Chapter 18

Drug Abuse

Background

• Humans discovered long ago that many substances in nature (e.g. plants materials) had medicinal qualities– Some of these also served as “recreational” drugs, or substances that

produced pleasing effects (most notable example is alcohol)

Addictive drugsDrug Sites of Action

Ethyl alcohol NMDA receptor ANT; GABAA receptor

ANTBarbiturates GABAA receptor AGO

Benzodiazepines (tranquil)

GABAA receptor AGO

Cannabis CB1 cannabinoid receptor AGO

Nicotine Nicotinic Ach receptor AGO

Opiates and receptor AGO

PCP and ketamine NMDA receptor ANT

Cocaine Blocks reuptake of DA, 5-HT and NE

Amphetamine Causes release of DA 

Physical vs Psychological Addiction

• Many people believe that “true” addiction is caused by the unpleasant side effects that occur when an addict tries to stop taking the drug

• Physical dependence vs. psychic dependence• Heroin addiction considered prototype for all drug addictions:

– Heroin addicts become physically dependent on the drug– Tolerance – decreased sensitivity to a drug that comes from its continued

use– Withdrawal – the appearance of symptoms opposite to those produced by

a drug when the drug is no longer taken

• Tolerance may be produced by the body’s attempt to compensate for the unusual condition of heroin intoxication, thus when the addict stops taking the drug, the compensatory mechanisms will become apparent

• However, tolerance and withdrawal do not occur immediately, something else must be happening in order to get the addict to start taking the drug in the first place (i.e. reinforcing effects)

Positive reinforcement

• Drugs that lad to dependency must first reinforce people’s behavior

• Positive reinforcement refers to the effect that certain stimuli have on the behaviors that preceded them

• Addictive drugs have reinforcing effects– i.e. their effects include activation of the reinforcement mechanism

• Role in drug abuse– The effectiveness of a reinforcing stimulus is greatest if it occurs

immediately after a response occurs

– This phenomenon explains why the most addictive drugs are those that have immediate effects

• e.g. heroin is preferred over morphine because it has a more rapid effect

– The immediate reinforcing effects of a addictive drug can overpower the recognition of the long-term aversive effects

Positive reinforcement

• Neural mechanisms– All natural reinforcers cause the release of DA in the nucleus accumbens

– Addictive drugs (including amphetamine, cocaine, opiates, nicotine, alcohol, PCP, and cannabis) trigger the release of DA in the NA

• Some do this by increasing te activity of DA neurons in mesolimbic system

• Some inhibit reuptake of DA by terminal buttons

Negative reinforcement

• A behavior that stops or reduces and aversive stimulus will be reinforced. This phenomenon is called negative reinforcment

• Do not confuse negative reinforcement with punishment– For neg. reinforcement – the response must make an aversive stimulus

stop

– For punishment – the response must make the aversive stimulus occur

• Reduction of withdrawal effects (by taking the drug again) serve as negative reinforcement

• Could also explain why a person starts taking a drug in the first place– Drug effects may help relieve bad feelings that person may be having (e.g.

drink when feeling upset)

Cravings and relapse

• When an addictive drug activates the mesolimbic DA system, it gives “incentive salience” to stimuli present at that time– i.e. stimuli associated with taking that drug become exciting and

motivating

• When a person with a history of drug abuse sees or thinks about these stimuli they experience a craving, or an impulsion to take the drug

• Small doses of the drug can also elicit cravings

• Reinstatement model of drug seeking in lab animals– First trained to make a response that is reinforced by IV injection of drug

(e.g. cocaine)

– Next, response is extinguished by only injecting saline after response

– Once animal has stopped responding, a “free” injection will be administered, and the animal will begin to respond again

– This relapse involves activation of the mesolimbic DA system

Cravings and relapse

• Long-term drug abuse in both humans and lab animals produces long-term changes in the brain

• Imaging studies show increase in activity in orbitofrontal cortex and anterior cingulate cortex when taking or craving an addictive drug– Decrease in activity during withdrawal

• NMDA-receptor-dependent LTP and LTD can take place in NA and VTA of mesolimbic system

• Other stimuli can also trigger relapse– e.g. stressful situations can cause former drug users to relapse

– However, social “satisfaction” produces less need of artifical reward via drugs

– Drug craving elicited by stress depends on the secretion of CRH (i.e. if CRH is not secreted, then relapse will not occur)

Opiates

• Opium is derived from resin produced by the opium poppy, and has been eaten and smoked for centuries

• Opiate use (usually heroin) is illegal in most countries, produces tolerance, addicts may often use unsanitary needles, and pregnant women taking the drug will pass on addiction to fetus

• Opiates (endogenous opioids) are secreted when an animal is performing behaviors that are important to its survival

• Neural basis of reinforcing effects– Lab animals will self-administer opiates

– When an opiate is administered it stimulates opiate receptors located on neurons in various parts of the brain and produces analgesia, hypothermia, sedation, and reinforcement

– μ and δ receptors responsible for analgesic effects; κ produces aversive effects (e.g. dynorphin – endogenous ligand for κ opiate receptor)

Opiates

• Neural basis of reinforcing effects– Opiate injection caused increased release of DA in NA– The reinforcing effects of opiates are produced by activation of neurons of

the mesolimbic system and release of DA in the NA– However, opiates can reinforce behavior independent of their effects on

the mesolimbic DA system– Animals with lesions of NA still have behavior reinforced with opiates

• Tested with conditioned place preference, which is the learned preference for one location over another in which an organism encountered a reinforcing stimulus

• CPP still occurs with opiates even after destruction of NA

• Neural basis of withdrawal effects– Periaqueductal gray (PAG), locus coeruleus, and amygdala– Antagonist-precipitated withdrawal – sudden withdrawal from long-term

admin of a drug caused by cessation of the drug and admin of an antagonistic drug (e.g. naloxone for opiates); most sensitive site was locus coeruleus

Opiates

• Neural basis of withdrawal effects– Intracellular process involved in development of withdrawal symptos to

opiates involves a protein called CREB (cyclic AMP-responsive element-binding protein)

– Long-term exposure to opiates causes tolerance, or a decreased sensitivity of neurons to opiates

– This decreased sensitivity (i.e. downregulation) occurs even though the number of opiate receptors does not change, suggesting some type of intracellular alteration

– CREB plays a critical role in the intracellular events responsible for the withdrawal effects of opioids

– CRH is involved in craving caused by stress for opiates

Cocaine and Amphetamine

• Have similar behavioral effects, because both act as potent DA agonists

• Cocaine binds with and deactivates the DA transpoter proteins, thus blocking reuptake

• Amphetamine directly stimulates the release of DA from terminal buttons

• Excitatory behavioral effects (e.g. euphoria, feelings of power, talkative)

• Animals will self-admin

• Also see psychotic behavioral effects (e.g. hallucinations, delusions of persecution, mood disturbances, and repetitive behaviors) that very closely resemble schizophrenia

• May have adverse long-term effects on brain– Decrease in number of DA transporters

Cocaine and Amphetamine

• Activate mesolimbic DA system and reinforce drug-taking behavior

• IV injection of both increase concentration of DA in NA

• NA is critical site for the reinforcing effects of cocaine and amphetamine

• Neurons in the NA participate in the reinforcing effects of cocaine, with groups of neurons participating in triggering behavioral response, reinforcing effects, and cravings

• Long-term use does not produce tolerance, and may even produce sensitization; withdrawal symptoms are not physical, but can still be unpleasant, such as dysphoria or decreased ability to experience pleasure

Nicotine

• The combination of nicotine and other sustances in tobacco smoke is carcinogenic and leads to cancer of the lungs, mouth, throat and esophagus

• 1/3 of adult population of the world smokes, even when aware of averse health effects

• Lab animals will also self-admin

• Stimulates ACh receptors, and increases activity of DA neurons of mesolimbic system and causes DA to be released in NA

• Injection of nicotinic agonist directly into VTA will produce a CPP

• Injection of nicotinic antagonist into the VTA will reduce the reinforcing effects of IV injections of nicotine

• Reinforcing effect of nicotine occurs in VTA, but not NA

• Some of the reinforcing effects of tobacco smoke may be mediated by nicotinic ACh receptors located outside CNS

Nicotine

• The nicotinic ACh receptor exists in 3 states:– When a burst of ACh is released by terminal button, the receptors open

briefly, permitting Ca+ to enter– Within milliseconds, AChE has destroyed ACh and receptors either close

again or enter a desensitized state, during which they do not react to ACh– However, when a person smokes, the level of nicotine in the brain raises

slowly and stays steady for a prolonged period of time because it is not destroyed by AChE

– Thus nicotine has dual effects on nicotinic receptors: activation and then desensitization

• The first dose of nicotine in the morning brings the most pleasure, because the period of abstinence during the night has allowed many of their receptors to enter the closed state and become sensitized again

• Cravings in long-term caused by LTP in the VTA• Cessation causes withdrawal symptoms (e.g. anxiety, restlessness,

insomnia, and inability to concentrate)

Alcohol and Barbiturates

• Alcohol has greater costs to society than any other drug

• Has the most serious effects on fetal development during the brain growth spurt period, which occurs during the last trimester of pregnancy and for several years after birth

• Alcohol has 2 primary sites of action:– Serves as an indirect agonist at GABAA receptors

– Indirect antagonist at NMDA receptors

• Both of these actions trigger apoptosis

• Exposure to alcohol later in life may also produce long-lasting changes in susceptibility to addiction

• At low doses, alcohol produces mild euphoria and has an anxiolytic effect; at higher doses it produces incoordination and sedation; also removes the inhibitory effect of social controls on behavior

Alcohol and Barbiturates

• Produces both positive (euphoria) and negative (anxiolytic) reinforcement

• Unique combination of both positive and negative effects that makes alcohol so reinforcing

• Lab animals can be induced to become dependent on alcohol– Most animals find the taste of alcohol to be aversive– However, can add supplements to alcohol to get them to consume it

• e.g. sucrose, beer, gelatin (Rowland et al. 2005)

• Increases activity of DA neurons in mesolimbic system and increases release of DA in NA

• The perceptual effects of alcohol are mimicked by both GABA agonists and NMDA antagonists– Drug discrimination procedure – an experimental procedure in which an

animal shows, through instrumental conditioning, whether the perceived effects of two drugs are similar

Alcohol and Barbiturates

• Like alcohol, NMDA antagonists produce sedative, hypnotic, and anxiolytic effects and interfere with cognitive performance

• Alcohol also disrupts LTP and interferes with spatial receptive fields of place cells in the hippocampus

• Withdrawal from alcohol intake decreases activity of mesolimbic neurons and their release of DA in the NA; can also cause seizures that may be mediated by activation of NMDA receptors– These seizures can be blocked by NMDA receptor antagonists

• The sedative effect of alcohol appears to be mediated by the GABAA receptor

• Barbiturates have similar effects to alcohol; however, binding sites appear to be different

Cannabis

• THC, active ingredient in marijuana, activates endogenous cannabinoid receptors

• Has a stimulating effect on DA neurons in NA

• Appears to act directly on DA terminal buttons

• Many lab animals will self-admin drugs that stimulate CB1 receptors

• A targeted mutation that blocks production of CB1 receptors abolishes the reinforcing effects of cannabinoids, morphine and heroin

• The hippocampus contains a large concentration of THC receptors

• Marijuana affects memory: it impairs ability to keep track of a particular topic, etc.

• Excessive activation of CB1 receptors in field CA1 appears to interfere with normal functioning of the hippocampus

• Long-term effects of marijuana include bronchitis, increased risk for lung cancer, minor impairments of memory and attention

Heredity and drug abuse

• Not everyone is equally likely to become addicted to a drug• 2 possible sources of individual differences: heredity and environment• Most research of effects of heredity on addiction have been devoted to

alcoholism• Alcohol consumption is not distributed equally across the population• Heredity appears to be more important than environment• 2 types of alcoholics: “steady drinkers” – those you cannot abstain but

drink consistently; and “bingers” – those who go without for long periods of tie, but unable to control themselves when they start

• Steady drinking strongly influenced by heredity, binge drinking by both heredity and environment

• Personality differences that may lead to alcoholism may be due to differences in the sensitivity of neural mechanisms involved in reinforcement, exploration and punishment

• Also may involve differences in DA mechanisms

Animal models and drug abuse

• Several different strains of alcohol preferring rats have been bred

• P rats (alcohol preferring) vs NP rats (non-alcohol preferring)– When given alcohol for first time, both groups show no preference

– However, after a short time of exposure to alcohol soltuion in addition to water, P rats will show a greatly increased preference for alcohol solution during next test

• Found lowered levels of DA in NA of P rats

• A low level of DA in NA correlates with ahedonia and dysphoria, and some forms of alcoholism may be caused by decreased sensitivity to reinforcement

Therapy for drug abuse

• Most common treatment for opiate addiction is methadone maintenance– Methadone is a potent opiate, which is administered by clinics in liquid

form, and does not produce a high, since the rate of admin is slow

• Opiate antagonist, such as naloxone, are used by hospitals for treatment of heroin overdose

• Several treatments for nicotine addiction:– Gum, patch, etc.: all methods maintain sufficiently high level of nicotine

in brain to decreases cravings; once smoking habit is gone, the dose can be lowered to wean them off

• 5-HT agonists can help with alcoholism, also NMDA receptor antagonists