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Summary GGZ3025 - Addiction - Task 3
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GGZ3025 VerslavingTASK 3 – VERSLAVING IS EEN HERSENZIEKTE
IS THERE A COMMON MOLECULAR PATHWAY FOR ADDICTION?
Bron: Nestler (2005)
Despite different mechanisms of actions and pharmacological effects, all drugs of abuse cause
certain common effects after both acute and chronic exposure. The drugs are all acutely
rewarding. Besides, all drugs produce similar negative emotional symptoms upon withdrawal,
a prolonged period of sensitization, and associative learning toward drug-related
environmental cues.
All drugs of abuse converge on a common circuitry in the brian’s limbic system, with the
most attention been given to the mesolimbic dopamine pathway, which includes DA neurons
in the ventral tegmental area (VTA) and their targets in the limbic forebrain, especially the
nucleus accumbens (NAc). This VTA-NAc pathway is one of the most important substrates
for the acute rewarding effects of all drugs of abuse. Each drug activates dopaminergic
transmission in the NAc and many produce dopamine-like (yet dopamine-independent)
effects on the same NAc neurons. In addition, several drugs seem to activate the brain’s
endogenous opioid and cannabinoid systems within the VTA-NAc pathway.
On the basis of these common acute actions, one would expect that chronic exposure to
drugs of abuse would also cause common chronic functional changes in the VTA-NAc
pathway. Recent work has established that several additional brain areas that interact with the
VTA and NAc are also essential for acute drug reward and chronic changes in reward
associated with addiction. The include the amygdala (and related structures of the extended
amygdala), hippocampus and several regions in the PFC.
Growing evidence indicates that the VTA-NAc pathway and other limbic regions mediate (in
part) the acute positive emotional effects of natural rewards, such as food, sex and social
interactions. These regions have also been implicated in so-called natural addictions
(compulsive consumption of natural rewards, such as overeating, gambling and sexual
addictions). Findings suggest that shared pathways may be involved; two examples are cross-
sensitization that occurs between natural rewards and drugs of abuse, and similar
abnormalities found in brain imaging scans in drug and natural addictions. Thus, early
findings in the field raise the possibility that the similar behavioral pathology that
characterizes drug addictions and certain natural addictions may be mediated, at least in part,
by common neural and molecular mechanisms.
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, GGZ3025 Verslaving
Figure; converging acute actions of drugs of abuse on the VTA-NAc. Stimulants directly
increase dopaminergic transmission in the NAc. Opiates do the same indirectly: they inhibit
GABAergic interneurons in the VTA, which disinhibits VTA dopamine neurons. Opiates also
directly act on opioid receptors on NAc neurons, and opioid receptors, like D2 dopamine
(DA) receptors, signal via Gi; hence, the two mechanisms converge within some NAc
neurons. The actions of the other drugs remain more conjectural. Nicotine seems to activate
VTA dopamine neurons directly via stimulation of nicotinic cholinergic receptors on those
neurons and indirectly via stimulation of its receptors on glutamatergic nerve terminals that
innervate the dopamine cells.
Alcohol, by promoting GABAA receptor function, may inhibit GABAergic terminals in VTA
and hence disinhibit VTA dopamine neurons. It may similarly inhibit glutamatergic terminals
that innervate NAc neurons. Many additional mechanisms (not shown) are proposed for
alcohol. Cannabinoid mechanisms seem complex, and they involve activation of CB1
receptors (which, like D2 and opioid receptors, are Gi linked) on glutamatergic and
GABAergic nerve terminals in the NAc, and on NAc neurons themselves. Phencyclidine
(PCP) may act by inhibiting postsynaptic NMDA glutamate receptors in the NAc. Finally,
there is some evidence that nicotine and alcohol may activate endogenous opioid pathways
and that these and other drugs of abuse (such as opiates) may activate endogenous
cannabinoid pathways (not shown). PPT/LDT = peduncular pontine tegmentum/lateral dorsal
tegmentum.
Common circuit-level adaptations
Just as all drugs increase dopaminergic transmission to the NAc after administration, they also
produce common adaptations in dopamine function after chronic exposure. Chronic
exposure to any of several drugs of abuse causes an impaired dopamine system, which can
be viewed as a homeostatic response to repeated drug activation of the system (or tolerance).
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After chronic drug use, baseline dopamine functioning is reduced, and normal rewarding
stimuli may be less effective at eliciting typical increases in dopaminergic transmission. These
change may contribute to the negative emotional symptoms observed between drug
exposures or upon drug withdrawal. At the same time, chronic drug exposure seems to
sensitize the dopamine system, with greater increases in dopaminergic transmission occurring
in response to the drug in question and to drug-associated cues. This sensitization can last
long after drug-taking ceases and may relate to drug craving and relapse.
Chronic drug states are also associated with common changes in central corticotropin
releasing factor (CRF) systems. Abrupt withdrawal leads to activation of CRF-containing
neurons in the amygdala. These neurons innervate many forebrain and brainstem regions.
Activation of these neurons during withdrawal partly mediates the negative emotional
symptoms as well as many of the somatic symptoms that occur upon drug withdrawal, and
may contribute to craving and relapse as well.
Another common adaptation to chronic drug use is cortical hypofrontality; reduced baseline
activity of several regions of frontal cortex, such as prefrontal cortex, anterior cingulate cortex
and orbitofrontal cortex. These regions are important for cognitive control, including working
memory, attention and behavioral inhibition, and are important in controlling an individual’s
response to environmental stimuli. The chronic drug-treated state is associated with reduced
basal activity of cortical pyramidal neurons and a reduced sensitivity of the neurons to
activation by natural rewards. This presumably underlies the hypofrontality noted in human
brain scans. In contrast, these neurons are hypersensitive to activation by drugs of abuse as
well as drug-associated stimuli.
Figure; highly simplified scheme of some common, chronic actions of drugs of abuse on the
VTA-NAc. The top panel (control) shows a VTA neuron innervating an NAc neuron and
glutamatergic inputs to the VTA and NAc neurons, under normal conditions. After chronic
drug administration (lower panel), several adaptations occur. In VTA, drug exposure induces
TH and increases AMPA glutamatergic responses (Glut) via regulation of glutamate
receptors. There is also evidence that VTA dopamine neurons decrease in size. Induction of
CREB activity and
alterations in neurotrophic
factor (NTF) signaling may
partly mediate these effects.
In NAc, all drugs of abuse
induce the transcription
factor ∆FosB, which may
then mediate some of the
shared aspects of addiction
by regulation of numerous
target genes. Several, but not
all, drugs of abuse induce
CREB activity in this region,
which may be mediated by
upregulation of the cAMP
pathway.
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