The neurobiology of drug addiction

Dr. Syed Faheem ShamsStudent of MD (Part-II)

Department of Psychiatry, BSMMU

Drug Abuse and Addiction are among the most seriousPublic Health problems that

our societyis facing.

and Frequently Coexist with Other Mental and Physical Disorders

Drug Addiction —

Chronically relapsing disorder that is characterized by a compulsion to seek and take drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug is prevented.

Koob GF. The neurobiology of addiction, 2006

Stages of the Addiction Cycle

• Acute rewarding effects of drugs of abuse — are mediated by neurochemical elements such as dopamine and opioid peptides in the nucleus accumbens and amygdala.

• Acute withdrawal from all major drugs of abuse — produces increases in reward thresholds, increases in anxiety-like responses and increases in CRF in the amygdala that are of motivational significance.

• Compulsive drug use associated with dependence— is mediated by not only loss of function of reward systems but recruitment of brain stress systems such as CRF, norepinephrine and dynorphin in the extended amygdala.

It is widely accepted that increased levels of dopamine in the nucleus accumbens are key in mediating the rewarding effects or positive reinforcement of drugs of misuse (Koob & Le Moal, 2001). Evidence is still accruing to support this.

Regarding Serotonin ⇒⇒⇒Serotonin does not directly participate in motivation-reward, but exerts influence through its effects on the DA system. Application of 5-HT onto dopaminergic neurons from the VTA increased their firing rate in vitro attributed to action of 5-HT on 5-HT2 receptors.

www.elsevier.com/locate/biochempharm Neurobiology of addiction

An integrative review, 2008

First Exposure to natural reward

Timeof Reward

First Exposure to drug reward

Timeof Reward

Repeated exposure to same natural reward & predictor:

DopamineSpike

DopamineSpike

DopamineSpike

Time ofReward

First time a better than predicted reward is had:

Cue

Cue DopamineSpikes

Time ofReward

Cue

T ime ofRew ardSpike DropsBelow Baseline

Cue

T ime ofRew ard Spike Continues

Cue

T ime ofRew ard Spike Continues

Anticipation In an elegant series of experiments, Schultz (2001) found that in primates trained to associate a cue with a pleasurable experience (food), increased dopaminergic activity was seen in response to the cue and not to the food. If the food was not then presented, dopaminergic function dropped. Reduced dopaminergic function is thought to be associated with negative affect (e.g. dysphoria). Thus, an individual with an addiction may see a ‘cue’ (e.g. a public house, mirror or needle) and if their drug of choice is not available may feel dysphoric, which is likely to increase the drive to obtain the drug.

Key Common Neuroanatomical Structures in Addiction

Nucleus Accumbens and Central Nucleus of the Amygdala — Forebrain structures involved in the rewarding effects of drugs of abuse and drives the binge intoxication stage of addiction. Contains key reward neurotransmitters: dopamine and opioid peptides.

Extended Amygdala — Composed of central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the nucleus accumbens. Contains “brain stress” neurotransmitter, corticotropin releasing factor that is involved in the anti-reward effects of drug dependence.

Medial Prefrontal Cortex — neurobiological substrate for “executive function” that is compromised in drug dependence and plays a key role in facilitating relapse. Contains major glutamatergic projection to nucleus accumbens and amygdala.

The Dopamine receptors

There are five types of receptors for dopamine in the human brain, identified as D1 to D5. They are not all equally involved in pleasure-seeking behavior. For instances, some studies have

shown that D3 receptors appear to be more involved in the phenomenon of dependency.

The functions of D1, D2 and D3 receptors primarily concern motivation and reward, while D4 and D5 receptors are more involved with behavioral inhibition.

http://www.britishpainsociety.org/book_drug_misuse

Neurobiological Substrates for the Acute Reinforcing Effects of Drugs of Abuse

Neurotransmitter

Dopamine

Opioid Peptides

GABA

Glutamate

Site

Ventral tegmental area, nucleus accumbens

Nucleus accumbens, amygdala, ventral tegmental area

Amygdala, bed nucleus of stria terminalis

Nucleus accumbens

Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus AccumbensArea and Nucleus Accumbens

From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.

Neurochemical Changes Associated with the Drug Use, Dependence and Relapse

Common Molecular Changes Associated with Dependence

Dopamine D-2 receptor binding- decreased in human imaging studies in dependent subjects.

CREB ( cyclic adenosine monophosphate response element binding protein) transcription factor- decreased in nucleus accumbens and extended amygdala during the development of dependence.

Delta-FosB transcription factor-changed during protracted abstinence to drugs of abuse.

Koob GF. The neurobiology of addiction, 2006

Neuro circuitry of Addiction

Reward Circuit- nucleus accumbens and extended amygdala (bed nucleus of the stria terminalis and central nucleus of the amygdala)

“Craving” Circuit- dorsal prefrontal cortex, basolateral amygdala

“Compulsivity” Circuit- ventral striatum, ventral pallidum,medial thalamic- orbitofrontal cortical loop

Koob GF. The neurobiology of addiction, 2006

Key Common Neurocircuitry Elements in Drug Seeking Behavior of Addiction

Role of Corticotropin-releasing Factorin Dependence

DrugCRF antagonist effects on withdrawal-induced anxiety-like responses

Withdrawal-induced changes in extracellular CRF in CeA

CRF antagonist effects on dependence-induced increases in self-administration

Cocaine Opioids Ethanol Nicotine 9-THC

↓↓↓↓↓

↑↑↑↑↑

↓↓↓↓↓

CeA = central nucleus of the amygdala.

Koob GF. The neurobiology of addiction, 2006

What Role Does Stress Play In Initiating Drug Use?

What Role Does Stress Play In Initiating Drug Use?

STRESSSTRESSSTRESSSTRESS

CRFCRFCRFCRF

AnxietyAnxietyAnxietyAnxiety DRUG USEDRUG USE(Self-Medication(Self-Medication))DRUG USEDRUG USE

(Self-Medication(Self-Medication))

CRFCRFCRFCRF

AnxietyAnxietyAnxietyAnxiety

What Happens When A Person Stops Taking A Drug?

What Happens When A Person Stops Taking A Drug?

ProlongedDRUGUSE

ProlongedDRUGUSE

Abstinence Abstinence

CRFCRF

AnxietyAnxietyAnxietyAnxiety

RELAPSRELAPSEE

RELAPSRELAPSEE

Extracellular CRF Levels in the CentralAmygdala During Ethanol Withdrawal

CNS Depressants

Alcohol [beer, wine, liquor, spirits, etc.]

OpiatesMorphineHeroin

Methadone Opium Codeine

Benzodiazepines Barbiturates General Anesthetics Sedative AntihistaminesVolatile Substances [solvents, glues, thinners, strippers, aerosols, paints, gasoline, etc.] Gamma hydroxybutyrate (GHB)

CNS StimulantsMajor Stimulants-----

Cocaine [coke, snow, crack, freebase]Amphetamines [meth, speed, ice, crystal, cat,

dexies]

Minor Stimulants----

Nicotine [tobacco, certain products to help people quit smoking]

Caffeine [coffee, tea, cocoa, chocolate, cola drinks, etc. ]

Hallucinogens• Cannabis and derivatives• Marijuana [pot, grass, joints]

Hashish [hash]THC (tetrahydrocannabinol)

• Other hallucinogens---• LSD (acid)

Ecstasy (MDMA) MescalineKetamine PCP (phencyclidine, angel dust) Psilocybin (magic mushrooms)

stimulationstimulation

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)• marijuana (activate cannabinoid receptors)• caffeine• alcohol (activate GABA receptors; an inhibitory transmitter)

How some drugs of abuse cause dopamine release:• opioids narcotics (activate opioid receptors)• nicotine (activate nicotine receptors)• marijuana (activate cannabinoid receptors)• caffeine• alcohol (activate GABA receptors; an inhibitory transmitter)

Drug :• cocaineAmphetamine

Vmat

transporter

Drug Types:• Amphetamines -methamphetamine -MDMA (Ecstasy)

• Release DA from vesicles and reverse transporter

Vmat serotonin/

OPIOIDS

Opiates act on— the reward circuitthe amygdalathe locus coeruleusthe cauadate nucleusthe periaqueductal grey matter.

Opiates also affect the thalamus, which would explain their analgesic effect.

The mechanism of action of heroin at the mu (m) opiate receptors

Heroin modifies the action of dopamine in the nucleus accumbens and the ventral tegemental area of the brain.

Once crossing the blood-brain barrier, heroin is converted to morphine, which acts as a powerful agonist at the mu opioid receptors subtype

Inhibits the release of GABA from the nerve terminal

Reduction of the inhibitory effect of GABA on dopaminergic neurones. The increased activation of dopaminergic neurones and the release of dopamine

Continued activation of the dopaminergic reward pathway leads to the feelings of euphoria

and the ‘high’ associated with heroin use.

Opioid tolerance

• In the face of repeated exposure, opiate sensitive neurons in the brain gradually become less responsive to opioid stimulation. Escalating doses of opioid are therefore required to stimulate the VTA to release dopamine into the NAc. This occur due to adaptive

changes to the sensitivity of opioid receiptor.

Opioid dependence

• Changes in the locus ceruleus (LC) at the base of the brain.

• Neurons in the LC produce noradrenaline, which stimulates wakefulness, breathing, blood pressure and general alertness. By attaching to mu cells in the LC, opioids suppress the release of noradrenaline, producing the familiar symptoms of opioid intoxication – drowsiness, slowed respiration and low blood pressure.

• In dependence, repeated exposure to opioids leads the LC neurones to increase their level of activity to counteract the opioid intoxication, so now the individual only feels relatively normal when taking opioid, and exhibits withdrawal symptoms when opioids are absent.

Opioid Withdrawal

• When opioids are not present to suppress the LC, excessive amounts of noradrenaline are released, triggering withdrawal symptoms, including:

• Anxiety• Muscle cramps• Diarrhoea Role of adrenoceptor agonist?• Alpha-2 agonist ↓NA release , as well as ⇒

↓Epinephrine and ↓Dopamine

ALCOHOL• Alcohol affects not

only the basic structures of the reward circuit, but also several other structures that use GABA as a neurotransmitter. GABA is one of the most widespread neurotransmitters in several parts of the brain, including the cortex, the cerebellum, the hippocampus, the amygdala, and the superior and inferior colliculi.

How does alcohol works?

Alcohol acts directly. ↓ ⇑ the effects of GABA. ⇓ the excitatory glutamate NMDA receptor. ⇑ the effects on 5-HT3 receptors. Possibly

2ndary to NMDA. ↓• CNS depressant action. There are numerous

additional effects, some of which may be secondary to the glutamatergic and GABA effects.

Alcohol withdrawal

⇑ glutamatergic NMDA function and is thought to be involved in seizures and cell death, by means of increased Ca2

+ influx through its channel and low Mg2

+. The hippocampus appears to be a critical site for such glutamatergic hyperactivity.

Cocaine

• Cocaine concentrate in the central link of the reward circuit. Cocaine’s effects on other structures such as the caudate nucleus may explain certain secondary effects of this drug, such as increased stereotyped behaviours (nail biting, scratching, etc.).

The M/A of cocaine

• Cocaine binds to dopamine re-uptake transporters on the pre-synaptic membranes of dopaminergic neurones. This binding inhibits the removal of dopamine from the synaptic cleft. Dopamine remains in the synaptic cleft and is free to bind to its receptors on the post synaptic membrane, producing further nerve impulses. This increased activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with cocaine use.

Slide : Positron emission tomography (PET) scan of a person on cocaine

Cannabis• It concentrates chiefly in the

ventral tegmental area and the nucleus accumbens, but also in the hippocampus, the caudate nucleus, and the cerebellum.

• THC’s effects on the hippocampus might explain the memory problems that can develop with the use of cannabis, while its effects on the cerebellum might explain the loss of coordination and balance experienced by people who indulge in this drug.

M/A of cannabis

Slide : THC binding to THC receptors in the nucleus accumbens: increased dopamine release

M/A of cannabis (cont.)

Slide: Increased cAMP produced in post-synaptic cell

• Cannabinoids have been shown to increase opioid synthesis and/or release (Manzanares et al, 1999). This may explain why opiate antagonists block some effects of cannabis and induce withdrawal in 9-THC-dependent rats or, conversely, why marijuana may reduce opiate withdrawal.

• There are two cannabinoid receptors: CB1 in the brain, for which the endogenous compound is anandamide, and CB2 on immune cells.

• CB1 receptors are widely distributed throughout the brain, but particularly in the cerebral cortex, hippocampus, cerebellum, thalamus and basal ganglia (Ameri, 1999).

• In mice lacking the CB1 receptor, rewarding and withdrawal responses to morphine and cannabinoids are reduced (Ledent et al, 1999; Martin et al, 2000). This suggests that the CB1 receptor is involved in dependence on not only cannabinoids but also opiates. As a result, CB1 agonists may have clinical utility in treating opiate addiction.

• The development of a CB1 receptor antagonist, SR141716A (Rinaldi-Carmona et

al, 1995), not only accelerated research into cannabinoids but also provided a possible treatment. This antagonist blocks both the physiological and psychological effects of smoked marijuana and therefore could be to cannabis what naltrexone is to heroin.

SEDATIVES

These modulate the GABA—benzodiazepine receptor

↓ ⇑ GABA (GABAA receptor) ↓ Inhibitory activity in the brain by opening of

Chloride channels and causing hyperpolarization by ⇑Cl¯ influx. (Nutt & Malizia, 2001).

In contrast to other drugs of misuse, benzodiazepines do not increase dopamine release in the mesolimbic system.

Sedative dependence and tolerance

• Chronic GABA stimulation results in less chloride channels opening→ ⇓Cl¯ influx.

• This down regulation is due to –

Lack of coupling between GABA binding site and chloride channel.

Not due to ⇓ in receptor number or ⇓ed affinity of the receptor for GABA.

Amfetamine and derivatives

• Amfetamine differs from cocaine in some extinct in M/A

1. It acts as a dopamine reuptake inhibitor like Cocaine.

2. It directly stimulates the release of dopamine.

ECSTASY

• Ecstasy (3,4-methylenedioxymethamphetamine or MDMA) and its derivatives MDA (Adam) and MDEA (Eve) have both stimulant and hallucinogenic properties.

M/A of Ecstasy

• MDMA → ⇑ 5-hydroxytryptamine (5-HT or serotonin) levels, and, to a lesser extent, dopamine levels, by stimulating release and inhibiting uptake.

Neuroimaging

PET and single photon emission tomography (SPET) to measure 5-HT transporter levels in persons who are regular heavy ecstasy users reported reduced levels. However, methodological questions about the tracer, contribution of blood flow and choice of subjects necessarily limit these conclusions (Semple et al, 1999; Reneman et al, 2001).

Image courtesy of Dr. GA Ricaurte, Johns Hopkins University School of Medicine

• In animal models, fluoxetine has been shown to be neuroprotective, apparently by blocking ecstasy uptake into 5-HT neurons, but it is unknown whether this protective effect occurs in humans. (Boot et al, 2000).

NICOTINE

• The nicotine in tobacco stimulates several distinct parts of the reward circuit, locus coeruleus and its noradrenergic neurons, which modulate movement. Several other areas in the brain that secrete acetylcholine also appear to be affected by nicotine. The hippocampus and the cortex are two such areas, which might explain the increased vigilance and attentiveness that smokers often report.

M/A of nicotine--

Reward circuit

↓

⇑ DOPAMINE

(main effect)

Ketamine

M/A----- As far as is currently known ⇒⇒⇒• The main pharmacological effect is antagonism

of glutamate at the NMDA receptor.• There is also evidence of some effect in the

dopamine, noradrenaline and serotonin systems. • Dependence has been described occasionally

and there are reports of compulsive use, tolerance and drug seeking behaviour but no documented withdrawal syndrome.

CAFFEINE

M/A---- Crosses the B-B barrier ↓ Acts as antagonist of adenosine receiptors ↓ ⇑ c. AMP in the neuron• At high doses, it can affect dopamine and

nonadrenergic neurons.• Clinical reports suggests that excessive caffeine

increases the psychotic symptoms in Schizophrenia patients.

Reward System in Addiction

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Ability to Experience Rewards Is DamagedAbility to Experience Rewards Is Damaged

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