Chapter 13 -- Drug Action and Addiction

- 60 million people in the USA alone are addicted to alcohol, nicotine or both; 5.5 million are addicted to illegal drugs and millions to legal pharmaceuticals

- it is important to note at the outset that the legal status of a drug says nothing about its safety or the health risks associated with it…for the most part, a drug's legal status was determined before we knew much about the risks associated with it

- ingestion; swallowing drugs is convenient but a major drawback is that the timing and magnitude of the drug effects are greatly influenced by food in the stomach; some drugs are deactivated before they can be absorbed from the digestive tract and thus cannot be administered by this route; most drugs are absorbed from the small intenstine, but those with small molecules (e.g., alcohol) can be absorbed through the stomach wall, and thus they act more rapidly

- inhalation; many inhaled chemicals are absorbed directly into the bloodstream from the lungs (e.g., chemicals in tobacco and marijuana smoke); lung damage is a serious risk from the repeated inhalation of chemicals

- mucous membranes; some drugs (e.g., cocaine) are readily absorbed through the mucous membranes of the nose, mouth, or rectum; this method of administration is problematic as these membranes can be easily damaged

- injection; SC, IM, or IV; addicts typically favor the IV route, which is particularly dangerous; because it is fast and direct, there is a risk of death from overdose, impure drugs, or allergic reactions; there are only a few sites on the body appropriate for IV injection, thus addicts frequently develop infections and scar tissue at these sites

- in order to produce psychoactive effects, drugs must enter the nervous system; fortunately, many drugs that are potentially dangerous neurotoxins do not readily penetrate the neurons of the CNS due to the blood-brain barrier; it is mediated by the particularly small pores in the walls of CNS blood vessels

- once a psychoactive drug has penetrated the CNS, it can influence neural activity in numerous ways; e.g., it can act diffusely on neural membranes or interact specifically with particular classes of neurotransmitters and receptors

- the effects of psychoactive drugs are terminated by their metabolism, i.e., by their conversion to nonactive metabolites; most drugs are metabolized by liver enzymes; only small amounts of unmetabolized active drugs are eliminated in sweat, breath, urine, etc.

- tolerance can be measured in two ways: (1) by measuring the decrease in the response elicited by the same dose of the drug, or (2) by measuring the increase in the amount of drug required to produce the same effect; in effect, drug tolerance is a shift in the dose-response curve to the right

- tolerance to most psychoactive drugs is primarily functional; an important thing to remember about functional tolerance is that it often develops for some effects of a drug but not others

- this specificity is difficult to explain in terms of the traditional idea that tolerance development is influenced entirely by drug-exposure-related variables such as the route, the dose, and the frequency of drug administration

- this drug-exposure view of tolerance has been seriously undermined by two different lines of psychopharmacological research: (1) contingent tolerance research has focused on the role of the subjects' behavior during drug exposure on the development of tolerance, and (2) conditioned tolerance research has focused on the role of the environment in which the drug is administered on the development of tolerance

- contingent drug tolerance is any drug-tolerance effect that is contingent on the occurrence of a particular experience or behavior while the subject is under the influence of the drug; it is usually demonstrated by before-and-after experiments

- in before-and-after experiments, the subjects in one condition (the drug-before-test condition) are tested after each injection so that they repeatedly experience the effect of the drug on the test behavior; the subjects in the other condition (the drug-after-test condition) are tested before each injection so that they do not repeatedly experience the drug's effect on the test behavior

- the typical finding in such experiments is that tolerance is substantially greater in the drug-before-test condition than in the drug-after-test condition

- During the tolerance-development phase of this experiment, the rats in one group received an alcohol injection once every 48 hours, 1 hour before a convulsive amygdala stimulation, thus they repeatedly experienced alcohol's anticonvulsant effect; the rats in the other group received alcohol injections on the same bi-daily schedule, but 1 hour after each convulsive stimulation, thus they never experienced alcohol's anticonvulsant effect; on the test day, only the rats in the alcohol-before-stimulation group were tolerant to alcohol's anticonvulsant effect

- the numerous reports of various contingent tolerance effects supports the idea that functional drug tolerance is an adaptation to the drug's effects on ongoing neural activity, rather than to the mere exposure of the nervous system to the drug; for example, it is the experience of alcohol's anticonvulsant effect that leads to the development of tolerance to it, not the mere exposure to alcohol

- conditioned drug tolerance refers to any tolerance effect that develops only in the presence of drug-predictive stimuli; the main support for the idea that drug tolerance can be conditioned comes from demonstrations of situationally specific tolerance

- for example; Crowell, Hinson, and Siegel (1981) demonstrated conditioned tolerance to the hypothermic effect of alcohol (Digital Image Archive Figure CH13F05.BMP). In this study, two groups of rats received 20 alcohol injections and 20 saline injections in alternating sequence, one every 48 hours; the only difference between the two groups was that the rats in one group always received their alcohol in a distinctive test room and their saline in their colony room, whereas the rats in the other group received their saline in the test room and their alcohol in the colony room; remarkably, tolerance to the hypothermic effect of alcohol was revealed only when the subjects were tested in the same environment in which they had previously received alcohol

- according to Siegel, Hinson, Krank, and McCully (1982), addicts develop tolerance to drug effects repeatedly experienced in the same environment and consequently start taking more of the drug, but when they take the elevated dose in a novel environment in which they are not tolerant, they run the risk of a drug overdose; in support of this hypothesis, Siegel et al. showed that rats were more susceptible to the lethal effects of a heroin overdose if they received the injection in an environment different from that in which they had experienced the effects of previous drug injections

- one theory of the situational specificity of tolerance is Siegel's conditioned compensatory response theory; Siegel proposed that each incidence of drug administration is like a Pavlovian conditioning trial; the drug effect is the UCS, which is preceded on each trial by the drug-environment CS; as the conditioning occurs, the drug-environment CS begins to elicit CRs that are opposite to the effects of the drug; these conditioned compensatory responses--as Siegel termed them--offset the effects of the drug, and tolerance is the consequence

- in support of this theory, several experiments have shown that drug tolerance can be extinguished by repeatedly presenting the drug-predictive environment, without the drug

- after large amounts of a drug have been in the body more or less continuously for a day or two, its sudden elimination can lead to withdrawal symptoms, which are typically opposite to the effects of the drug (e.g., anticonvulsant drugs such as alcohol and barbiturates typically induce epileptic withdrawal effects and sleeping pills typically induce insomnia if they are suddenly withdrawn)

- tolerance and withdrawal are thought to be different manifestations of the same underlying physiological change (Digital Image Archive Figure CH13F03.BMP); when the drug is removed, the drug-offsetting physiological changes that are the basis of tolerance, are no longer held in check by the drug, and withdrawal symptoms opposite to the original effects of the drug are the result

- not all drug users are addicts; addicts are drug users who habitually use a drug despite their efforts to stop and despite its adverse effects on their health and social life

- individuals who display withdrawal symptoms if their drug are withheld are said to be physically dependent; most people think that only hard-core addicts are physically dependent, but if you have experienced a hangover, you have been physically dependent on alcohol; a hangover is a mild alcohol withdrawal syndrome

- early theories attributed drug addiction to physical dependence; the addict was seen as someone trapped by the need to keep taking the drug to prevent withdrawal symptoms; thus, early treatment programs were based on the idea that addicts could be cured by hospitalizing them until all of the drug was out of their system and all of their withdrawal effects had subsided

- however, this approach has proven to be almost totally ineffective; it is now clear that addicts are motivated to take their drug even after they have been detoxified; addiction in the absence of physical dependence is sometimes referred to as psychological dependence; by this definition, every addict displays substantial psychological dependence

- research is now focused on addicts who are motivated primarily by the anticipated pleasurable effects of their drugs; this view of addiction is called the positive-incentive theory. According to the positive-incentive theory of drug addiction (which is similar to the positive-incentive theory of feeding that you have already encountered), drugs may sometimes be taken to avoid withdrawal symptoms but it is much more often the case that they are ingested because the addict is seeking their pleasurable consequences. This idea will be explored more fully in the next lecture.

An interview with Dr. Steven Hyman and Dr. Howard Shaffer on the neural bases of addiction; from Harvard University's Mahoney Neuroscience Institute. See also:

- Tobacco is used more than any other drug except caffeine; usually inhaled or absorbed through oral mucosa; nicotine is the major psychoactive ingredient; 4,000 other known chemicals are in tobacco; tobacco is highly addictive (e.g., patients with Buerger's disease will still smoke, even after their limbs are amputated); effects ranging from nausea to relaxation; consequences of smoking range from coughing to failure of the cardiorespiratory system to cancer

- Alcohol is consumed by 66% of the US population and 15 million are addicted; orally ingested; at most doses it is a depressant resulting in impaired function and is implicated in almost 50% of traffic fatalities; is believed to act primarily at the GABA-A receptor complex; alcohol is a small molecule and thus crosses the blood-brain barrier resulting in brain damage such as seen in Korsakoff's syndrome; alcohol also crosses the placenta and can result in birth defects such as Fetal Alcohol Syndrome. Very severe withdrawal effects; delerium tremens represent the 3rd stage of withdrawal, and may be lethal.

- Marijuana elicits psychoactive responses largely due to THC; may be inhaled or ingested orally (usually baked into an oil-rich substrate to aid absorption); act at THC receptors throughout the brain; effects range from craving sweets to very relaxed states to periods of impaired judgement and short-term memory impairment; a possible negative consequence is lung damage due to inhaling the drug; clinically, marijuana has been shown to block the nausea of cancer drugs, stimulate appetite, and decrease the severity of glaucoma

- Cocaine and other stimulants have the same general effect, but differ greatly in their potency; may be inhaled, absorbed across mucosal membranes, or ingested orally; cocaine is very addictive; it acts by blocking catecholamine reuptake; it is a general stimulant, producing a feeling of energy, well-being, and self-confidence; extremely high doses can lead to cocaine psychosis characterized by sleeplessness, nausea, restlessness and psychotic behavior. Very high doses can produce stroke, seizures, and respiratory arrest; withdrawal symptoms are mild. Clinically, cocaine derivatives are effective as local anesthetics

- Opiates include morphine and heroin; these are unmatched as analgesics and are very addictive; act at receptors for endogenous opiate neurotransmitters that are located throughout the brain; elicits moderately severe withdrawal symptoms but these are not lethal; over 2 million Americans use heroin to experience a rush of pleasure and drowsy euphoria; tolerance leads to an ever greater use of the drug which has many crime implications; outside of IV transmitted diseases and problems, very few health risks are seen in users

- the failure of this treatment approach is not surprising in the light of two well-established facts about drug taking: (1) some highly addictive drugs produce little withdrawal distress (e.g., cocaine), (2) the pattern of drug taking in many addicts typically involves self-imposed cycles of binges and detoxification

- modern physical-dependence theories of addiction attempt to account for the inevitability of relapse after detoxification by postulating that withdrawal effects can be conditioned; there are two problems with this theory: (1) many of the conditioned effects elicited by drug-taking environments are similar to the effects of the drug, not to the drug's withdrawal effects; (2) addicts and experimental animals often find drug-related cues rewarding, even in the absence of the drug (e.g., needle freaks enjoy sticking empty hypodermic needles in their arms)

- the failings of physical-dependence theories have lent support to positive-incentive theories; according to positive-incentive theories of addiction, most addicts take drugs to obtain their pleasurable effects rather than to escape their aversive aftereffects

- Robinson and Berridge (1993) have suggested that the expectation of the pleasurable effects of drugs may become sensitized in addicts; a key point of this incentive-sensitization theory is that addicts don't receive more pleasure from the drug, it is the anticipated pleasure that motivates their behavior.

- the positive-incentive theories of addiction led investigators interested in the physiological bases of addiction to consider what was known about the physiological systems in the brain that subserve the experience of pleasure and reward

- since the early 1950s, the physiological bases of pleasure have been investigated by studying the rewarding effects of electrical stimulation to various parts of the brain; these rewarding effects are measured by determining the degree to which rats will press a lever to deliver electrical stimulation to certain areas of their own brains (the intracranial self-stimulation paradigm)

- although animals self-stimulate a variety of brain structures, most studies in the 1950s and 1960s focused on the septum and lateral hypothalamus because the self-stimulation rates at these sites are impressively high

- early studies suggested that lever pressing for brain stimulation was fundamentally different from lever pressing for food or water; ICSS was often characterized by (1) extremely high response rates, (2) rapid extinction, and (3) priming; these and other differences appeared to discredit Olds and Milner's original premise that animals self-stimulate sites that activate natural reward circuits (e.g., circuits that normally mediate the rewarding effects of food, water, sex, etc.)

(1) in the presence of the appropriate goal objects, stimulation at positive self-stimulation sites often elicits natural motivated behaviors such as eating, drinking, and copulation;

(3) self-stimulation at sites other than the septum and lateral hypothalamus is frequently similar to lever pressing for natural reinforcers (e.g., slower response rates, slower extinction, no priming); and

(4) subtle differences between the paradigm used to assess lever pressing for natural reinforcers and the paradigm used to assess lever pressing for brain stimulation contributed to the impression that the rewarding effects of brain stimulation and those of natural reinforcers were fundamentally different

- Panksepp and Trowill (1967) pointed out that in contrast to rats' lever pressing for food, self-stimulating rats are not deprived and they don't have to perform an additional consummatory response (e.g., eating) after each lever press to obtain the reinforcement; Panksepp and Trowill showed that nondeprived rats' lever pressing to inject small amounts of chocolate milk directly into their mouths through an implanted tube, performed remarkably like self-stimulating rats: (1) they learned very rapidly to lever press, (2) they extinguished almost immediately, and (3) some even had to be primed

- a variety of neural circuits can mediate self-stimulation but one neural system that appears to play a particularly important role is the mesotelencephalic dopamine system (use Digital Image Archive Figure CH13F10.BMP)

- the mesotelencephalic dopamine system ascends from two mesencephalic dopaminergic nuclei: the substantia nigra and the ventral tegmental area; at one time it was thought that all of the axons of substantia nigra neurons terminated in the striatum and they were commonly referred to as the nigrostriatal pathway (which we have discussed with respect to Parkinson's disease); similarly, it was thought that all of the axons of ventral tegmental area neurons projected to the limbic system and cortex (hence the name mesocortical limbic pathway). Recent findings indicate that there is considerably more intermingling between these two dopamine pathways than was once thought, and it has become common to refer to them together as the mesotelencephalic dopamine system

(1) Mapping Studies: areas that support ICSS are typically part of the mesotelencephalic dopamine system or else project there (use Digital Image Archive Figure CH13F09.BMP);

(2) In vivo Cerebral Microdialysis Studies: Phillips and his colleagues have demonstrated an increase in the release of dopamine from the mesotelencephalic dopamine system when an animal is engaged in ICSS (use Digital Image Archive Figure CH13F11.BMP);

- the most isomorphic animal model of human addiction is the drug self-administration paradigm (use Digital Image Archive Figure CH13F12.BMP); animals will self-administer many addictive drugs, often mimicing many of the drug-taking behaviors characteristic of human addicts

- during the conditioning phase, rats repeatedly receive a drug in the drug compartment of a two-compartment box; during testing, drug-free rats are placed in the box and the proportion of time spent in the compartment where it used to receive the drug is compared to time spent in the control compartment

- Using ICSS, self-administration and place-prefence conditioning paradigms, investigators have established five major lines of evidence support the view that the mesotelencephalic dopamine system, particularly its mesocortical-limbic division, mediates the rewarding effects of drugs:

(1) laboratory animals self-administer microinjections of addictive drugs into various structures of the mesotelencephalic dopamine system but usually not into other brain areas;

(3) addictive drugs have been shown to increase the rewarding effects of electrical stimulation to the mesotelencephalic dopamine system, whereas nonaddictive drugs do not;

(5) systemic self-administration of most addictive drugs is associated with increased dopamine release from the nucleus accumbens, the striatum and other terminals of the mesotelencephalic system

Conclusion: current evidence suggests that the mesotelencephalic dopamine system can mediate the rewarding effects of some addictive drugs; thus, it may eventually prove possible to help those addicts who wish to give up their habit by the pharmacological manipulation of this system

A collection of animations, PET images, and other images illustrating the effects of cocaine, nicotine, and other drugs of abuse on the brain. Highly recommended