Disorders of the reward system

Disorders of Reward, Drugs of Abuse and Their

Treatment

ADONIS SFERA, MD

The Reward PathwayThe Bottom Up System vs. The Top Down System

Nicotine, Alcohol, Opiates, Stimulants, HallucinogensPsychopharmacology of Feeding, Hunger and Sex

A natural high or drug induced high is mediated by the mesolimbic dopamine pathway which is sometimes referred to as the pleasure center of the brain, with dopamine as the pleasure neurotransmitter.

The Final Common Pathway of Reward

The Mesolimbic Dopamine Pathway: The Players

The Bottom Up System (Reactive)

1. Ventral tegmental

area(VTA), (dopamine cell bodies)

2. Nucleus

accumbens, (dopaminergic axons

project)

3. Amygdala, connects with both the VTA and the nucleus accumbens

The Top Down System (Reflective)

Projections from : 1. orbitofrontal

cortex(OFC) involved in regulating impulses,

2. ventromedial prefrontal cortex(VMPFC) involved in regulating emotions,

3. dorsolateral prefrontal cortex(DLPFC) involved in analyzing situations and regulating whether an action takes place.

Interaction Between the Two Systems

The brain makes its own drugs:

Endorphines and Enkephalins = Morphine/Heroin

Anandamide = Cannabis/marijuana

Acetylcholine = Nicotine

Dopamine = Cocaine/amphetamine

Why Are Drugs Addictive?

The numerous psychotropic drugs of abuse that occur in nature mimic the brain’s own neurotransmitters.

Directly stimulate the brain’s receptors in

the reward system, causing dopamine release and a consequent “artificial high”.

Drugs Are Addictive Because They Hijack The Reward System Of The Brain

Addiction CycleImpulsive Cycle*Occasional substance use is an impulsive choice driven by positive reinforcement of the drug’s expected effect (pleasure and reward).

*This “teaches” the brain to anticipate reward on subsequent exposure to the drug.

*When the substance is taken, pleasure will be experienced again, usually followed by regret

Compulsive Cycle*With repeated exposure to drug neurobiological changes occur in the brain, leading to craving, reduced reward on drug exposure and withdrawal during abstinence(negative reinforcement). *This leads to craving which is released by drug ingestion.

The rate of dopamine release in the nucleus accumbens determines how addictive a substance is.

Two ways of dopamine release: Regular (Tonic) and Irregular (Phasic)

Constant (tonic) dopamine release is not addictive. Bursts of dopamine (Phasic) release is addictive.

The Law of Addiction

How Addictive Are Stimulant Drugs?

How Addicting Are Different Substances?

Nicotine

Nicotine Causes Phasic Bursts of Dopamine

Three mechanisms of action: Directly causes dopamine release in the nucleus accumbens by binding to

α4β2 nicotinic postsynaptic receptors on dopamine neurons in the VTA Indirectly causes dopamine release by binding to the alpha 7 nicotinic

receptors on the glutamatergic neurons. Disinhibits mesolimbic dopamine neurons by desensitizing α4β2 on GABA

interneurons in the VTA.

Nicotine Actions On The Reward System

Varenicline (Chantix) Actions on Reward Circuits

Varenicline is a nicotinic partial agonist (NPA) selective for the α4β2 nicotinic receptors located on dopamine neurons and GABA interneurons in the VTA

CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes.

The recommended dose of CHANTIX is 1 mg twice daily following a 1week titration as follows:

Days 1 – 3: 0.5 mg once dailyDays 4 – 7: 0.5 mg twice dailyDay 8 - 1 mg twice dailyPatients should be treated with CHANTIX for 12 weeks.

Box Warning: Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking CHANTIX.

Varenicline (Chantix)

Bupropion in Smoking Cessation

In addition to enhancing GABA inhibition and reducing glutamate excitation, alcohol also enhances euphoric effects by releasing opiates and endocannabinoids, thereby mediating its “high”.

Alcohol Actions On The Reward System

Naltrexone is a mu opiate receptor antagonist Available in oral formulation and a once-monthly intramuscular injection

(extended-release 380 mg every 4 weeks). Extended-release form requires less will power to refrain from drinking. With oral naltrexone, one must decide daily whether or not to continue the

treatment.

Naltrexone (VIVITROL)

Acamprosate (Campral®) Acamprosate is a derivative of the amino acid taurine . It can be thought of as “artificial alcohol” because :

-Reduces excitatory glutamate neurotransmission - Enhances GABA neurotransmission.

Acamprosate: dosage for alcohol dependence:

The recommended dose of acamprosate for most people is 666 mg TID

It is not approved for use in people who have not yet stopped drinking.

Acamprosate should be used with an appropriate treatment program, including counseling and group sessions as necessary.

Adverse effects: Acamprosate is renally excreted, thus for people with moderate kidney problems,

the recommended dose is acamprosate 333 mg TID. For people with severe kidney problems, the drug is not recommended.

Opiate Neurons originate in the arcuate nucleus and project to both the ventral tegmental area(VTA), and to the nucleus accumbens. Opiate neurons release endogenous opiates such as enkephalin. Enkephalin increases dopamine in nucleus accumbens.

Actions of Opiates on Reward Circuits

Endogenous Opiate Neurotransmitters Opiate drugs act on opiate receptors such as mu, delta, and kappa. Endogenous opiate- are peptides derived from precursor proteins called

POMC (pro-opio-melano-cortin). They are proenkephalin and prodynorphin. Endorphins, enkephalins or dynorphin, which are then stored in opiate

neurons. Sigma receptors are no longer considered opiate receptors.

Methadone vs. Buprenorphine

Methadone is a full agonist at all opioid receptors.

Buprenorphine is a partial agonist µ-opioid receptors, partial agonist at δ-opioid receptors, and antagonist at the κ-opioid receptors.

Buprenorphine is much harder to abuse (partial agonist) so patients are allowed to take it home. Methadone can be abused, so patients need to travel to a clinic each day to take their medication.

Withdrawal from Buprenorphine is generally less severe than Methadone.

The risk of a fatal overdose on Buprenorphine is less than with Methadone.

For people with heavy opiate habits and serious addiction, Buprenorphine cannot provide effective relief from withdrawal symptoms. Methadone works better for such individuals.

Methadone and Buprenorphine in Opiate Addiction

Buprenorphine is used for:1. Treatment of opioid addiction in higher dosages (>2 mg),2. Control moderate chronic pain in dosages ranging from 20–70 µg/hour.

Formulations:

Buprenorphine

Buprenorphine- Naloxone Combination (Suboxone)

Stimulants

Actions of Stimulants on Reward Circuits

The abuse properties of stimulants stem from their ability to enhance dopamine release in the nucleus accumbens.

Cocaine The main mechanism of action of cocaine is to block

reuptake of monoamines, principally dopamine(DA) but also norepinephrine(NE) and serotonin(5HT).

There is also a local anesthetic action.

Amphetamine/Methamphetamine Amphetamine and methamphetamine are both

pseudosubstrates reverse transporters of dopamine (DAT) act as inhibitors of the vesicular monoamine

transporter(VMAT).

Methamphetamine and Schizophrenia

Changes in dopamine neurons, include: -long lasting depletions of dopamine levels -axonal degeneration, -a state that clinically and pathologically is called “burn-out”

Benzodiazepines and Sedative Hypnotics

Actions of Sedative Hypnotics and Benzodiazepines on Reward Circuits

Decrease in the release of GABA from GABA-ergic neurons causes DA neurons to be disinhibited and their firing rate increases (see example single-unit recording in red).

This results in more DA being released in the nucleus accumbens.

Cannabis

Marijuana delivers its active ingredients, the cannabinoids to the brain’s own cannabinoid receptors, triggering dopamine release in the nucleus accumbens.

Actions of Marijuana and THC on Reward Circuits

Cannabinoid Receptors

Receptors: *CB1 receptor is found primarily in the brain, and mediates the psychological effects of THC.

*CB2 receptor is associated with the immune system

Nonpsychotropic cannabinoids act as N-methyl-D-aspartate receptor blockers.

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide.

Elevation of anandamide levels in cerebrospinal fluid is inversely correlated to psychotic symptoms.

Enhanced anandamide signaling leads to a lower transition rate from initial prodromal states of schizophrenia into frank psychosis.

Currently in Phase 2 clinical trials.

Non-Psychotropic Cannabinoids

Hallucinogens and Club Drugs

Actions of Club Drugs on Reward Circuits

Club drugs such as phencyclidine(PCP) and ketamine are antagonists at N-methyl-D-aspartate(NMDA) receptors and thus cause NMDA hypoactivity, which in turn leads to disinhibition of dopamine release.

Gamma hydroxybutirate(GHB) is an agonist at GHB and GABA-B receptors.

GHB is used in the treatment of fibromyalgia.

Natural Rewards and Dopamine Levels

Eating, Hunger and Reward Circuits

The circuitry of hunger is interconnected with the circuitry of reward, however food consumption is also regulated by peripheral signaling systems (leptin and insulin).

Dopamine projections extend to the mamilary nucleus (MAM) of the hypothalamus, an area important for regulatory control of eating

Projections from the MAM nucleus extend to the nucleus accumbens.

The Spiral of Binge Eating

Psychopharmacology of Sex

Dopamine activity in reward circuitry is thought to play a central role in sexual desire and arousal.

Dopaminergic neurons also project to the hypothalamus, where they may have input to the regulation of sexual desire and arousal via neurons in the medial preoptic area (MPOA) and the projection of those neurons to the nucleus accumbens.