DRUGS AND ADDICTION (Chapter 15)
In USA, over 60 million people are addicted to nicotine, alcohol, or both.
About 5.5 million are addicted to illegal drugs, and several millions to prescription drugs.
Psychoctive drugs: Drugs that influence behavior and subjective experience by acting on the nervous system.
(Hormones and neurotransmitters can also act on the nervous system and produce changes in behavior.)
We will refer to drugs that are administered and abused by humans.
Basic Principles of Drug Action.
Drug Administration and Absorption. The route of administration influences the rate at which, and the degree to which, the drug reaches its site of action.
Oral ingestion: easy and safe, but unpredictable: rate depends on presence of foods, etc. Alcohol can be absorved at the level of the stomach
Injection. Used in medical practice because the effects can be large, rapid and predictable. Subcutaneous (SC), intramuscular (IM), or intravenous (IV). However, there is little opportunity to counteract overdoses, impurities in the drug and allergic reactions. There is also damage to veins.
Inhalation. Through the capillaries in the lungs. Some anesthetics, tobacco and marijuana. It is difficult to precisely regulate the dose of drugs, and there can be damage to airways and lungs after chronic use.
Absorption through the mucous membrane, for instance in the mouth, nose (cocaine) or rectum.
Drug Penetration of the Central Nervous System
Drugs eventually reach the blood stream, and from here, to the brain.
Blood brain barrier protects the brain from many blood borne substances.
Mechanism of Drug Action (see FIGURE)
Drugs can act through many mechanisms, and often these are not very well-understood. For instance:
By binding to some receptors,
By influencing the synthesis, transport, release, or deactivation of neurotransmitters.
Although some drugs are specific, most drugs influence brain activity in more than one way.
Drug Metabolism and Elimination
Why does the effect of a drug stop?
Drug metabolism: The drug can be metabolized, that is, it is transformed by the effect of enzymes synthetized in the liver.
Some drugs can be eliminated through the urine, feces, sweat, breath, and mother's milk.
Drug Tolerance. Decreased sensitivity to a drug that develops as a result of exposure to it.
There is a shift in the dose-response curve. More drug is needed to produce the same effect (Fig. 15.1).
Development of tolerance is not necessarily specific to the drug that induces it, or to all of its effects.
1. Tolerance to one drug may cause tolerance to other drugs that have similar mechanisms of action (cross tolerance).
2. There can be tolerance to some effects of one drug but not to other effects of the same drug. Sometimes, sensitivity to other effects of the same drug increases, a phenomenon called drug sensitization. This can be dangerous.
3.Tolerance can be Metabolic or Functional.
Metabolic Tolerance occurs when the amount of drug reaching the sites of action decreases.
Functional Tolerence occurs when there is a reduction in the reactivity of the sites of action to the drug.
Tolerance to psychoactive drugs is mainly Functional. For instance, there can be a reduction in the receptors to the drug, or less binding of the drug to cell receptors, or less effect on the cells.
Drug Withdrawal Effects and and Physical dependence.
Withdrawal syndrome: Set of clinical symptoms that develops when there is a sudden drop in the blood levels of certain drugs. They can be quite serious in some cases.
The symptoms are often the opposite to the initial effects of the drug.
For example, if the drug is an anticonvulsant (it prevents convulsions), withdrawal of the drug may cause convulsions.
Individuals who suffer withdrawal syndromes when they stop taking a drug are said to be physically dependent on that drug.
It is thought that withdrawal effects are produced by the same neural changes in the nervous system that offset the drug's effects and produce tolerance (Fig. 15.2).
ADDICTION: WHAT IS IT?
Not all habitual drug users are addicts. Addicts are those that are incapable of stopping the use of a certain drug despite the adverse effects that the drug habit has on the person's health and social life, and despite the addict's repeated efforts to stop the use of drugs.
Addiction is not merely caused by physical dependence (withdrawal symptoms) because even when the withdrawal symptoms end, the addict will often take the drug again.
Role of Learning in Drug Tolerance and Drug Withdrawal.
Contingent Drug Tolerance occurs when tolerance develops only to drugs whose effects are actually experienced.
Example: tolerance develops when alcohol is injected so that it prevents subsequent convulsions, but not when convulsions occur before the alcohol administration (alcohol would not have a chance to act as anticonvulsant). (Fig. 15.3).
Conditioned Drug Tolerance: tolerance effects are maximally expressed only when a drug is administered in the habitual conditions. There is less tolerance in novel conditions.
For instance, tolerance that develops in one environment may not be present in a novel environment. Danger of overdose in a motel for somebody that developed tolerance at home.
Siegel proposes that each incidence of drug administration is a Pavlovian conditioning trial. The constant environmental stimuli that predict when the drug will be administered (e.g., a certain room) are the conditional stimuli, and the drug effects are the unconditional stimuli.
The conditional stimuli (predict drug use) would elicit conditioned compensatory responses, which would oppose the effects of the unconditional stimuli (the drug effects).
This opposition would cause situationally specific drug tolerance (Fig. 15.4).
Conditioned Withdrawal Effects are the effects that are elicited by the drug environment or by other drug-associated cues.
For instance, a drug user is in the room that is used for drug administration, but no drug is available. The effects would be opposite to those produced by the drug.
(Note: the section Five Commonly Used Drugs (page 379-388) is covered further below.
BIOPSYCHOLOGICAL THEORIES OF ADDICTION
Are addicts driven by internal need? Or, are they driven by anticipated pleasure?
Physical-Dependence and Positive-Insentive Perspectives of Addiction.
Physical-Dependence Theory of Addiction.
Initially it was thought that drug addiction was related to physical dependence. Addicts would be driven by their withdrawal symptoms to self-administer the drug.
Addicts would be trapped in a vicious circle of drug taking and withdrawal symptoms.
Treatment: gradual withdrawing drugs in hospital environment. Unfortunately, after being detoxified, most addicts go back to drugs.
Detoxified addicts are addicts who have no drugs in their bodies and no longer experience withdrawal symptoms.
Relapse of detoxified addicts is no surpring because:
-some drugs like cocaine and anphetamines do not cause severe withdrawal symptoms
-some addicts go through cycles of binges and detoxification because of working schedules, lack of money, jail time, etc.
Positive-Incentive Theories of Addiction. Failure of physical-dependence theories have focused attention on positive-incentive theories.
According to positive-incentive theories, the users of drug seek the pleasure-producing effects of drugs.
e.g., one addict would need $25 to get rid of withdrawal symptoms, yet he would use all his money for drugs: “I like drugs better than anything else, including sex”.
Some pleasurable effects could be indirect, like disinhibition: e.g., effect of alcohol in single bars.
It has been proposed that the positive-incentive value of addictive drugs increases with use.
-tolerance develops for aversive effects rather than pleasurable effects
-drug sensitizes their positive incentive value, leading to increased motivation to use drug.
The positive-incentive value may appear out of proportion with the the pleasure actually derived from it: addicts are miserable, in ruins, and the drug effects are not that great anymore, but they stilll crave the drug.
Most evidence suggests that the positive-incentive value of addictive drugs is the primary factor in addiction.
Causes of Relapse.
Relapse is common, and the following reasons contribute to this:
1. Stress. For instance, cigarette and alcohol consumption increased after Sept 11th.
2. Priming. Trying the formerly abused drug brings full blown addiction.
3. Exposure to environmental cues associated with previous drug use.
Intracraneal Self-Stimulation and the Pleasure Centers of the Brain.
Reward circuits in the brain.
Pioneer research by James Olds and Peter Milner in 1954 showed that rats preferred corners at which shock were delivered in certain brain regions.
Intracranial self-stimulation. Animals including humans press lever to deliver electric pulses to self-stimulate pleasure centers (FIG. 15.6).
Olds and Milner proposed that the brain sites mediating self-stimulation are the same that normally mediate the effects of natural rewards, including food, water and sex.
These pleasure centers are now believed to mediate the experience of pleasure mediated by drugs, raising the possibility that these centers play a major role in addiction.
Fundamental Characteristics of Intracranial Self-stimulation.
Most early studies used lateral hypothalamic and septal stimulation because rats can be induced to press a lever thousands of times per hour, stopping only after they are exhausted. However, many other structures have been identified.
At first, some puzzling observations suggested that lever pressing after lateral hypothalamic and septal stimulation was different than pressing for natural rewards (food, water, sex, etc):
-The instant that electrical pulses were stopped, rats stopped pressing the lever immediately, not gradually , showing a rapid rate of extinction (if bills were delivered by pressing a lever, one would not stop immediately after a few failures).
-After stopping stimulating, rats would not immediately start after being returned to the cage; the operator had to get them started again (priming).
However, further research has revealed that pleasure centers mediating self-stimulation are related to natural reward circuits:
1. Brain stimulation through electrodes that mediate self-stimulation often leads to natural motivated behaviors if the appropriate objects are present: food, water, etc.
2. Increasing natural motivation by, for example, food or water deprivation ofen increases the rate of electrical self-stimulation.
3. Confounding experimental factors were addressed.
For instance, rats that pressed a lever for intracraneal sel-stimulation were not deprived, while those that pressed a lever for natural rewards (food pellets, water drops) were deprived.
When experimental confounds were removed, the major differences between lever pressing for food or water and lever pressing for self-stimulation disappeared.
For instance, nondeprived rats which had chocolate delivered to their mouths by a lever learned to press just like when electrical stimulation was used (fast onset, rapid extinction, and showed a priming effect).
THE MESOTELENCEPHALIC DOPAMINE SYSTEM AND INTRACRANIAL SELF-STIMULATION
The mesotelencephalic dopamine system is a system of dopaminergic neurons that projects from the mesencephalon (midbrain) into various regions of the telencephalon (Fig. 15.7).
These neurons are in the substantia nigra and ventral tegmental area (midbrain), and project to a variety of telencephalic sites including the striatum (basal ganglia), portions of the frontal cortex, limbic cortex, the olfactory tubercle, the amigdala, the septum and the nucleus accumbens (Fig. 15.7).
The substantia nigra projects mainly to the dorsal striatum (nigrostriatal pathway), and degeneration of this pathway is associated with Parkinson's Disease, as we saw earlier.
The projection from the ventral tegmental area to various cortical and limbic sites is called the mesocorticolimbic pathway.
The projection from neurons in the ventral tegmental area to the nucleus accumbens (FIG. 15.7) has been most often implicated in the rewarding effects of brain stimulation, natural rewards, and addictive drugs.
Evidence that the mesotelencephalic dopamine system plays an important role in intracranial self-stimulation.
1) Mappig studies: Many sites at which self-stimulation occurs are part of the mesotelencephalic dopamine system. Other sites that do not contain a lot of dopamine project directly to nuclei of the dopamine system.
2) Cerebral dialysis studies: samples of extracellular fluids are collected for about 15 min and analyzed chemically. Self-stimulation is associated with an increase in dopamine release (Fig. 15.8).
3) Dopamine agonist and antagonist studies have revealed that agonists tend to increase intracraneal self-stimulation, while dopamine antagonists tend to decrease self-stimulation.
4) Lesion studies: lesions of the mesotelencephalic dopamine system disrupts self-stimulation. One side was used as control. Lesions in one side reduced self stimulation to electrical pulses in that side but not to stimulation of the other side.
Neural Mechanisms of Motivation and Addiction
Brain mechanisms did not evolve to mediate addiction. The idea that the mesocorticolimbic pathway is involved in drug addiction is supported by:
1. Evidence that the pleasurable effects of drugs, rather than the alleviation of withdrawal symptoms, are the major factors in addiction.
2. Evidence that the mesocorticolimbic pathway plays an important role in intracraneal self-stimulation.
3. Evidence that the mesocorticolimbic pathway is involved in the effects of natural rewards (food, water, sex, etc).
Current research aims at understanding how addictive drugs use the natural reward systems resulting in addiction.
Two Key Methods for Measuring Drug-Produced Reinforcement.
Two behavioral paradigms have been used in experimental animals.
1. Drug self-administration. Rat presses lever to self-inject drug through implanted cannulas.
Cannulas can be intravenous or they can deliver drug directly into brain structures.
The rat's drug-taking habits mimic in many ways the drug taking of human addicts.
2. Conditioned place preferences (Fig. 15.9).
In a box made of two different, but equal-sized compartments, rats repeatedly receive drug in only one of the compartments.
When rats are drug-free, their preference to either of the two compartments is measured.
Rats prefer the compartment associated with the drug administration.
Early Evidence of the Involvement of Dopamine in Drug Addiction
Experiments in the 1970's suggest that dopamine signals something related to reward value or pleasure:
Dopamine antagonists blocked the self-administration of, or conditioned preference for, several different addictive drugs.
Dopamine antagonists also reduced the reinforcing effect of food.
The Nucleus Accumbens and Drug Addiction. Evidence suggesting a role of the nucleus accumbens in addiction:
1) Animals self-administer microinjections of addictive drugs (e.g., cocaine, amphetamine and morphine) directly into the nucleus accumbens.
2) Microinjections of addictive drugs into the nucleus accumbens produced a conditioned place preference for the compartment in which they were administered.
3) Lesions to either the nucleus accumbens or the ventral tegmental area blocked the self-administration of drugs into general circulation or the development of drug-associated conditioned place preferences.
4) Both the self-administration of addictive drugs and the experience of natural reinforcers were found to be associated with elevated levels of extracellular dopamine in the nucleus accumbens.
Support for the Involvement of Dopamine in Addiction: Evidence from Imaging Human Brains.
Imaging techniques for meaqsuring dopamine suggest that dopamine is involved in human reward and in addiction.
It was observed that cocaine exerts an agonist effect on dopamine. Cocaine blocks the reuptake of dopamine by dopamine transporters that are located in the presynaptic terminal.
This leads to an increase of dopamine in the synaptic cleft.
The intensity of the "highs" experienced by the addicts was correlated with the degree to which radioactively labeled cocaine bound to the dopamine transporters. Binding to more than 50% of dopamine transporters was required to experience a high.
In nonaddicts, increased levels of dopamine in the nucleus accumbens caused by IV injections of amphetamine are associated with an increase in their experience of euphoria.
Dopamine, Nucleus Accumbens, and Addiction: Current View.
It is not clear how the release of dopamine in the nucleus accumbens relates to the experience of reward.
Studies of the activity of dopaminergic neurons in the ventral tegmental area (which projects to the n. accumbens) have shown that these neurons responded to rewards only when the rewards were presented unpredictably, as in the early stages of a conditioning experiments.
On the other hand, if a reward was expected, as in the late stages of a conditioning experiment, the reward itself did not increase the activity of dopaminergic neurons, but the conditional stimulus that predicted the reward did.
Thus, it appears that dopamine is involved in the expectation of reward, rather than the reward itself.
In addition to the nucleus accumbens, other nuclei of the mesotelencephalic dopamine system (Fig. 15.8) are thought to be involved in reward.
In fact, lesions of the n. accumbens have failed to block the relapse in opiate addicts, confirming that other structures play a role in addiction.
In addition of dopamine, other neurotransmitters may also be involved in reward.
This idea is supported by the observation that mice lacking dopamine are capable of being rewarded by sweet solutions.
What can be done for addicts?
Perhaps one possibility will be to develop selective dopamine antagonists that reduce the positive-incentive value of drugs in addicts without reducing the positive-incentive value of natural motivated behaviors.
GROUPS OF PSYCHOACTIVE DRUGS
1. Depressants: Alcohol, barbiturates, benzodiazepines (Valium). Increase binding of GABA.
2. Stimulants: Amphetamine, cocaine. Increase action of dopamine, norepinephrine.
3. Opiates (pain relief, euphoria): These drugs mimic effect of neurotransmitter.
From plants: opium (opium poppy), morphine, codeine.
Synthetic: Mepiridine (Demerol), methadone.
4. Psychedelics (alter conciousness). LSD, marijuana. Mimic effect of neurotransmitter.
5. Antipsychotics.
1.- Antischizophrenics: Phenotiazines (Chlorpromazine). Block dopamine.
2. Antidepressants: MAO inhibitors, tricyclic antidepressants. Increase action of monoamines such as serotonin (an indolamine) and norepinephrine (a catecholamine).
FIVE COMMONLY ABUSED DRUGS
1.- TOBACCO. Next to caffeine (in coffee, Coca-cola), tobacco is the most widely used psychoactive drug.
Nicotine is the major psychoactive ingredient of tobacco, but other chemicals, including carbon monoxide are also inhaled when smoking. Nicotine stimulates ACh receptors (nicotinic ACh receptors).
Smoking causes addiction. Many people find it impossible to quit smoking, even when the are fully aware of the negative effects of smoking.
About 70% of people who experiment with tobacco become addicted, compared with 10% for alcohol, and 30% for heroin.
Only 20% of attempts to stop smoking are successful for two years of more.
Twin studies indicate that the heritability estimate for nicotine addiction is about 65%.
Tobacco is responsible for about 450,000 death each year in USA.
Long-term effects of tobacco use:
Smoker's syndrome:
-chest pain
-labored breathing
-wheezing
-coughing
-higher susceptibility to infections of the respiratory tract:
-pneumonia
-bronchitis
-emphysema
-Increased risks for cancers of the lungs, larynx, mouth, esophagus, kidneys, bladder, pancreas and stomach.
-Circulatory problems: Heart attacks and strokes (brain hemorrages).
Buerger's Disease:
Blodd vessel, specially in the leg, are constricted when nicotine is present in the blood. It can lead to gangrene (necrosis or tissue death) and amputation.
Second-hand smoke may also increase the chances for cancer and heart disease.
Pregnancy: Smoking can cause miscarriage, stillbirth or early death of the newborn.
Breast-fed infants can also suffer because their blood level of nicotine can be as high as that of a smoking mother.
2. ALCOHOL
About 100,000 die each year in USA from alcohol-related diseases and accidents.
Ethyl alcohol is a depressant, but at low doses it can be a mild stimulant, inducing feelings of well-being, and facilitating social interaction.
The heritability estimates for alcohol addiction are about 55%.
Effects of acute alcohol blood levels:
Moderate doses: impairment of motor, cognitive, perceptual, and verbal abilities.
High doses cause unconsciousness. At levels of 0.5% there is risk of death from respiratory depression.
Alcohol use may result in hypothermia (decrease in body temperature) due to dilation of blood vessels in the skin (facial flush)
Alcohol is a diuretic: increases the amount of urine.
Alcohol produces tolerance and physical dependence (mostly functional)
Withdrawal Syndrome:
5-6 hours after cessation of heavy drinking, severe tremors, agitation, headache, nausea, vomiting, abdominal cramps, sweating and hallucinations occur.
15-30 hours after cessation drinking, convulsions are added.
2 days after the cessation of drinking, delirium tremens (the DTs) occurs: hallucinations, delusions, agitation, confusion, hyperthermia and tachycardia. This status can be lethal.
Effects of chronic alcohol consumption:
Korsakoff's syndrome:
-memory loss
-sensory and motor dysfunction,
-dementia (intellectual deterioration), associated with extensive brain damage
-cirrhosis of the liver (scarring)
-ulcers-gastritis
-increases risk of cancer of the mouth and liver
Fetal Alcohol Syndrome (FAS). Alcohol readily penetrates the placental membrane and affect the fetus. It can produce:
-mental retardation
-poor coordination
-poor muscle tone
-low weight
-retarded growth
-physical deformities.
3. MARIJUANA
The name Marijuana refers to the dry leave and flower of the plant Cannabis sativa.
Consumption is commonly in the form of joints or brownies.
Active component is delta-9-tetrahydrocannabinol (delta-9-THC), and this, as well as some 80 other cannabinoids (of the same chemical class as THC), act on cannabinoid receptor 1 (CB1).
Most of the cannabonoids are in the sticky resin that covers the stems and leaves. This resin can be extracted and dried to produce hashish, and can be further processed into hash oil, which is quite potent.
Effects of marijuana are milder than alcohol and there are efforts to legalize in some states.
However, although drivers intoxicated with marijuana can stop as quickly as normal drivers, they may not notice the things for which they should stop.
High doses of marijuana can impair psychological functioning, motor function, short term memory, and the ability nto carry out complex tasks. Speech may become blurred.
The effects may also include a sense of unreality, emotional intensification, sensory distortion and lack of motivation
Marijuana use presents low risk of addiction, compared to other drugs.
Hazards of long-term use:
-lung damage, chronic bronchitis, cough and asthma.
-marijuana can also cause tachycardia (elevated heart rate), which as been associated with heart attacks in susceptible individuals
Potential benefitial effects: in cancer patients, it stops nausea caused by chemotherapy. Also useful in glaucoma (increase of pressure inside the eye), and to stimulate the appetite of patients.
Mechanisms of action: delta-9-THC binds to receptors in the basal ganglia, hippocampus, cerebellum and neocortex, but is its not yet clear what these receptors do.
An endogenous THC-like chemical that binds to THC receptors has been named anandamide which means “internal bliss”.
4. COCAINE AND OTHER STIMULANTS
Prepared from the coca bush found primarily in Peru and Bolivia. The white powder produced is called cocaine hydrochloride. Crack is an impure product that is cheaper to produce than cocaine.
Cocaine and its derivatives are the most commonly abused stimulants.
Cocaine induces a sense of well-being, self-confidence, being alert, energetic, friendly, outgoing, talkative, etc
Cocaine sprees or binges (lasting a day or two) can be associated with cocaine psychosis, a syndrome characterized by psychotic behavior that is similar to paranoid schizophrenia.
Cocaine sprees are often followed by lethargy and depression.
Overdose can cause death from respiratory arrest or stroke.
Cocaine snorting can damage the nasal membranes, and cocaine smoking can damage the lungs. Fatalities are usually associated with IV use.
Cocaine is very addictive, but with little withdrawal symptoms.
Mechanism of action. Cocaine blocks the reuptake of catecholamines (dopamine, norepinephrine, and epinephrine) into the presynaptic terminals, leading to an increase of these transmitters in the synaptic cleft.
Increases of dopamine in the synaptic cleft appear to mediate the euphoria-inducing effects of cocaine.
OTHER STIMULANTS.
Amphetamine (speed)
The effects of d-amphetamine (dextroamphetamine) are comparable to those of cocaine. For example, d-amphetamine induces a syndrome called amphetamine psychosis.
More potents forms of amphetamine are methamphetamine (meth), and the crystalline form of methamphetamine.
Another potent relative of amphetamine is 3,4-methyl-enedioxymethamphetamine (MDMA, or ecstasy) which is taken orally. Commonly used in "raves".
Stimulants are considered to be neurotoxins which damage the brain.
For instance, experimental evidence that MDMA (ecstasy) can have toxic effects on both serotonergic and dopaminergic neurons.
Studies in humans support the idea that MDMA can cause brain damage. Abnormalities include deficits in memory, psychomotor fuction and mood.
5. OPIATES: HEROIN AND MORPHINE
Opium is the sap from the seeds of the opium poppy. It has several psychoactive ingredients called opiates, including morphine, codeine and heroin.
These drugs are excellent analgesics, but have tremendous risk of addiction.
The direct hazards of chronic exposure are surprinsingly minor, including constipation, pupil constriction, menstrual irregularities, and reduced sex drive (libido).
The withdrawal symptons usually begin after 6-12 hours after the last dose.
In addition to nausea, vomiting, diarrhea, cramps, tremors, etc, they include gooseflesh and leg spasms (kicking), symptoms that are the basis for the expressions "going cold turkey" and "kicking the habit"
By the senventh day the withdrawal symptoms dissapear.
Opiates cause few direct health problems. The main risks are indirect, specially in the poor: undernourishment, prostitution, AIDS, and death by overdose.
The endogeneous chemicals that bind to opiate receptors are called endorphins, and there are at least 20 different kinds of endorphins.
Treatment for heroin addiction.
Methadona, another opiate that produces less pleasure than heroin, has been used for replacement therapy, with little results.
Buprenorphine has a high and long lasting affinity for opiate receptors and therefore blocks the effects of other opiates, without producing their euphoric effects. It appears to be a promising treatment.
Comparison of the Hazards of Tobacco, Alcohol, Marijuana, Cocaine and Heroin.
Tobacco and alcohol have the greatest impact (Fig. 15.5).
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