Tolerance (I) PDF

TOPIC 7 Topic 7: Withdrawal & Tolerance (I) **Diagnostic Definition** We use: Diagnostic & Statistical Manual of Mental Disorders 5th Edition (APA, 2013) -is aHandbook for the standardisation of psychiatric diagnosis & classification Which help: Treatment providers/researchers use to identif...

TOPIC 7 Topic 7: Withdrawal & Tolerance (I) **Diagnostic Definition** We use: Diagnostic & Statistical Manual of Mental Disorders 5th Edition (APA, 2013) -is aHandbook for the standardisation of psychiatric diagnosis & classification Which help: Treatment providers/researchers use to identify individuals who cross the boundary (from 'normality') to be diagnosed with a particular mental disorder Manual is currently in 5^th^ edition and lists Substance Use Disorder: for Alcohol, for sedatives, for cannabis, stimulants, tobacco, hallucinogens, opioids all separately So 11 general substance symptoms of substance use. - Severity ranges from mild to severe (6 or more symptoms) - Tolerance is defined in terms of a need to Increase substance dose to achieve intoxication or desired effect, or diminished effect with the same amount of dose of the substance - Withdrawal: having experienced the characteristic withdrawal syndrome for the substance - The substance (or related substance) is taken to relieve or avoid withdrawal symptoms ex: heroin withdrawal take heroin again to relief symptoms, or alcohol withdrawal keep drinking to avoid those bad symptom **TOLERANCE: RECEPTOR desensitisation AND DOWN-regulation** -neurons need to fire within a certain frequency to remain healthy, if the fire too much frequently or infrequently it dies: neurotoxicity So then, brain cells have various mechanisms to modify their states, balance synaptic communication and firing rate within optimal physiological limits for that particular cell -super optimal states can cause cell death because of 2 things, so Drugs of abuse cause super-optimal states of synaptic communication which can lead to cell death: if the drug acts on inhibitory receptors, the cell will under-fire if the drug acts on excitatory receptors, the cell will over-fire **These both can lead to neurotoxicity/death** There are 2 mechanism that cells employ to protect themselves from super optimal receptor binding resulting from chronic drug exposure: desensitization & down-regulation **Desensitization**: when the number of receptors on the cell membrane remains constant but the associated ion channels because insensitive such that binding to the receptor has no impact on the excitation or inhibition of the cell **Down-regulation:** is where there is a decrease in the number of receptors such that neurotransmitter release or drug presence has less effect on the excitation or inhibition of the cell. **Behavioural Tolerance** -As a result to desensitization and down- regulation in the response to the drug= known as TOLERANCE. \- seen a lot when following chronic drug exposure \- tolerance is classically represented as a shift to the right in the dose-response curve -the shifting to the right means that it reaches to a point and does not go up anymore became a "linear", and a larger dose is required to achieve the same effect, the same dose yields a smaller effect and lower maximum response to the drug because the upper limit of the cells firing rate is capped by desensitization and down-regulation. **Withdrawal** - Can be explain receptor desensitization & down-regulation occur to optimize the level of binding when a drug is chronically present As a consequence, abstinence from the drug will result in the opposite problem: supra-optimal(low) level of binding this supra-optimal binding will occur in the same neurotransmitter systems to which the drug binds so then, withdrawal will produce the opposite responses to acute drug administration. Ex: amphetamine causes people to stay awake for long time, difficulty sleeping, and when is chronic use amphetamine withdrawal the person needs lots of sleep **Withdrawal: Alcohol** Alcohol acts upon various neurotransmitter systems, to collectively produce abroad state of relaxation & euphoria. By contrast, the adaptation to chronic alcohol exposure shows the opposite psychological effects, over-excitation & dysphoria. - ALCOHOL ENHANCES GABA= sedation - Decrease in GABA FUNCTION: agitation excitation -The over-excitation of brain activity resulting from decreased GABA (less inhibition) & increased glutamate (more excitation) following alcohol withdrawal can be life-threatening & neurotoxic in its own right, so treatments for alcohol dependence are increasingly using self-paced alcohol reduction programs to negate these harms prior to full abstinence  -too much inhibition by TOO MUCH GABA we have death or coma as a result, less inhibition caused by glutamate: excited, so seizure and death **Withdrawal: Stimulants** -Stimulants: Amphetamines, meth, cocaine, caffeine, nicotine \- Stimulants: Stimulants increase the activity of DA (dopamine) (key neurotransmitter involved in the brain\'s **reward system)** & 5-HT -serotonin (positive mood) producing a state of motivation, euphoria & confidence during acute (single or short-term use) drug administration. Accordingly, the withdrawal syndrome is marked by a loss of motivation, depression & anxiety. Cocaine withdrawal steps:A diagram of a disease Description automatically generated with medium confidence -Given that stimulants activate mesolimbic DA neurons, withdrawal should be characterized by a decrease in activity in these cells. -Ackerman & White (1992): recorded the number of DA cells within the VTA that were spontaneously active during the recording period. They compared rats that had been withdrawn for 10-14 days following 2 weeks of repeated treatment with either cocaine or saline. -Found: that the number of cells found to be active was reduced by 49% in the cocaine withdrawn rats. -Reduced DA activity thought to contribute to cocaine withdrawal syndrome, in particular, the loss of motivation. \- In humans, withdrawal from meth is similarly marked by a loss of DA activity in the mesolimbic pathway. \- Volkow et al. (2001): meth users underwent brain imaging following 1 and 14 months abstinence. - compared to normal controls, meth abusers showed reduced DA activity at one month abstinence, but showed some recovery by 14 months abstinence. - Also, that the level of recovery was less in meth abusers with a longer history of meth abuse, suggesting a persistent desensitization or down regulation of DA receptors with longer drug use. **Withdrawal: Opiates** -Opiates primarily act on the endorphin & DA systems, to produce analgesia, euphoria & reward. -The withdrawal syndrome is correspondingly characterised by pain, dysphoria & loss of motivation.  -Opiate withdrawal increases rapidly following abstinence peaking around 2 days and then declines. But withdrawal is not fully abated (reduced in intensity/amount) by 10 days post-abstinence.\ Some have suggested that negative mood or depression is a permanent, or very persistent, psychological condition of ex-opiate addicts, presumably resulting from irreversible desensitization or down-regulation of opioid &/or DA receptors. Withdrawal: Cannabis -THC binds to CB1 receptor -Breivogel et al. (1999): pretreated rats with THC for 21 days. Found desensitization (**CB1 receptors** (which respond to THC in the brain) didn't react as strongly as they did before, meaning the brain became **less sensitive** to THC.) and down-regulation (The brain **reduced the number of CB1 receptors**, making it harder for THC to have the same effect as it did at the start) of CB1 in the cerebellum, hippocampus & striatum. As well the S shaped function which relates to the dose of the drug to the amount of receptor binding is both shifted to the right & has a lower maximum (tolerance) so the rates needed higher doses of THC to get the same effect and even with higher doses it wasn't as strong as before =so tolerance -Endocannabinoid system involved in retrograde inhibition of neurotransmission, damping synaptic communication broadly across the brain and creating a sense of calm (**reducing (inhibiting) neurotransmission**), It does this in a **retrograde** way, meaning it sends signals backward (from the receiving cell to the sending cell), telling the brain to calm down. - Withdrawal is marked by anger, anxiety & sleep disturbance. - In heavy marijuana users, withdrawal symptoms last around **27 days**, peaking at 1 week after abstinence A white background with black text Description automatically generated **Withdrawal: Nicotine** -Nicotine primarily acts upon Ach receptors (Ach important for cognitive enhancement) & DA (reward).\ Nicotine withdrawal syndrome is characterised by impaired cognition, depression & anxiety \- Jacobsen et al. (2005): compared smokers & non- smokers' performance on a task (assesses sustained attention & memory). - Smokers performed worse than non-smokers (Consistent with a pre-existing cognitive impairment or toxic damage) - Importantly, abstinence increased this cognitive impairment in smokers, suggesting that nicotine withdrawal is characterised by a cognitive deficit, compared to the acute cognitive enhancing effects of nicotine. So: Nicotine can temporarily improve cognitive performance (like attention and memory) when it's in the system. However, when smokers stop using nicotine (abstinence), their cognitive abilities can get worse compared to when they were smoking. This means that **nicotine withdrawal causes cognitive problems**, such as difficulty focusing or thinking clearly. **Topic 7: Lecture 2** **Conditioned Withdrawal** Abraham Wikler: First to argue that withdrawal represented a significant barrier to abstinence that promotes relapse to drug use - cycle of abstinence-withdrawal-relapse. - articulated this idea with reference to instrumental learning: Addicts learn to perform a particular action (drug use) in order to pre-emptively (doing something in advance) avoid an expected withdrawal syndrome or terminate a current withdrawal syndrome (negative reinforcement). - Recreational drug use maintained by the rewarding properties of the drug (positive reinforcement) - The full state of clinical addiction was driven by the manifestation of withdrawal syndrome and learning to take the drug in order to negate this withdrawal symptom by negative reinforcement -Why does relapse occur after withdrawal when the probability of another withdrawal is unlikely? He says: Wikler argued that environmental cues that predicted withdrawal could come to elicit a conditioned withdrawal state, through the process of Pavlovian conditioning.\ e.g. an addict has undergone withdrawal in a particular environment (e.g. bedroom). That environment (CS) may elicit a conditioned withdrawal state (CR) when encountered in the future, which would motivate a relapse to drug use (via negative reinforcement). Evidence for conditioned withdrawal: O'Brien (1977): studied conditioned withdrawal in opiate addicts maintained on methadone (lower version of heroin). - Baseline: skin temperature measured whilst subjects were placed in a room & injected with saline - Conditioning: subjects were placed in the same room with a sound & a peppermint odour added. They were also Injected with naloxone (opiate antagonist) to produce a withdrawal state (indexed by reduced skin temperature) - Test: subjects were placed in the same room with the sound & peppermint odour, but injected with saline conditioned decrease in skin temperature similar to that produced by naloxone precipitated withdrawal, but this was not seen with saline prior to conditioning suggesting that environmental cues can produce conditioned withdrawal, which may promote relapse. **Conditioned Tolerance** \- One problem for Conditioned Withdrawal as a model of addictive behaviour were anecdotal reports from relapsed addicts which suggested that the cause of their relapse were cues/contexts that were most strongly associated with drug use in the past, not those associated with withdrawal -in order for cues linked to drug use to become conditioned to the withdrawal state, these cues would have to be stored in memory for hours if not days until the withdrawal event occurred long 'trace' conditioning is less effective than short 'delay' conditioning.\ Thus, it seemed unlikely that cues associated with drug use should elicit conditioned withdrawal. So: **Conditioned Withdrawal** suggests that withdrawal symptoms trigger relapse, but **relapsed addicts** often report that their **relapse is triggered by cues** (like places or people) linked to drug use, not withdrawal. For **cues** to trigger withdrawal, they would need to be stored in memory for a long time which is **less effective** than cues being linked immediately to the withdrawal (short-term conditioning). **memories of places or people associated with drug use are more powerful relapse triggers than withdrawal symptoms themselves** **-**Shepard Siegal addressed this criticism & defended the negative reinforcement account by way of the "compensatory response hypothesis" which is built on:\ 1. Solomon & Corbit (1974) Opponent Process Model (Suggests that when we experience a strong effect (like drug use), the body tries to balance it out with an opposite response over time.), and 2. Bernard & Cannon: homeostasis, where the body seeks to maintain an optimal internal state by possessing an array of detectors which detect whether the current internal state is greater or less than a 'set-point' or optimum (The body works to keep things balanced (like temperature or heart rate) by using systems that detect whether things are above or below an optimal state) \- **Siegel** argued that **drugs** mess with the body's natural balance, moving it away from the ideal state (homeostasis). - In response, the body **creates compensatory responses** (like withdrawal symptoms) to try to bring things back to normal. In short, as a person continues using the drug, the positive effects fade, and the negative effects (like withdrawal) become more noticeable. \- body starts **compensating immediately** after the drug is taken to restore balance. - The **"A" process** is the **direct effect** of the drug on the brain, like binding to receptors and causing the initial pleasure (reward). - The **"B" process** is the body's **compensatory response** (like withdrawal symptoms) that tries to correct the imbalance caused by the drug. experienced states: - "A" is the pleasure or reward felt from the drug. - "B" is the withdrawal or negative feeling. Over time, after many exposures, the body's "B" process (withdrawal response) becomes stronger, making the user feel more withdrawal as tolerance builds. \- Siegel suggested that the **growth of the \"B\" process** (the body's compensatory response, like withdrawal symptoms) happens because these responses become **conditioned** to external **cues** (like places or people) linked to drug use. \- **Pavlovian conditioning** means that **certain cues** (like seeing a drug or being in a place where drugs are used) can trigger the body's **drug-opposite response** (like withdrawal symptoms), even without the drug being taken. -The result is that **cues** associated with drug use can cause a **\"conditioned tolerance\"** effect, similar to withdrawal. In short, the body learns to associate drug-related cues with withdrawal, and those cues can trigger withdrawal-like feelings even before the drug is used. **-Siegel\'s argument**: Tolerance to high doses of drugs (like heroin) is influenced by **conditioned compensatory responses**, which are triggered by **drug-associated cues** (like places or environments linked to drug use \- This study shows that **drug-associated cues (contexts)** can trigger a **drug-opposite response**, helping to explain how tolerance and overdose risks are influenced by the environment in which drugs are used. In short, the body learns to adjust to drug use in specific environments, and this can protect against overdose if the drug is used in familiar places. If not used in familiar place: more chance of overdose because of absence of those cues. \-\-\--slide 10\-\-- if I need to come back to it -How Siegel addressed criticisms of the **conditioned withdrawal theory:** **Criticism**: The **conditioned withdrawal theory** was questioned because it suggested that **cues associated with drug use**(like certain places or people) couldn't easily trigger withdrawal symptoms that occur **long after** drug use. **Siegel's contribution**: He showed that **conditioned compensatory responses** (like withdrawal symptoms) don't wait until withdrawal happens much later---they can be triggered **immediately after drug ingestion**. **Example**: When an addict encounters **drug-associated cues** (like a place where they used to use drugs), these cues can **trigger a withdrawal-like state** (an unpleasant, aversive feeling). This **motivates the addict to take the drug** again to relieve this **aversive state** (which is **negative reinforcement**, as they take the drug to get back to a normal state). - **Siegel's framework**: He could explain **relapse caused by drug cues** (when an addict is triggered by places or people associated with drug use) as a way to correct an **uncomfortable state**. The addict uses the drug again to feel better, which fits within a **negative reinforcement framework**. In short, Siegel showed that cues linked to drug use can trigger withdrawal-like feelings immediately, motivating the addict to use the drug again to relieve those feelings, leading to relapse. QUIZ: 1)In the DSM-5, the diagnostic definition of Substance Use Disorder consists of \_\_\_ core symptoms. **a. 11** b. 7 c. 9 d. 13 2\) Neurotoxicity can occur when: a. cells fire too frequently. **b. cells fire both too frequent and too infrequently.** c. cells fire in a balanced manner. d. cells fire too infrequently. 3)\_\_\_\_\_\_\_\_\_ is when there is a decrease in the number of receptors such that neurotransmitter release or drug presence has less effect on the excitation or inhibition of the cell. **a. Down-regulation** b. Withdrawal c. Craving d. Desensitisation 4\) According to research by Budney and colleagues (2004) heavy marijuana users experience withdrawal symptoms that last for around \_\_\_\_ days. a. 3 b. 5 **c. 27** d. 11 5\) Is the following statement True or False: Exposure to environmental cues can produce conditioned withdrawal and promote relapse **A) true** b\) false