INTRODUCTION
Drugs are abused (used in non-medically approved ways)










Cause strong feelings of euphoria or alter perception

Compulsive drug use → hallmark of addiction


Repetitive exposure → widespread adaptive changes in the
brain
BASIC NEUROBIOLOGY OF DRUG ABUSE
DEPENDENCE VERSUS ADDICTION
Formerly : “physical dependence” - now: dependence.
Formerly : “Psychological dependence” - now: addiction.
Common characteristic : induces strong feelings of euphoria and
reward.
Repetitive exposure, addictive drugs induce adaptive changes such
as tolerance.
Tolerance: Escalation of dose to maintain effect.

Once the abused drug is no longer available, signs of withdrawal
become apparent.
Withdrawal syndrome - A combination of such signs,

defines dependence.
Dependence is not always a correlate of drug abuse.

Can also occur with many classes of non-psychoactive drugs:

Sympathomimetic vasoconstrictors
Bronchodilators


Organic nitrate vasodilators
Addiction consists of compulsive, relapsing drug use despite negative
consequences.

Triggered by cravings that occur in response to contextual cues
Dependence invariably occurs with chronic exposure, only a

small percentage of subjects develop a habit, lose control, and
become addicted.
Example:

 Very few patients who receive opioids as analgesics
desire the drug after withdrawal.
 Only one person out of six becomes addicted within
10 years of first use of cocaine.
Relapse is very common in addicts after a successful withdrawal.

By definition, they are no longer dependent at this point.

Optogenetic methods in reinforcement studies
Blue light activation of channelrhodopsin (light-gated

cation channel) in dopamine neurons

Results in:
 Mice self-administering light to activate
VTA dopamine neurons
 Long-lasting place preference after
repeated pairings
 Seeking behavior when light is unavailable
 Self-stimulation despite punishment (light
electric shock)

Inhibitory optogenetic activation or upstream inhibitory
neuron activation causes aversion
General rule: All addictive drugs activate the mesolimbic dopamine
system
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

Selective activation of dopamine neurons drives
reinforcement and adaptive behavioral changes
Behavioral significance of dopamine increase is debated
Hypothesis: Dopamine codes for the difference between
expected and actual reward, acting as a strong learning
signal
Three classes of addictive drugs (based on molecular target and
cellular mechanism):
1. Binds to Gio protein-coupled receptors
2. Interacts with ionotropic receptors or ion channels
3. Targets the dopamine transporter
ADDICTIVE DRUGS INCREASE THE LEVEL OF DOPAMINE: REINFORCEMENT
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


Understanding long-term changes in drug abuse

Requires identifying initial molecular and cellular targets

Animal and human studies (including functional imaging)
identify the mesolimbic dopamine system as the prime target
 Mesolimbic dopamine system:

This system originates in the ventral tegmental area
(VTA), a tiny structure at the tip of the brainstem.

The VTA projects to:
 Nucleus accumbens
 Amygdala
 Hippocampus
 Prefrontal cortex
Most projection neurons of the VTA are dopamine-producing
neurons.
Dopamine release mechanism
 Dopamine neurons in the VTA fire in bursts → large
dopamine release in the nucleus accumbens and
prefrontal cortex
Early animal studies
o Pairing electrical stimulation of the VTA with operant
responses (e.g., lever pressing) reinforced behavior
o Established the central role of the mesolimbic
dopamine system in reward processing
 Direct drug application to the VTA acts as a strong
reinforcer
 Systemic administration of addictive drugs releases
dopamine

Mechanisms of dopamine increase:
1. Direct stimulation of dopamine neurons (e.g., nicotine)
2. Interference with dopamine reuptake or promotion of
nonvesicular release (e.g., amphetamines)
o Occurs in target regions and VTA
o Dopamine neurons express somatodendritic
transporters that normally clear dopamine
released by dendrites
o Affects transporters of norepinephrine and
serotonin but dopamine transporter is central
for addiction
o Antidepressants that block serotonin and
norepinephrine uptake but not dopamine
uptake do not cause addiction
3.
Name
Indirect inhibition of GABA interneurons (e.g., opioids)
Main Molecular
Target
Pharmacology
Effect on Dopamine
(DA) Neurons

RR²
Drugs That Activate G Protein-Coupled Receptors
Opioids
μ-OR (Gᵢₒ)
Agonist
Disinhibition
Cannabinoids
CB₁R (Gᵢₒ)
Agonist
Disinhibition
γ-Hydroxybutyric
GABAᴮR (Gᵢₒ)
Weak agonist Disinhibition
acid (GHB)
LSD, mescaline,
Partial
5-HT₂A R (Gq)
—
psilocybin
agonist
Drugs That Bind to Ionotropic Receptors and Ion Channels
Nicotine
nAChR (α4β2) Agonist
Excitation
GABAᴬR, 5HT₃R, nAChR,
Excitation,
Alcohol
—
NMDAR, Kir3
disinhibition (?)
channels
Positive
Benzodiazepines
GABAᴬR
Disinhibition
modulator
Phencyclidine,
NMDAR
Antagonist
—
ketamine
Drugs That Bind to Transporters of Biogenic Amines
DAT, SERT,
Blocks DA
Cocaine
Inhibitor
NET
uptake
Blocks DA
DAT, NET,
Reverses
Amphetamine
uptake, synaptic
SERT, VMAT
transport
depletion
Blocks DA
SERT > DAT,
Reverses
Ecstasy
uptake, synaptic
NET
transport
depletion
4
2
?
1
4

3
3

1
5

5
Adenylyl cyclase adaptation
o Activation of μ-opioid receptors initially strongly
inhibits adenylyl cyclase.
o With repeated exposure, this inhibition weakens.
o Counteradaptation of the enzyme system → leads to
overproduction of cAMP during withdrawal.
o Several mechanisms contribute to this compensatory
response, including:
 Upregulation of adenylyl cyclase
transcription.
CREB activation
o Increased cAMP strongly activates cyclic AMP
response element binding protein (CREB).
o CREB regulates downstream genes, including:
 Dynorphin gene (endogenous κ-opioid
ligand).
Dynorphin and dopamine regulation
o Dynorphin targets presynaptic κ-opioid receptors,
which regulate dopamine release in the nucleus
accumbens.
Thalamic input to nucleus accumbens
o Conveys an aversive state during withdrawal.
o Further elucidates neural circuits underlying opioid
dependence.
?
DEPENDENCE: TOLERANCE & WITHDRAWAL
Brain adaptation to chronic drug exposure

Example: Morphine requires progressively increasing doses over days
to maintain effects

Tolerance: Reduced drug effect requiring higher doses

Can be dangerous due to side effects like respiratory
depression, which do not develop tolerance as quickly →
risk of overdose
Types of opioid tolerance
1.
Pharmacokinetic tolerance: Reduced drug concentration or shorter
duration of action in the target system
2.
Pharmacodynamic tolerance: Changes in μ-opioid receptor function
a) μ-opioid receptor agonists promote receptor
phosphorylation → recruits β-arrestin → G proteins
uncouple → receptor internalization
b) Reduced signaling could explain tolerance, but:
 Morphine induces strong tolerance but
does not recruit β-arrestins or internalize
receptors
 Other agonists that internalize efficiently
induce only modest tolerance
c)
Hypothesis: Receptor internalization protects against
overstimulation
 Morphine fails to trigger endocytosis →
excessive stimulation of adaptive
processes → tolerance
 Adaptive processes may also play a role in
withdrawal
Withdrawal



Addiction: A Disease of Maladaptive Learning
Definition & Characteristics

Addiction is characterized by:
1. A high motivation to obtain and use a drug despite
negative consequences.
2. Drug use becoming compulsive ("wanting without
liking").
3. A chronic, stubbornly relapsing disease that is
difficult to treat.
The Problem of Relapse


Becomes apparent once drug exposure is terminated
Occurs to varying degrees across different drugs
Opioid withdrawal in humans is particularly strong
Rodent studies on dependence

FIGURE 32–2 Neuropharmacologic classification of addictive drugs by primary
target (see text and Table 32–1). DA, dopamine; GABA,γ-aminobutyric acid;
GHB, γ-hydroxybutyric acid; GPCRs, G protein-coupled receptors; THC, Δ9 tetrahydrocannabinol.
Knockout mice lacking μ-opioid receptors show:
o No dependence, analgesia, or reward.
o Mice lacking δ or κ opioid receptors do not show this
effect.

Even after successful withdrawal and prolonged drug-free
periods, individuals remain at high risk of relapse.
Relapse is typically triggered by:
1. Re-exposure to the addictive drug.
2. Stress.
3. Context associated with prior drug use.
A neutral stimulus paired with drug use may undergo a switch
and begin to trigger addiction-related behavior.
Neural Mechanisms Underlying Addiction


Synaptic plasticity plays a key role in addiction.
The mesolimbic projection is a major pathway implicated in
addiction:
o
Includes projections from the medial prefrontal
cortex to nucleus accumbens neurons expressing D1
receptors.
o Recent studies suggest the dorsal striatum is
responsible for compulsive drug-seeking behavior.
o The nucleus accumbens of the ventral striatum
integrates dopaminergic and glutamatergic inputs to
modulate addiction-related behaviors.
Dopamine, Learning, and Memory in Addiction


If dopamine release codes for reward prediction error,
pharmacologic stimulation of the mesolimbic dopamine system
creates an abnormally strong learning signal.
o
Multiple alleles (possibly hundreds) work together to
influence addiction risk.
o Identifying specific genes remains challenging, but
some substance-specific candidate genes include:
 Alcohol dehydrogenase (alcohol
metabolism).
 Nicotinic acetylcholine receptor subunits
(nicotine addiction).
Epigenetics & Future Research

Unlike natural rewards, addictive drugs:
o Continue to increase dopamine release even when
the reward is expected.
o Override the prediction error signal, which may lead
to the usurping of memory processes by addictive
drugs.
Clinical Evidence Supporting the Role of Learning & Memory in Addiction


Environmental context plays a major role in relapse:
o Vietnam War soldiers who became addicted to heroin
had better outcomes when treated after returning
home compared to those who remained in the drugusing environment.
o Contextual cues (e.g., people, places, drug
paraphernalia) can trigger cravings and relapse.
Research focuses on how addictive drugs affect associative
synaptic plasticity (e.g., long-term potentiation (LTP)), which is
critical for learning and memory.
Behavioral Addictions & Neurobiologic Overlap
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


Large individual differences exist in addiction susceptibility:
o Some individuals become addicted quickly, while
others can use drugs occasionally without ever
developing addiction.
Even with chronic exposure, only a small percentage of users
progress to addiction:
o Cocaine: ~20% of chronic users become addicted.
o Cannabis: ~10% develop addiction.
o Animal studies mirror human trends:
 Similar addiction rates (~20%) are observed
in rats/mice with extended cocaine access.
 Surprisingly, with dopamine neuron selfstimulation, >50% of mice continue selfstimulation despite punishment.
Personality traits like impulsivity and anxiety may increase
addiction risk.
Genetics & Epigenetics in Addiction



Addiction is influenced by a combination of environmental and
genetic factors.
Heritability of addiction varies by drug:
o Lower for cannabinoids.
o Very high for cocaine.
Genetic studies suggest:
o Addiction liability correlates with heritability.
Current research is investigating how these cellular mechanisms
influence addiction and relapse risk.
NONADDICTIVE DRUGS OF ABUSE
Some drugs alter perception without causing reward or euphoria.
Unlike addictive drugs that target the mesolimbic dopamine system,
these primarily affect cortical and thalamic circuits.
Mechanism of Nonaddictive Drugs
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
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
Non-substance-related addictions (e.g., pathological gambling,
compulsive shopping) share many features with drug addiction.
Clinical observations suggest a common neurobiological
mechanism:
o Dopamine agonists used in Parkinson’s disease can
cause addiction-like behaviors.
o Parkinson’s patients on dopamine agonists may
develop pathologic gambling, compulsive eating,
hypersexuality, or shopping addiction.
o Estimated 1 in 7 Parkinson’s patients develops an
addiction-like behavior when receiving dopamine
agonists.
Individual Variability in Addiction Vulnerability


Epigenetic mechanisms are emerging as key contributors to
addiction vulnerability:
o Cocaine modifies histones, DNA methylation, and
non-coding RNA signaling.
o These epigenetic changes may impact behavior and
synaptic plasticity.


Unlike addictive drugs that primarily target the mesolimbic
dopamine system, these substances act on cortical and thalamic
circuits.
Hallucinogens (e.g., LSD)
o Lysergic acid diethylamide (LSD) activates serotonin
5-HT2A receptors in the prefrontal cortex.
o This enhances glutamatergic transmission onto
pyramidal neurons.
o Excitatory afferents primarily originate from the
thalamus and carry sensory information, possibly
linking to enhanced perception.
Dissociative Anesthetics (e.g., PCP, Ketamine)
o Induce a feeling of separation of mind and body
(hence the term “dissociative”).
o At higher doses, they cause stupor and coma.
o Act primarily through use-dependent inhibition of
NMDA glutamate receptors.
Dextromethorphan (OTC cough suppressant)
o At high doses, elicits a dissociative state.
o Nonselectively affects:
 Serotonin reuptake
 Opioid receptors
 Acetylcholine receptors
 NMDA receptors
Reevaluation of Nonaddictive Classification

Early assessments classified NMDA antagonists as nonaddictive,
but recent research challenges this:
o PCP can increase mesolimbic dopamine
concentrations and has some reinforcing properties
in rodents.
o Other addictive drugs (e.g., cannabinoids,
amphetamines, cocaine) also affect thalamocortical
structures.
o Cannabinoids:
 Act on mesolimbic dopamine system.
 Enhance excitation in cortical circuits by
presynaptic inhibition of GABA release.
Long-Term Effects of Hallucinogens & NMDA Antagonists

Even without producing dependence or addiction, they can have
lasting consequences:
o LSD: Flashbacks of altered perception can occur years
later.
o PCP: Chronic use may lead to irreversible
schizophrenia-like psychosis.
BASIC PHARMACOLOGY OF DRUGS OF ABUSE


All addictive drugs increase dopamine concentrations in target
structures of the mesolimbic projections.
They can be classified based on their molecular targets and
mechanisms of action:
Classification of Addictive Drugs

Drugs that act through Gi/o protein-coupled receptors
1. Opioids
2. Cannabinoids
3. γ-Hydroxybutyric acid (GHB)
4. Hallucinogens
 Drugs that interact with ionotropic receptors or ion channels
1. Nicotine
2. Alcohol
3. Benzodiazepines
4. Dissociative anesthetics
5. Some inhalants
 Drugs that bind to monoamine transporters
1. Cocaine
2. Amphetamines
3. Ecstasy (MDMA)
Classification of Nonaddictive Drugs

Classified using the same criteria as addictive drugs.
1. OPIOIDS
DRUGS THAT ACTIVATE Gi/o-COUPLED RECEPTORS

Among the first drugs to be abused, still commonly used
nonmedically.
Pharmacology & Clinical Aspects
Opioid receptors:
o Three G protein-coupled receptors: μ (mu), κ (kappa),
and δ (delta).
o All inhibit adenylyl cyclase, but have distinct effects
due to cell-type-specific expression.
o μ-opioid receptors (expressed on GABA neurons) →
Inhibition of GABAergic interneurons → Disinhibition
of dopamine neurons → Euphoria.
o κ-opioid receptors (expressed on dopamine neurons)
→ Inhibition of dopamine neurons → Dysphoria.
Evidence from knockout mice:
o Rewarding effects of morphine are absent in μreceptor knockout mice but persist when other opioid
receptors are ablated.
Commonly abused μ-opioids:
o Morphine, heroin (diacetylmorphine), codeine,
oxycodone, meperidine.
o Meperidine abuse is common among health
professionals.
Tolerance & Dependence:
o Strong tolerance & dependence seen with most
opioids.
o Severe withdrawal syndrome (except for codeine)
includes:
 Dysphoria, nausea, vomiting, muscle aches
 Lacrimation, rhinorrhea, mydriasis,
piloerection
 Sweating, diarrhea, yawning, fever
Addiction risk:
o Rare when used as analgesics.
o Highly addictive when used recreationally.
o Relative addiction risk: 4/5 (on a scale of 1 to 5).
Acute Overdose

Treatment
Naloxone (opioid antagonist):
o Reverses opioid effects within minutes (life-saving in
overdose).
o
Triggers acute withdrawal in dependent individuals
(precipitated abstinence).
Opioid Addiction Treatment
1. Substitution therapy:
o Long-acting opioid substitutes short-acting, more
rewarding opioids.
o Common substitutes:
 Methadone (given orally once daily, allows
supervised intake).
 Buprenorphine (partial agonist, reduces
drug sensitization).
 Morphine sulfate (long half-life).
o Abrupt methadone withdrawal still precipitates
withdrawal syndrome.
2. Levomethadone (only active enantiomer of methadone):
o Similar effects to methadone, but fewer side effects.
o Less impact on cardiac repolarization (long QT interval
risk lower).
3. Heroin substitution therapy (in select countries: Canada, Denmark,
Netherlands, UK, Switzerland):
o Medical heroin administered in a controlled setting.
o Improved health & social integration in addicts
receiving supervised heroin therapy.
Opioid Epidemic in the USA


Prescription opioid abuse has surged over the past decade.

Some transition to heroin addiction.
NIDA estimates >2 million people dependent on prescription
opioids.
2. CANNABINOIDS
Endogenous Cannabinoids (Neurotransmitters)
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





2-arachidonyl glycerol (2-AG) & anandamide bind to CB1
receptors
Highly lipid-soluble compounds
Released at the postsynaptic somatodendritic membrane
Diffuse through the extracellular space to bind at presynaptic CB1
receptors
Inhibit release of glutamate or GABA
Function as retrograde messengers due to backward signaling
In the hippocampus, they affect inhibitory transmission and may
contribute to synaptic plasticity, learning, and memory formation
Exogenous Cannabinoids (e.g., Marijuana, THC)



Marijuana contains thousands of organic & inorganic chemical
compounds
Active substance: Δ9-tetrahydrocannabinol (THC)
Mechanism:
o Causes disinhibition of dopamine neurons
o Acts presynaptically to inhibit GABA neurons in the
ventral tegmental area (VTA)
Pharmacokinetics of THC



Half-life: 4 hours

Common effects:
o Euphoria, relaxation, well-being, grandiosity
o Altered perception of time
Onset of effects (smoked marijuana): Minutes
Peak effects: 1–2 hours
Effects of THC


Dose-dependent effects:
o Visual distortions, drowsiness, diminished
coordination, memory impairment
Rare high-dose effects (e.g., hashish):
o Visual hallucinations, depersonalization, psychotic
episodes
Medical Uses of Cannabinoids

THC effects utilized in medicine:
o Increased appetite

o
o
o
Attenuation of nausea
Decreased intraocular pressure
Chronic pain relief
Legalization status:
o Medical marijuana legalized in 25 U.S. states + D.C.
o Remains controversial due to concerns about:
 Gateway drug theory
 Potential to trigger schizophrenia in
predisposed individuals
Dependence & Withdrawal


Chronic exposure → Dependence
Withdrawal syndrome (mild, short-lived):
o Restlessness, irritability, mild agitation
o Insomnia, nausea, cramping
 Relative risk of addiction: 2
FDA-Approved Synthetic Cannabinoids



Dronabinol (Δ9-THC analog)
o Approved in the USA & some European countries
Nabilone (Δ9-THC analog)
o Recently reintroduced in the USA for chemotherapyinduced emesis
Nabiximols (botanical drug containing Δ9-THC & cannabidiol)
o Initially available in the UK, now widely used for
multiple sclerosis symptoms
o In phase III trials in the USA for cancer pain
Future of Cannabinoid Research


The cannabinoid system is emerging as an important drug target
Potential for new therapeutics due to its involvement in various
desirable effects
3. GAMMA-HYDROXYBUTYRIC ACID (GHB, Sodium Oxybate)
Production & Function


Produced during the metabolism of GABA
Function as an endogenous agent is unknown at present
Pharmacology

Complex due to two distinct binding sites:
 High-affinity binding site (1 μM)
 Protein containing this site has been cloned
 Involvement in the cellular effects of GHB at
pharmacologic concentrations remains unclear
 Low-affinity binding site (1 mM) → Identified as the
GABAB receptor
In mice that lack GABAB receptors, even

very high doses of GHB have no effect
Suggests GABAB receptors are the sole

mediators of GHB’s pharmacologic action
History & Medical Use
First synthesized in 1960 and introduced as a general

anesthetic

Not available in the USA for anesthesia due to:
Narrow safety margin


Addictive potential

Sodium oxybate can be prescribed under restricted
access to treat narcolepsy
 Decreases daytime sleepiness
 Reduces episodes of cataplexy
 Mechanism unrelated to the reward
system
Psychoactive & Recreational Effects

Before sedation and coma, GHB induces:

Euphoria
Enhanced sensory perceptions


Feeling of social closeness
Amnesia

Popular as a "club drug" with street names:


"Liquid ecstasy"
"Grievous bodily harm"


"Date rape drug"

Used in date rapes because:

Odorless

Can be readily dissolved in beverages
Pharmacokinetics
o
o
Rapidly absorbed after ingestion
Reaches maximal plasma concentration:
 20–30 minutes after ingestion of a 10–20
mg/kg dose
o Elimination half-life:
 About 30 minutes
Neurophysiological Effects

GABAB receptors are expressed on all neurons of the ventral
tegmental area (VTA)

GABA neurons are much more sensitive to GHB than dopamine
neurons

EC50 values differ by about one order of magnitude

Indicates difference in coupling efficiency of the GABAB
receptor and potassium channels responsible for
hyperpolarization
Because GHB is a weak agonist:

Only GABA neurons are inhibited at concentrations typically

obtained with recreational use
May underlie the reinforcing effects of GHB and the basis for

addiction
At higher doses:
 GHB also hyperpolarizes dopamine neurons
 Eventually completely inhibits dopamine release
Such inhibition of the VTA may:

Preclude its activation by other addictive drugs

Explain why GHB might have some usefulness as an
"anticraving" compound
4. LSD, MESCALINE, & PSILOCYBIN
General Properties
 Commonly called hallucinogens because they alter
consciousness, making individuals sense things that are not
present.
 Induce perceptual symptoms, often unpredictably, such as:
 Shape and color distortion
 Psychosis-like manifestations have led some to classify these
drugs as psychotomimetics, including:
 Depersonalization
 Hallucinations
 Distorted time perception
 Also produce somatic symptoms, such as:
 Dizziness
 Nausea
 Paresthesias
 Blurred vision

Flashbacks:
 Some users report intense reexperiencing of
perceptual effects
 These effects can occur up to several years after the
last drug exposure
Addiction & Tolerance
 Unlike most other drugs in this chapter, hallucinogens:

Do not induce dependence or addiction

Still lead to rapid tolerance (tachyphylaxis) with
repetitive exposure
 Animals do not self-administer hallucinogens, suggesting they are
not rewarding.
 Fail to stimulate dopamine release, further supporting the idea
that only drugs activating the mesolimbic dopamine system are
addictive.
 Instead, hallucinogens:
 Increase glutamate release in the cortex
 Presumably by enhancing excitatory afferent input via
presynaptic serotonin receptors (e.g., 5-HT2A)
from the thalamus
LSD (Lysergic Acid Diethylamide)
 Chemical Origin:

LSD is an ergot alkaloid
 Preparation & Consumption:

Blotter paper or sugar cubes are sprinkled with the liquid
and allowed to dry
When swallowed, psychoactive effects appear after 30

minutes
Effects last 6–12 hours

 Impaired Judgment & Risk:

Subjects under LSD influence have an impaired ability to:
Make rational judgments


Understand common dangers

This increases the risk for accidents and personal injury
 Typical Adult Dose:
 20–30 mcg
 Toxicity & Side Effects:
 LSD is not considered neurotoxic
 However, like most ergot alkaloids, LSD may cause
strong contractions of the uterus
 These contractions can induce abortion
Mechanism of Action

Main molecular target:
5-HT2A receptor

Receptor Mechanism:

Couples to G proteins of the Gq type

Generates inositol trisphosphate (IP3), leading to

intracellular calcium release

Therapeutic Potential:

Hallucinogens, especially LSD, have been proposed
for several therapeutic indications

However, efficacy has never been demonstrated
DRUGS THAT MEDIATE THEIR EFFECTS VIA IONOTROPIC RECEPTORS
1. NICOTINE
Prevalence and Addiction

Nicotine addiction exceeds all other forms of addiction in terms of
numbers affected.
In some countries, nicotine addiction affects more than 50% of all

adults.
Primary exposure occurs through smoking tobacco, which leads to

diseases responsible for many preventable deaths.

Chronic use of chewing tobacco and snuff tobacco is also addictive.
Mechanism of Action

Nicotine is a selective agonist of the nicotinic acetylcholine receptor
(nAChR), which is normally activated by acetylcholine (see Chapters 6
and 7).


Cognitive Effects:
 Nicotine enhances cognitive performance.
 The loss of ACh-releasing neurons from the nucleus basalis of
Meynert is associated with Alzheimer’s dementia, suggesting
nAChRs play an important role in cognitive processes.
Addiction and Reward Pathway:

The rewarding effects of nicotine involve the ventral
tegmental area (VTA), where nAChRs are expressed on
dopamine neurons.

When nicotine excites projection neurons, dopamine is
released in:

Nucleus accumbens
Prefrontal cortex


This dopamine release fulfills the requirement of
addictive drugs.
α4β2-containing channels in the VTA are required for

nicotine's rewarding effects, based on:
Knockout mice deficient in the β2 subunit

lose interest in self-administering nicotine.

This behavior can be restored by in vivo
transfection of the β2 subunit in VTA
neurons.

Homomeric nAChRs made exclusively of α7 subunits
also contribute to nicotine reinforcement:

These receptors are mainly expressed on
synaptic terminals of excitatory afferents
projecting onto dopamine neurons.

They contribute to nicotine-evoked
dopamine release and long-term synaptic
potentiation of excitatory inputs, related to
addiction.
Nicotine Withdrawal
Milder compared to opioid withdrawal.


Symptoms include:

Irritability
Sleep problems


Highly addictive (Relative risk: 4)

Relapse is very common after attempted cessation.
Treatment

Nicotine replacement therapy (NRT):
Chewed, inhaled, or transdermal nicotine can be substituted for

nicotine in cigarettes.

Slows pharmacokinetics and eliminates complications from
toxic substances in tobacco smoke.

Partial agonists of α4β2-containing nAChRs:
Cytisine (plant extract)

Varenicline (synthetic derivative)

Occupies nAChRs on dopamine neurons of the VTA,

preventing nicotine from exerting its effects.

May impair driving ability.

Associated with suicidal ideation.

Bupropion (antidepressant)

Approved for nicotine cessation therapy.

Most effective when combined with behavioral therapies.
Public Health Measures
Many countries have banned smoking in public places to create
smoke-free environments.
Benefits include:


Reducing passive smoking and hazards of
secondhand smoke.

Reducing the risk of relapse in ex-smokers due to
exposure to contextual cues (e.g., seeing others
smoke).
2. BENZODIAZEPINES
Medical Use & Risk of Abuse



Commonly prescribed for:
o Anxiety (anxiolytics)
o Sleep disorders (sedative-hypnotics)
Risk of abuse must be weighed against benefits.



Abuse may occur for euphoric effects, but more commonly:
o Used concomitantly with other drugs (e.g., to reduce
anxiety during opioid withdrawal).
Benzodiazepine Dependence & Withdrawal



Dependence is common and often undiagnosed.
Withdrawal symptoms appear within days of stopping.
o
Symptoms (vary with half-life of the drug):
o Irritability
o Insomnia
o Phonophobia & photophobia
o Depression
o Muscle cramps
o Seizures (in severe cases)
o
o
 Symptoms typically resolve within 1–2 weeks.
Mechanism of Action & Addiction





Benzodiazepines = Positive allosteric modulators of the GABA_A
receptor.
They increase:
o Single-channel conductance
o Open-channel probability
GABA_A receptors:
o Pentameric structures (contain α, β, and γ subunits;
see Chapter 22).
o GABA receptors on dopamine neurons (VTA) lack α1
but are present on GABA interneurons.
o Effect on VTA:
 Interneurons have larger synaptic currents
than dopamine neurons.
 Benzodiazepines silence interneurons,
preventing GABA release.
 Disinhibition of dopamine neurons →
Increased dopamine release →
Reinforcement & addiction.
Subunit-Specific Roles in Addiction & Tolerance:
o α1-containing GABA_A receptors → Mediate addiction
& rewarding effects.
o α5-containing receptors → Mediate tolerance to
sedative effects.
o α2β3-containing receptors → Linked to alcohol
dependence (GABA_A receptors are also targets of
alcohol).
Future treatments:
o α1-sparing benzodiazepine compounds may reduce
addiction risk.
o Experimental compounds (not yet approved) may be
preferred for anxiety treatment.
Comparison to Barbiturates




Street sales of barbiturates continue.

Regularly used by a majority of the population in many Western
countries.
Although only a minority becomes dependent and addicted,
abuse is a very serious public health problem because of the
social costs and many diseases associated with alcoholism.
Pharmacology



Treatment


Management of barbiturate withdrawal/addiction is similar to
benzodiazepine withdrawal treatment.
3. ALCOHOL

Dependence and Withdrawal
Barbiturates (older sedative-hypnotics) were once the most
abused before benzodiazepines.
Rarely prescribed to outpatients now, reducing their prescription
drug abuse.
The pharmacology of alcohol is complex, and no single receptor
mediates all of its effects.
o Alters the function of several receptors and cellular
functions:
 GABA_A receptors
Kir3/GIRK channels
Adenosine reuptake (through the
equilibrative nucleoside transporter, ENT1)
 Glycine receptor
 NMDA receptor
 5-HT3 receptor
They are all, with the exception of ENT1, either
ionotropic receptors or ion channels.
It is not clear which of these targets is responsible for
the increase of dopamine release from the mesolimbic
reward system.
The inhibition of ENT1
 Probably not responsible for the rewarding
effects (ENT1 knockout mice drink more
than controls).
 Seems to be involved in alcohol
dependence through:
 An accumulation of adenosine.
 Stimulation of adenosine A2
receptors.
 Ensuing enhanced CREB
signaling.

Dependence becomes apparent 6–12 hours after cessation of
heavy drinking as a withdrawal syndrome that may include:
o Tremor (mainly of the hands).
o Nausea and vomiting.
o Excessive sweating.
o Agitation and anxiety.
In some individuals, this is followed by:
o Visual, tactile, and auditory hallucinations (12–24
hours after cessation).
o Generalized seizures (24–48 hours after cessation).
o Alcohol withdrawal delirium (delirium tremens) (48–
72 hours after cessation), characterized by:
 Hallucinations.
 Disorientation.
 Evidence of autonomic instability.
o Delirium tremens is associated with 5–15% mortality.
Treatment of ethanol withdrawal
o Supportive and relies on benzodiazepines, taking care
to use compounds such as:
 Oxazepam and lorazepam (not as
dependent on oxidative hepatic
metabolism as most other
benzodiazepines).
 Chlordiazepoxide (preferred in patients in
whom monitoring is not reliable and liver
function is adequate).
As in the treatment of all chronic drug abuse problems:
o Heavy reliance is placed on psychosocial approaches
to alcohol addiction.
o This is perhaps even more important for the alcoholic
patient because of the ubiquitous presence of alcohol
in many social contexts.
The pharmacologic treatment of alcohol addiction is limited,
although several compounds, with different goals, have been
used.
4. KETAMINE & PHENCYCLIDINE (PCP)

Ketamine and PCP were developed as general anesthetics
o Only ketamine is still used for this application.
o Both drugs are now classified as “club drugs” and sold
under names such as:
 “Angel Dust”
 “Hog”



“Special K”
Mechanism of action
o Effects are due to use-dependent, non-competitive
antagonism of the NMDA receptor.
Effects observed in surgical patients
o Unpleasant vivid dreams and hallucinations after
anesthesia.
Forms and Methods of Use



Pure forms: White crystalline powders.
Street forms: Also sold as liquids, capsules, or pills.
Routes of administration:
o Snorted
o Ingested
o Injected
o Smoked
Psychedelic and Physiological Effects



Duration: Effects last for about 1 hour.
Effects include:
o Increased blood pressure.
o Impaired memory function.
o Visual alterations.
High doses may cause:
o Unpleasant out-of-body experiences.
o Near-death experiences.
Dependence and Long-Term Effects


Do not cause dependence and addiction (relative risk = 1).
Chronic exposure, especially to PCP, may lead to:
o Long-lasting psychosis closely resembling
schizophrenia.
o Psychosis may persist beyond drug exposure.
Antidepressant Effects of Ketamine



Intravenous administration of ketamine
o Can eliminate episodes of depression within hours
o Contrasts with SSRIs and other antidepressants, which
take weeks to act.
Mechanism of antidepressant effect
o Believed to involve NMDA receptor antagonism,
favoring the mTOR pathway downstream of other
glutamate receptors.
o Recent evidence suggests an alternate explanation:
 Hydroxynorketamine (a metabolite of
ketamine) may target AMPA receptors to
exert the antidepressant effect.
Limitation
o
The effect is transient, wearing off within days even
with repetitive administration.
5. INHALANTS



Inhalant abuse is defined as recreational exposure to chemical
vapors, including:
o Nitrites
o Ketones
o Aliphatic and aromatic hydrocarbons
Sources: Found in various household and industrial products.
Methods of use:
o Sniffing: Inhalation from an open container.
o Huffing: Soaking a cloth in the volatile substance
before inhalation.
o Bagging: Breathing in and out of a paper or plastic bag
filled with fumes.
o Progression: Novices often start with sniffing and
progress to huffing and bagging as addiction develops.
Prevalence
 Particularly common in children and young adults.
Mechanism of Action


Effects



Exact mechanism unknown for most volatile substances.
Known effects on ionotropic receptors and ion channels in the
CNS:
o Nitrous oxide binds to NMDA receptors.
o Fuel additives enhance GABAA receptor function.
Most inhalants produce euphoria.
Toluene increases excitability of the VTA, contributing to
addiction risk.
Amyl nitrite ("poppers"):
o Primarily causes smooth muscle relaxation.
o Enhances erection.
o Not addictive.
Chronic Exposure & Toxicity

Aromatic hydrocarbons (e.g., benzene, toluene) cause toxic
effects in many organs.
 White matter lesions may develop in the central nervous system.
Overdose Management

Supportive care is the primary treatment.
DRUGS THAT BIND TO TRANSPORTERS OF BIOGENIC AMINES
1. COCAINE
Prevalence & Public Health Concern
 Cocaine abuse has increased greatly over the last decade.
 It represents a major public health problem worldwide.
 Highly addictive (relative risk = 5).
 Associated with multiple complications.
Source & Historical Use
Alkaloid found in Erythroxylum coca (a shrub indigenous to the

Andes).
Extracted and used for over 100 years in clinical medicine:

 Local anesthetic.

Pupil dilation in ophthalmology.
Sigmund Freud proposed its use for depression and alcohol

dependence, but addiction concerns ended this idea.
Forms & Routes of Administration

Cocaine hydrochloride:
Water-soluble salt.


Can be injected or absorbed through mucosal
membranes (e.g., nasal snorting).
Crack cocaine:


Formed by heating cocaine in an alkaline solution.
Can be smoked.

Rapid lung absorption → swift brain penetration →

instant "rush".
Mechanism of Action
Peripheral Nervous System:
o Inhibits voltage-gated sodium channels → blocks
action potential conduction (basis for local anesthetic
effects).
o This does not contribute to rewarding or addictive
effects.
Central Nervous System:
o Blocks uptake of dopamine (DA), norepinephrine (NE),
and serotonin (5-HT) via their transporters:
 Dopamine transporter (DAT) blockade → ↑
dopamine in nucleus accumbens →
rewarding effects.
 Norepinephrine transporter (NET) blockade
→ sympathetic activation → ↑ blood
pressure, tachycardia, ventricular
arrhythmias.

Serotonin transporter (SERT) blockade →
additional CNS effects.
o Evidence of DAT involvement:
 Cocaine’s rewarding effects are abolished
in mutant mice with a cocaine-insensitive
DAT.
Effects & Complications
Acute Effects:
o ↑ Sympathetic activity: hypertension, tachycardia,
arrhythmias.
o CNS effects: appetite loss, hyperactivity, reduced sleep.
Severe Health Risks:
o Intracranial hemorrhage.
o Ischemic stroke.
o Myocardial infarction.
o Seizures.
o Overdose risks: hyperthermia, coma, death.


Use & Popularity
o
Impact on Pregnancy ("Crack Baby" Controversy):
o 1970s: Crack cocaine was believed to cause a specific
fetal syndrome.
o Mothers faced legal consequences.
o Follow-up studies:
 No drug-specific cognitive handicap found
in exposed children.
 Same drug use rates as socioeconomically
matched controls.
Addiction, Withdrawal, & Treatment
Addiction Potential
o Some individuals become addicted after just a few
exposures.
o Cravings are extremely strong, contributing to high
addiction liability.
Decrease normal vesicular release of dopamine due to
lower neurotransmitter content in vesicles.
Increase nonvesicular release of dopamine.
Similar mechanisms apply to other biogenic amines
(serotonin and norepinephrine).

o
o
o
Often referred to as "club drugs" along with GHB and
ecstasy.
Increasingly popular in the club scene.
Often produced in small clandestine laboratories,
making chemical identification difficult.
Differ from ecstasy primarily in context of use:
 Intravenous administration and “hardcore” addiction are far more common
with amphetamines (especially
methamphetamine).
Tolerance & Sensitization
o Tolerance may develop in some users.
o Reverse tolerance (sensitization) in others →
increased response to small doses.
o Behavioral sensitization is context-dependent.
Effects on Neurotransmitter Systems
o Elevated catecholamine levels:
 Increase arousal.
 Reduce sleep.
o Effects on dopamine system:
 Mediate euphoria.
 May cause abnormal movements.
 May precipitate psychotic episodes.
o Effects on serotonin transmission:
 May play a role in hallucinogenic and
anorexigenic (appetite-suppressing)
functions.
 Involved in hyperthermia often caused by
amphetamines.
Treatment
Neurotoxicity
Withdrawal
o Reported but not as severe as opioid withdrawal.
o
o
o
No specific antagonist available.
Management of intoxication remains supportive.
Developing pharmacologic treatments for cocaine
addiction is a top priority.
2. AMPHETAMINES
Classification & Mechanism of Action

Amphetamines are a group of synthetic, indirect-acting
sympathomimetic drugs.
Causes the release of endogenous biogenic amines, such

as dopamine and noradrenaline

Amphetamine, methamphetamine, and their derivatives exert effects
by reversing the action of biogenic amine transporters at the plasma
membrane.
Amphetamines are substrates of these transporters and are taken up

into the cell.

Once inside the cell:
Interfere with the vesicular monoamine transporter

(VMAT).
Deplete synaptic vesicles of neurotransmitter content.

Increase dopamine (or other transmitter amine) levels

in the cytoplasm.
Causes release into the synapse by reversal of the

plasma membrane dopamine transporter (DAT).
o
o
Unlike many other abused drugs, amphetamines are
neurotoxic.
Exact mechanism is unknown, but:
 Depends on NMDA receptor.
 Mainly affects serotonin and dopamine
neurons.
Routes of Administration
o Typically taken initially in pill form.
o Can also be smoked or injected.
o Heavy users often progress rapidly to intravenous
administration.
Acute Effects
o
o
Within hours after oral ingestion:
 Increase alertness.
 Cause euphoria, agitation, and confusion.
 Bruxism (tooth grinding) and skin flushing
may occur.
Cardiovascular effects:
 Minimal with some compounds (e.g.,
methamphetamine).
 With increasing dosage:

o
Often leads to tachycardia and
dysrhythmias.
 Hypertensive crisis and
vasoconstriction may lead to
stroke.
Public health concerns:
 Spread of HIV and hepatitis infection in
inner cities has been closely associated
with needle sharing by intravenous
methamphetamine users.
Chronic Use & Addiction
o With chronic use:
 Amphetamine tolerance may develop,
leading to dose escalation.
o Withdrawal symptoms:
 Dysphoria.
 Drowsiness (or in some cases, insomnia).
 General irritability.
3. ECSTASY (MDMA)
Definition & Background
 Class of drugs derived from methylenedioxy​ methamphetamine
(MDMA).
 Originally used in psychotherapy but had no documented medical
benefits.
 Fosters intimacy and empathy without impairing intellect.
 Produced in small quantities, distributed at parties or “raves,”
and taken orally.
 A prototypic designer drug, increasingly popular.
Mechanism of Action

Similar to amphetamines, reverses biogenic amine
transporters.
Prefers serotonin transporter (SERT), increasing extracellular

serotonin.

Causes marked serotonin depletion for 24 hours after
one dose.

Repetitive use may cause permanent depletion, raising
neurotoxicity concerns.

Animal models show weak evidence, but studies report longterm cognitive impairment in heavy users.
Acute Toxic Effects
Hyperthermia, which, along with dehydration, may be fatal.

Serotonin syndrome (mental status changes, autonomic hyperactivity,

neuromuscular abnormalities).
Seizures.


Some users overhydrate to counter hyperthermia, causing water
intoxication:

Severe hyponatremia.

Seizures.

Death.

Withdrawal Effects
 Mood “offset” with depression lasting weeks.
 Increased aggression reported during abstinence in chronic users.
Safety Concerns
 Evidence for irreversible brain damage is inconclusive.
 Findings suggest even occasional use is unsafe.
CLINICAL PHARMACOLOGY OF DEPENDENCE & ADDICTION
General Overview
o No single pharmacologic treatment (even with
behavioral interventions) eliminates addiction.
o Addiction is not necessarily irreversible.
o Pharmacologic interventions may help at all stages,
particularly in massive overdose (life-saving reversal).
o
FDA-approved antagonists exist only for opioids and
benzodiazepines.
Withdrawal Management
o Withdrawal may involve central adrenergic
hyperactivity.
o Clonidine (α2-adrenoceptor agonist) reduces
withdrawal symptoms.
o Preferred approach: Slow tapering of long-acting
opioids.
Substitution Therapy
o
o
o
o
Uses a legally available agonist that acts on the same
receptor as the abused drug.
Approved for opioids and nicotine:
 Methadone replaces heroin.
 Nicotine patches replace smoking.
Rationale: Reduces health risks, crime, and improves
social integration.
Dependence remains but may lead to gradual dose
reduction and abstinence.
Pharmacologic Reduction of Cravings
o Naltrexone (μ-opioid receptor antagonist & partial
agonist):
 FDA-approved for opioid and alcohol
addiction.
 Modest effect via modulation of
endogenous opioid systems.
o Baclofen (GABAB-receptor agonist):
 Reduces cravings by inhibiting dopamine
neurons in the VTA.
 Effective at oral doses due to high GABAB
receptor affinity.
Experimental Treatments
o Rimonabant (CB1 inverse agonist/antagonist):
 Initially developed for smoking cessation
and weight loss.
 Withdrawn due to severe depression and
suicide risk.
 Rodent studies: Reduced selfadministration of drugs.
o Neuromodulatory Interventions:
 Inspired by optogenetics in rodent models.
 Deep brain stimulation (DBS) of nucleus
accumbens.
 Transcranial magnetic stimulation (TMS)
of prefrontal cortex.
 Case studies suggest potential, but no
controlled clinical trials.
POST-TEST: True or False

Cannabinoids act by blocking dopamine transporter leading to
addiction

Dopaminergic system that is implicated on addiction originates from
the nucleus accumbens and projects to the VTA

The opioid receptor tha is implicated in addiction is the kappa opioid
receptor

Nicotine acts directly on the dopamine neuron to cause its excitation.

Recent studies suggst that the ecruitment of the thalamus is
responsible for the compulsive behavior in addiction

Benzodiazepine is used for the treatment of alcohol withdrawal

Toluene (in rugby) addiction increases excitability of the VTA possibly
by altering the function of ionotropic receptors and ion channels.

Dopamine is the only neurotransmitter that is increased by cocaine
asit specifcally blocks the dopamine transporter

Varenicline is a drug used in opioid addiction.
 Naloxone may be used to treat craving during alcohol rehabilitation.