neurobiology of drug craving

2. Definition of craving
 Although drug craving has been defined in numerous
ways, it has generally been regarded as a desire to
use a drug.
 It is a combination of thoughts and feelings. There is a
powerful physiological components to craving that
makes it a very powerful event and very difficult to
resist.
 Craving is sometimes defined as a "subjectively
experienced" desire or urge to approach and consume
a particular substance

4. Brain Networks Associated
With Craving
Drugs of abuse activates the brain’s “reward circuit.”
Neurons located in the nucleus accumbens extend to both
the amygdala and the frontal cortex areas. The
amygdala, which is highly connected to brain regions that
control emotions (i.e., the limbic system), plays a role in
the modulation of stress and mood. The frontal cortex
areas integrate incoming sensory information, such as
sights, smells, and sounds.

6. • Integration of sensory
Prefrontal information
cortex • reward memory is
thought to be located
Neucleus • plays a role in the
accumbence amygdala modulation of stress
and emotions
• which plays a role in
basal
repetitive thought and
ganglia
behavior patterns

7.  Neurons located in the amygdala also send information to
the DLPC and the basal ganglia. The DLPC sends
information back to the basal ganglia (a connection that
may play a role in obsessive-compulsive behaviors) and to
the nucleus accumbens.
 Feedback from the DLPC to the nucleus accumbens may
sensitize the latter to further drug exposure.

8.  Neuroscientists discovered drugs also alter connections in
brain circuits that govern learning and memory, causing the
formation of strong associations between the drug’s
pleasurable sensation and the circumstances under which
it was taken.
 Drugs also disrupt brain circuits involved in impulse control
in the prefrontal cortex, making it more difficult for addicts
to resist taking drugs. Conversely, research suggests
existing deficiencies in prefrontal function increase the risk
of drug addiction.
 This finding may help explain why adolescents are more
susceptible to addiction — the prefrontal cortex does not
become fully developed until people reach their mid-20s.

10. Craving Cycle

11. Stage I: Set-up behaviors:
Including: Physical factors, Psychological factors & Social factors.
Stage II: Trigger Events for Craving:
 Thought Triggers.
 Feeling Triggers.
 Behavioral Triggers.
 Situational Triggers.
Stage III: The Craving Cycle:
Gorski (2001) proposed the craving cycle as a series of self reinforcing
thoughts and behaviors that continue to activate and intensify the craving
response.
This cycle is marked by obsession, compulsion, physical craving, and drug-
seeking behavior.

12. Anti- Craving medications

13. Neurotransmitters …………
Neurotransmitter Site
Dopamine Ventral tegmental area, nucleus accumbens
Opioid Peptides Nucleus accumbens, amygdala, ventral
tegmental area
GABA Amygdala, bed nucleus of stria terminalis
Glutamate Nucleus accumbens

14. Opioid system:
 The mu subtype appears to be a key in opiate addiction: for
mice lacking this receptor, morphine is no longer rewarding or
reinforcing.
 Neuroimaging studies suggest that alterations in mu receptor
level may be fundamental to addiction. Increased receptor
levels in the anterior cingulate was found in recently abstinent
humans addicted to cocaine or opiates; which may reflect
elevated mu opiate receptor levels or decreased endogenous
opioid levels leading to craving.
 Roles for kappa and delta opiate receptors in addiction are
also evident. Unlike mu receptors, kappa receptor stimulation
reduces dopamine function in the NAcc. This may possibly
result in dysphoria. In animal models, delta antagonists can
reduce self-administration of alcohol, suggesting that this
receptor also plays a key role in reinforcement.

15. GABA Systems
Gamma-aminobutyric acid (GABA) is the primary inhibitory
neurotransmitter in the brain.
Sedative-hypnotic drugs including alcohol, benzodiazepines
(e.g., Valium®), and barbiturates have long been hypothesized
to modulate receptors in GABA systems.
Supporting this concept, experimental drugs that decrease the
function of GABA receptors reduce alcohol consumption by rats.
Microinjections of GABA antagonists into various rat brain.
Regions suggest that an important brain area for alcohol- GABA
interactions is the central nucleus of the amygdala, a structure
that communicates with the basal forebrain structures and is
associated with emotion and stress.

16. NALTREXONE (ReVia®; Vivitrol®)
 opioid antagonist medication that binds to opioid receptors
but does not activate them.
 useful for highly motivated recently detoxified patients who
want total abstinence .
 How it works: Naltrexone blocks the part of your brain that
feels pleasure when taking narcotics. Because it blocks the
opioid receptors it prevents the body from responding to
opiates
 It can be taken by mouth once daily or every other day, has
minimal side effects and is not addicting.
 A favorable treatment outcome requires some form of
psychotherapy, careful monitoring of medication compliance
and effective behavioral interventions.
 Side effects: Nausea, vomiting, diarrhea, constipation,
headache, dizziness.

17. METHADONE (Dolophine®; Methadone
Diskets®)
 Methadone blocks the receptors in the brain that are affected by
opiates such as heroin, enabling users to gradually detoxify
from opiates without experiencing painful withdrawal symptoms.
 Methadone occupies the receptors in the brain that opiates use,
blocking the high feeling that opiates provide and making the
user feel more stable.
 This reduces the drug cravings and withdrawal symptoms that
often lead to relapse. Because Methadone’s effects last
between 24 and 36 hours, most patients can be maintained on
one daily dose.
 Side effects: Drowsiness, weakness, nausea, constipation,
headache, loss of appetite.

18. BUPRENORPHINE (Buprenex®; Subutex®,
Suboxone)
 Buprenorphine hydrochloride is a semi-synthetic partial µ-
opioid receptor agonist
 Approved for treatment of pain and as a maintenance
treatment for opioid dependence .
 Several studies have shown that a dose of 8 mg of
Buprenorphine daily, administered sublingually is roughly
equivalent of a 60 mg daily dose of methadone.
 SUBOXONE :Buprenorphine and Naloxone
 Because Naloxone has poor oral and sublingual bio-
availability, it does not interfere with the effects of sublingually
administered Buprenorphine. This combined preparation
appears to be as effective as Buprenorphine alone and is less
likely to be abused by patients

19. Baclofen
 a GABA B receptor agonist that inhibits the release of several
neurotransmitters, including dopamine, noradrenaline, 5HT, and
glutamate .
 Baclofen, through inhibition of somatodendritic dopamine
release, prevents development of cocaine-induced behavioral
sensitization and abolishes the motor-stimulant actions of
cocaine.
 Baclofen was recently shown to attenuate the reinforcing effects
of cocaine in rats.
 Other studies suggest that baclofen may be a fast acting
treatment for the affective state that occurs during cocaine
abstinence and, hence, may promote greater engagement in
psychosocial treatment.

20. Antalarmin
 Corticotropin releasing hormone antagonist
 inhibit CRF-stimulation of cAMP or CRF-stimulated ACTH
release from cultured rat anterior pituitary cells.
 sauvagine binding to CRF1 receptors in brain sections
demonstrating their ability to cross the blood-brain-barrier.
In in vivo studies, peripheral administration of these
compounds attenuate stress-induced elevations in plasma
ACTH levels in rats demonstrating that CRF1 receptors
can be blocked in the periphery

21.  In several experiments on rats; Antalarmin prevent dose
escalation with prolonged use, suggesting that it might
stabilise cocaine use and prevent it increasing over time,
although without consistently reducing it.
 Antalarmin also showed positive effects in reducing
withdrawal syndrome from chronic opioid use, and
significantly reduced self-administration of ethanol in
ethanol-addicted rodents.
