neuroscience of substance abuse and dependence
Post on 04-Jun-2018
225 Views
Preview:
TRANSCRIPT
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
1/62
Neuroscience of Substance
Abuse and Dependence
Dr Shambu SugathanC/P: Dr Preethi Rebello
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
2/62
Introduction
Drug addiction constitutes a chronicCNS disorder characterized by
recurrent episodes of relapse in which
individuals resume drug-seeking anddrug-taking behavior
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
3/62
Detailed information exists on:
the neural pathways that underlie drug
reinforcement and drug-seeking
behavior,
selective alterations in neurochemical
activity
persisting neuroadaptations inneuronal signal transduction pathways
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
4/62
Phases of the Addiction Process
Addiction has been generally definedas uncontrolled, compulsive use of a
substance over time.
An initial period of drug use occurs
without clear evidence of addictive
behavior, followed by ever increasinglevels of drug consumption that
eventually leads to addiction.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
5/62
Stages of the Addiction Cycle
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
6/62
The process where addiction beginsinvolves complex changes in
mechanisms of positive reinforcement,
negative reinforcement, and hedonicdysregulation.
It also has been described in terms ofpersisting forms of maladaptive
learning and response patterns.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
7/62
Positive Reinforcement
definedas the process by which presentation
of a stimulus (drug) increases the
probability of a response (nondependent drug taking paradigms).
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
8/62
Negative Reinforcement
defined asa process by which removal of anaversive stimulus (negative emotional
state of drug withdrawal) increases theprobability of a response.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
9/62
In individuals with substance usedisorders, periods of chronic
substance use are invariably followed
by periods of abstinence andwithdrawal, during which various
withdrawal signs at the behavioral and
biological levels become manifested.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
10/62
These withdrawal episodes have beenmodeled using both active extinction
of drug-seeking behavior as well as
forced abstinence from drugavailability and drug context.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
11/62
Periods of withdrawal from drug useare followed by instances of relapse,
which are reinitiated by various trigger
factors: internal (e.g., stress states)
external (e.g., previously drug-paired
environmental cues)
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
12/62
Clinical evidence has clearlyestablished the ability of drug-
associated environmental cues to elicit
drug craving and consequentlyreinstate drug-seeking and drug-
taking.
Conditioned-cued responses have
been demonstrated for a variety of
drugs of abuse.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
13/62
Nucleus
accumbens Ventral
tegmental
area
Corpus Callosum
Connects Hemispheres
Creativity and Problem
Solving
Cerebellum
Coordinates muscles/ movement
and thinking processes
Hippocampus
Forms Memories
Coordinates thinkin rocesses
Extended Amygdala
Emotional responses: fear
and anger
Frontal Cortex
Planning, Strategizing, Logic,
Judgment
Thalamus
Locus
coeruleus
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
14/62
Brain Pathways of Reward and
Addiction Pathways That Underlie Drug
Reinforcement:
The common neural substrate of all
addictive drugs, including alcohol, isthe mesocorticolimbic dopamine
pathway.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
15/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
16/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
17/62
Dopamine Pathways: Reward, Pleasure, Euphoria,Motor Function, Decision making
Serotonin Pathways: Mood, Memory, Sleep, Cognition
Raphe
Prefrontal cortex
Hippocampus
Nucleus
accumbensVentral
tegmentalarea
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
18/62
Reward Pathway
Dopamine
Receptors: D1, D2
Function: pleasure,euphoria, mood, motorfunction
Serotonin
Receptors: 5HT3
Function: mood, impulsivity,anxiety, sleep, cognition
Cannabinoids
Receptors: CB1, CB2
Function: Pain, appetite,memory
Opioid peptides (Endorphins,Enkephalins)
Receptors: Kappa, Mu, DeltaFunction: pain
The following neurotransmitters act on the reward pathway:
In all rewards, dopamine is the final activation chemical
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
19/62
Reward Pathway
Dopamine
Ventral tegmental area,nucleus accumbens
Opioid Peptides
Nucleus accumbens,
amygdala, ventral
tegmental area
GABA
Amygdala, bed nucleus
of stria terminalis
Glutamate
Nucleus accumbens
Neurotransmitters and anatomical sites involved in the acute
reinforcing effects of drugs of abuse
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
20/62
Repeated exposure to nondrugrewards (e.g. food) activates this
pathway in a manner that does not
result in supranormativeneurotransmitter release and
stimulation of postsynaptic signaling.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
21/62
In contrast, drugs of abuse canhijack the reward system in a
manner that produces abnormal levels
of neuronal activation
Causes subsequently profound and
long-lasting adaptive changesfollowing repeated exposure to the
drug and intervening withdrawal
periods.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
22/62
Extensive data using a variety ofexperimental approaches have shown
that mesolimbic dopamine pathway
activity is required for the primaryreinforcing effects of drugs of abuse
Extracellular dopamine release in the
terminal fields of the nucleusaccumbens is significantly enhanced
during drug self-administration
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
23/62
Primary reinforcement by drugs ofabuse engages a widespread network
of the brain's motivational pathways
including: cortical regions and limbic structures
such as the prefrontal cortex,
amygdala, hippocampus, andhypothalamus.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
24/62
Differences across classes of abuseddrugs have been recognized.
Psychostimulants such as cocaine andamphetamine directly increase levels ofdopamine and other monoamines.
Opioids opiate receptors in VTAdecrease the activity of inhibitory GABA
interneurons, subsequently resulting in agreater release of dopamine in forebrainregions
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
25/62
Other drugs, including nicotine andcannabinoids, lead to enhanced
dopamine release through the
activation of their respective receptorsand subsequent disinhibition or
excitation of dopamine neurons.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
26/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
27/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
28/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
29/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
30/62
Conditioned Cue-Induced
Relapse Through a process of associative
learning, previously neutral stimuli
acquire incentive-motivational
properties during repeated pairingswith consumption of an abused drug.
These drug-associated stimuli
subsequently elicit subjective drugdesire and physiological arousal in a
manner that perpetuates a return to
further drug use
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
31/62
In the animal model several lines ofresearch have extensively implicated
cortico-striato-limbic pathways in the
development and maintenance ofdrugcue associations that drive drug-
seeking behavior after periods of
withdrawal.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
32/62
Of particular interest has been theamygdala,.
Excitotoxic lesions of the basolateral
amygdala have no effect on cocaine-taking during daily cocaine self-
administration
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
33/62
But these lesions completely abolishthe reinstatement of cocaine-seekingproduced by cocaine-paired cues longafter the cessation of cocaine self-administration
Other studies have examined drug-seeking after reversible forms of
neuronal inactivation of discrete brainregions with sodium channel blockersor GABA receptor agonists.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
34/62
Studies have demonstrated that theamygdalar mediation of conditioned-cued reinstatement is dopamine-dependent,
Intrabasolateral amygdala blockade ofD1receptors abolishes cue-induced
reinstatement, while enhancingdopamine levels in the amygdaladuring cue presentation will potentiatecocaine-seeking.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
35/62
Recent studies have implicated theamygdala in the acquisition and
consolidation of drugcue
associations.
Amygdalar disruption during the
memory reconsolidation of previouslylearned cues will abolish cue-induced
relapse.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
36/62
Other brain regions involved inconditioned-cued reinstatement
include discrete subregions of the
prefrontal cortex and striatum.
Pharmacological inactivation of the
dorsal medial PFC, lateral OFC, or thenucleus accumbens core subregion
significantly attenuates cue-induced
cocaine-seeking.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
37/62
Drug-induced adaptive changes in thecircuitry that drives stimulusresponse
(SR) learning, in particular the dorsal
regions of the striatum (caudate andputamen), which are known to
mediate habitual responses acquired
by the strengthening of SRassociations.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
38/62
It has been well-established thatpsychostimulant administration
produces the most notable changes in
gene expression in the dorsalstriatum, in contrast to the lesser
degree of changes observed in the
ventral striatum. Furthermore, the caudate-putamen
receives the densest innervation by
dopamine afferents.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
39/62
In rodent models, extracellulardopamine in the caudate-putamen is
increased during response for a
cocaine-associated cue, whileinactivation of the caudate-putamen
by pharmacological means blocks
response for cocaine-associated cuesor context.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
40/62
Recent studies PET in cocaine-dependent subjects during cue-
induced craving have shown that
dopamine in the caudate-putamen, butnot in the ventral striatum ie NA is
positively correlated with self-reports
of craving.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
41/62
In sum, a growing body of evidencesupports the idea of long-term
changes in striatal circuitry, whereby
the caudate-putamen criticallymediates habitual patterns of drug-
seeking at the time of relapse.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
42/62
Drug-Primed Reinstatement
Small doses of an abused drug caninitiate subjective states of drug desire
that prompt renewed drug consumption
in humans.
One notable contrast in the neural
circuitry underlying drug-primed versus
conditioned-cued reinstatement of
cocaine-seeking is the fact that
amygdala inactivation has no effect on
cocaine-primed reinstatement
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
43/62
Prelimbic cortex, NA core, and ventralpallidum are also involved in drug
induced reinstatement
Neurotransmitter projections may
drive cocaine-primed reinstatement,
including dopaminergic inputs to theinfralimbic cortex and NA shell.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
44/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
45/62
Stress-Induced Reinstatement
Stress clearly plays a role inacquisition, maintenance, and relapse
with drugs of abuse.
Stress in rats (usually footshock
presented in the drug-paired context)
has been commonly used to studystress-induced reinstatement of drug-
seeking..
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
46/62
Examination of the pathways thatmediate footshock-induced stress
have shown that some of the same
circuitry required for conditioned-cuedor drug-primed reinstatement of
cocaine-seeking is also necessary for
stress-induced reinstatement,
including the prelimbic cortex and
nucleus accumbens
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
47/62
Inactivation of extended amygdalastructures, including the central
amygdala and bed nucleus of the stria
terminalis, will attenuate stress-induced reinstatement,
while basolateral amygdala
inactivation fails to block stress-induced reinstatement
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
48/62
The withdrawal/negative affect stageconsists of key motivational elements
such as:
chronic irritability, emotional pain,malaise, dysphoria, alexithymia, and
loss of motivation for natural rewards,
characterized in animals by increasesin reward thresholds during withdrawal
from all major drugs of abuse.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
49/62
Significant plasticity occurs in theneurotransmitter circuits identified as
critical for the acute reinforcing effects
of drugs of abuse. In animal models of the transition to
addiction, increases in brain reward
threshold (decreased reward) occurthat temporally precede and highly
correlate with escalation in drug intake
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
50/62
During acute withdrawal, there isdecreased activity of the reward
systems as well as decreased opioid
peptide, GABA, glutamate, andneuropeptide Y activity in elements of
the extended amygdala and/or
nucleus accumbens
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
51/62
However, as dependence andwithdrawal develop, brain antireward
systems such as corticotropin-
releasing factor (CRF),norepinephrine, and dynorphin are
recruited
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
52/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
53/62
For example, extracellular CRF in theextended amygdala is increased
during acute withdrawal from drugs of
abuse, and critically, CRF antagonistsblock excessive drug-taking during
dependence
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
54/62
The observation that CRF receptorantagonists in the amygdala can block
excessive drug intake associated with
the development of dependenceprovides a compelling example of a
key aspect of the plasticity of the
extended amygdala in the
development of addiction.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
55/62
The development of the aversiveemotional state that drives the
negative reinforcement of addiction
may also contribute to the criticalproblem in drug addiction of chronic
relapse, where addicts return to
compulsive drug-taking long after
acute withdrawal
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
56/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
57/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
58/62
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
59/62
This effect suggests that stress maysensitize an individual to be more
attentive to drug-paired cues, increase
the incentive salience of the cues, orperhaps increase motivation to reduce
negative affect states through
renewed drug use.
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
60/62
CONCLUSION
Maladaptive alterations in spontaneousbehavior & the behavioral response tore-administration of the drug due todrug-induced changes in the CNS(transmitters, receptors, circuits,volume)
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
61/62
The classic anatomical areas of thebrain involved in the reward pathway
include the nucleus accumbens,
ventral tegmental area and theprefrontal cortex
Dopaminergic activity is the finalchemical action in most behaviours
relating to reward
-
8/13/2019 Neuroscience of Substance Abuse and Dependence
62/62
Drugs of abuse may work withreceptors and transporters to directly
or indirectly influence dopaminergic
activity
Addiction is the result of and results in
lasting changes to neurocircuitry,cellular and molecular mechanisms.
top related