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The Reward Pathway
The Bottom Up System vs. The Top Down System
Nicotine, Alcohol, Opiates, Stimulants, Hallucinogens
Psychopharmacology 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.
1. Ventral tegmental
area(VTA), (dopamine cell
ic axons project)
3. Amygdala, connects
with both the VTA and
the nucleus accumbens
Projections from :
1. orbitofrontal cortex(OFC)
involved in regulating
2. ventromedial prefrontal
cortex(VMPFC) involved in
3. dorsolateral prefrontal
cortex(DLPFC) involved in
analyzing situations and
regulating whether an
action takes place.
The brain makes its own drugs:
Endorphines and Enkephalins = Morphine/Heroin
Anandamide = Cannabis/marijuana
Acetylcholine = Nicotine
Dopamine = Cocaine/amphetamine
The numerous psychotropic drugs of abuse
that occur in nature mimic the brain’s own
Directly stimulate the brain’s receptors in the
reward system, causing dopamine release and
a consequent “artificial high”.
*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
*When the substance is
taken, pleasure will be
experienced again, usually
followed by regret
*With repeated exposure to drug
neurobiological changes occur in
the brain, leading to
craving, reduced reward on drug
exposure and withdrawal during
*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.
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.
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
The recommended dose of CHANTIX is 1 mg twice daily
following a 1week titration as follows:
Days 1 – 3: 0.5 mg once daily
Days 4 – 7: 0.5 mg twice daily
Day 8 - 1 mg twice daily
Patients 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.
In addition to enhancing GABA inhibition and reducing glutamate
excitation, alcohol also enhances euphoric effects by releasing
opiates and endocannabinoids, thereby mediating its “high”.
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
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.
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.
Opiate drugs act on opiate receptors such as mu, delta, and kappa.
Endogenous opiate- are peptides derived from precursor proteins called
They are proenkephalin and prodynorphin.
Endorphins, enkephalins or dynorphin, which are then stored in opiate
Sigma receptors are no longer considered opiate receptors.
Methadone is a full agonist at all
Buprenorphine is a partial agonist
µ-opioid receptors, partial
agonist at δ-opioid
receptors, and antagonist at the
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
The risk of a fatal overdose on Buprenorphine is less than
For people with heavy opiate habits and serious
addiction, Buprenorphine cannot provide effective relief
from withdrawal symptoms. Methadone works better for
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.
The abuse properties of stimulants stem from their ability to
enhance dopamine release in the nucleus accumbens.
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 and methamphetamine are both
reverse transporters of dopamine (DAT)
act as inhibitors of the vesicular monoamine
Changes in dopamine neurons, include:
-long lasting depletions of dopamine levels
-a state that clinically and pathologically is called “burn-out”
Decrease in the release of
GABA from GABA-ergic
neurons causes DA neurons
to be disinhibited and their
firing rate increases (see
recording in red).
This results in more DA being
released in the nucleus
Marijuana delivers its active ingredients, the cannabinoids to the brain’s own
cannabinoid receptors, triggering dopamine release in the nucleus accumbens.
*CB1 receptor is found
primarily in the
brain, and mediates
effects of THC.
*CB2 receptor is
associated with the
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
Currently in Phase 2 clinical trials.
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
Gamma hydroxybutirate(GHB) is
an agonist at GHB and GABA-B
GHB is used in the treatment of
The circuitry of hunger is
interconnected with the
circuitry of reward, however
food consumption is also
regulated by peripheral
signaling systems (leptin and
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
Dopamine activity in reward
circuitry is thought to play a
central role in sexual desire
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