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Behavioural: L2 - Neuroadaptive theories of Addiction ((Koob & Le Moal…
Behavioural: L2 - Neuroadaptive theories of Addiction
Koob & Le Moal, 1996
1) Counteradaptation/ opponent-process
: linked to the development of hedonic tolerance via opponent-process theory
Drug-opposite, or opponent, processes produce a hypo-functional state of reward pathways which leads to dysphoria &/or anxiety during withdrawal. In this case drug-seeking behaviour represents an attempt to alleviate discomfort.
Opponent-process:
The acute effects of initial drug intake can trigger the beginnings of counteradaptive mechanisms (e.g. neuroadaptations in DA & opioid peptide systems), & the recruitment of opposing systems such as the activation of brain stress systems (e.g. corticotropin -releasing factor)
Homeostasis of reward:
An organism maintains equilibrium in all of its systems including brain reward systems.
Environmental factors (e.g. drug taking) that challenge homeostasis are met with counteractions to maintain the equilibrium
Counteradaptive processes:
Body fails to return to the normal homeostatic state & therefore form an allostatic state.
Allostasis:
maintenance of stability outside the normal homeostatic range: e.g. reset the system parameters at a
new set point
These changes to neurotransmitter and reward systems start addiction cycle - dysregulation of reward system produce loss of control over drug intake and addiction.
mPFC is hypoactive at rest in addicts & Adolescents more vulnerable to drug addiction than adults.
2) Incentive-salience:
the progressive increase in a drug’s effect is conceptualised as a shift in an incentive-salience state
Relapse is triggered by drug-like processes that activate reward pathways in a manner directionally similar to the acute effects of the drugs themselves (increase in drug “wanting” not the hedonic effects of the drug or drug “liking”)
Drugs of abuse can promote drug-taking behaviour in the absence of any subjective hedonic effects (Fischman 1989, Fischman & Foltin 1992)
manipulations of DA neurotransmission have effects on motivated behaviour (wanting) without changing basic hedonic reactions (liking) to unconditioned rewards (Berridge et al 1989; Ohuoha et al 1997)
Escalation
Progressive increase in frequency and intensity of use is one behavioural phenomenon characterising the development of addiction
Ahmed & Koob, 2002
1hr low access group Vs 6hr long access (self-administration)
reward thresholds for 6hr increased far more than 1hr accross sessions.
= Increase in hedonic set point
Neuroadaptive models explain changes in the motivation for drug seeking that reflect compulsive drug use
Incentive-sensitisation
1) potentially addictive drugs share the ability to produce long-lasting changes in brain organisation
2) Brain systems that are changed include those normally involved in the process of incentive motivation and reward
3) Critical neuroadaptations for addiction render these brain reward systems hypersensitive (sensitised) to drugs and drug-associated stimuli
4) brain systems that are sensitised do not mediate the pleasurable effects of drugs (“liking”), but instead they mediate a sub-component of reward (incentive salience/ “wanting”)
Psychological components of reward
(Berridge & Robinson (2003)
2)
Affect/Emotion:
Implicit 'liking' & conscious pleasure
Distributed neural network including opioid transmission onto GABAergic neurons in NAcc (shell) & mesolimbic outputs to the ventral pallidum & related structures
DA is neither necessary nor sufficient for generating ‘liking’
1)
Learning:
Implicit & explicit knowledge produced by associative conditioning and cognitive processes
Associative learning
; neural substrates are distributed across subcortical and cortical structures
Cognitive processes
are more cortical including orbitofrontal, insular & other cortical areas & subcortical structures that interact with cortical areas
3)
Motivation
: implicit incentive salience ‘wanting’ & cognitive incentive goals
Influenced by DA neurotransmission
Other substrates are also involved including intrinsic spiny neurons of NAcc& connections to the amygdala, basal forebrain & cortex
Two classes of drug effects
sensitized
by addictive drugs:
Psychomotor activating effects
Incentive motivational effects
Both are, in part, mediated by NAcc-related circuitry
NEUROADAPTATIONS: Chronic Drug Administration
Chronic psychostimulant administration produces
long-term increases
in drug-induced
DA
release in
NAcc
(Robinson, 1993)
r
einforcement-enhancing
: may lead to compulsive drug-taking & relapse
Chronic psychostimulant,
opiates
or
ethanol
administration produces short term reductions in basal & drug-induced DA release in NAcc (Parsons et al. 1991; Imperato et al. 1992; Segal & Kuczenski 1992)
-
reinforcement-opposing
: may underlie aversive motivational symptoms associated with drug withdrawal & contribute to craving
Chronic administration alters
D2
receptor
binding density
, & levels of
D1
receptor binding in
NAcc
(Kleven et al 1990; Neisewander et al 1994)
Increases in
dynorphin
function in
NAcc
during chronic
cocaine
administration
Opioids
inhibit locus
coeruleus firing (NA system)
; following chronic morphine administration, LC neurons show tolerance to this inhibition; in withdrawal LC firing increases above control levels (Nestler et al 1994)
When rats are made dependent on morphine - naloxone injected into the LC produce withdrawal symptoms (antagonist-precipitated withdrawal) Maldonado et al (1992)
NEUROADAPTATIONS: Drug Withdrawal
Early in cocaine withdrawal spontaneous activity of VTA neurons is increased but later in withdrawal it is decreased (Henry et al 1989; Ackerman & White 1992)
There are changes in opiate receptor function during withdrawal from chronic opiate administration (Nestler 1992, Nestler & Aghajanian, 1997)
Chronic nicotine use increases the number of nAChRs (Marks et al 1992)
Reduction of GABAerigc and increased glutaminergic transmission during ethanol withdrawal
Dopaminergic and serotonergic neurotransmission is reduced in the nucleus accumbens (NAc) during drug withdrawal (Weiss et al. 1992)
Augmentation of brain stress systems (e.g. increased corticotropin-releasing factor (CRF)-response) associated with cocaine, opiates, ethanol & THC withdrawal (Rassnick et al 1993)
Treatment of withdrawal symptoms is not effective in the treatment of addiciton
Sensitisation
Sensitization is very persistent - Lasts for months/years after drug treatment
May account for relapse long after quitting the drug
Individual differences in susceptibility to sensitization
May explain why some users become addicted and others do not
Counteradaptation
The allostatic state:
represents a chronic deviation of the reward set point & is fuelled by both the dysregulation of reward circuits & activation of brain & hormonal stress responses.
Behavioural manifestation
of this allostatic state = compulsive drug taking (expressed through activation of brain circuits involved in compulsive behaviour e.g. the cortico-striatal-thalamic loop)
Relapse
-Involves activation of mesolimbic DA system
Drug withdrawal & allostasis
Motivational changes associated with acute drug withdrawal reflect opponent-process-like changes in the reward circuitry activated by the acute reinforcing effects of drugs of abuse
It has been suggested that different brain regions mediate the physical & motivational symptoms of dependence (Koob, 1992)
Withdrawal Symptoms
physical signs: these may be largely irrelevant to the motivation to take drugs:
withdrawal symptoms of addiction can now be managed with appropriate medication
Not all addictive drugs produce severe physical symptoms e.g. crack cocaine
addicts report craving long after the physical symptoms have subsided
Acute withdrawa
l is also associated with a negative affective state:
dysphoria, depression, anxiety, irritability; reduced reward (increased ICSS reward thresholds) associated with withdrawal from all major drugs of abuse
If you do manage to quit and stay in longer term abstinence, you still lower affectively that you should be, but you still do recover some of the good parts of the drug again.
Neural substrates of motivational withdrawal may involve:
1) Disruption of the same neural systems implicated in the positive reinforcing effects of drugs:
Decreases in activity of mesolimbic DA system and 5-HT neurotransmission in NAcc occur
during acute withdrawal from all major drugs of abuse. (Weiss et al 1992, 1996).
-
2) Neurochemical systems involved in stress modulation: HPA axis and brain stress system mediated by CRF are activated during withdrawal – elevated adrenocorticotropic hormone, corticosterone and amygdala CRF in acute withdrawal (Koob 2008)
CRF
Both the hypothalamic-pituitary-adrenal axis and the brain stress system mediated by corticotropin-releasing factor (CRF) are dysregulated by the chronic administration of all major drugs with dependence or abuse potential, with a common response of elevated adrenocorticotropic hormone, corticosterone and amygdala CRF during acute withdrawal
Sensitisation
Theory is about drug craving even though you know you should quit and we are showing tolerance to it.
If the neural systems that mediate incentive salience become sensitised, & if the incentive salience attributed to drug taking & to associated stimuli becomes amplified, then compulsive drug-seeking & drug taking behaviour may follow