Mechanisms Addiction

1 mechanisms

1.1 summary of addiction-related plasticity
1.2 reward system

1.2.1 mesocorticolimbic pathway
1.2.2 role of dopamine , glutamate


1.3 reward sensitization

mechanisms

chronic addictive drug use causes alterations in gene expression in mesocorticolimbic projection. important transcription factors produce these alterations Δfosb, camp response element binding protein (creb), , nuclear factor kappa b (nf-κb). Δfosb significant biomolecular mechanism in addiction because overexpression of Δfosb in d1-type medium spiny neurons in nucleus accumbens necessary , sufficient many of neural adaptations , behavioral effects (e.g., expression-dependent increases in drug self-administration , reward sensitization) seen in drug addiction. Δfosb expression in nucleus accumbens d1-type medium spiny neurons directly , positively regulates drug self-administration , reward sensitization through positive reinforcement while decreasing sensitivity aversion. specific drug addictions in Δfosb has been implicated in addictions alcohol, amphetamine, cannabinoids, cocaine, methylphenidate, nicotine, phenylcyclidine, propofol, opiates, , substituted amphetamines, among others. Δjund, transcription factor, , g9a, histone methyltransferase, both oppose function of Δfosb , inhibit increases in expression. increases in nucleus accumbens Δjund expression (via viral vector-mediated gene transfer) or g9a expression (via pharmacological means) reduces, or large increase can block, many of neural , behavioral alterations seen in chronic drug abuse (i.e., alterations mediated Δfosb).

Δfosb plays important role in regulating behavioral responses natural rewards, such palatable food, sex, , exercise. natural rewards, drugs of abuse, induce gene expression of Δfosb in nucleus accumbens, , chronic acquisition of these rewards can result in similar pathological addictive state through Δfosb overexpression. consequently, Δfosb key transcription factor involved in addictions natural rewards (i.e., behavioral addictions) well; in particular, Δfosb in nucleus accumbens critical reinforcing effects of sexual reward. research on interaction between natural , drug rewards suggests dopaminergic psychostimulants (e.g., amphetamine) , sexual behavior act on similar biomolecular mechanisms induce Δfosb in nucleus accumbens , possess bidirectional cross-sensitization effects mediated through Δfosb. phenomenon notable since, in humans, dopamine dysregulation syndrome, characterized drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, , gambling), has been observed in individuals taking dopaminergic medications.

Δfosb inhibitors (drugs or treatments oppose action) may effective treatment addiction , addictive disorders.

the release of dopamine in nucleus accumbens plays role in reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli palatable food , sex. altered dopamine neurotransmission observed following development of addictive state. in humans , lab animals have developed addiction, alterations in dopamine or opioid neurotransmission in nucleus accumbens , other parts of striatum evident. studies have found use of drugs (e.g., cocaine) affect cholinergic neurons innervate reward system, in turn affecting dopamine signaling in region.

summary of addiction-related plasticity



reward system


mesocorticolimbic pathway

understanding pathways in drugs act , how drugs can alter pathways key when examining biological basis of drug addiction. reward pathway, known mesolimbic pathway, or extension, mesocorticolimbic pathway, characterized interaction of several areas of brain.

the projections ventral tegmental area (vta) network of dopaminergic neurons co-localized postsynaptic glutamate receptors (ampar , nmdar). these cells respond when stimuli indicative of reward present. vta supports learning , sensitization development , releases da forebrain. these neurons project , release da nucleus accumbens, through mesolimbic pathway. virtually drugs causing drug addiction increase dopamine release in mesolimbic pathway, in addition specific effects.
the nucleus accumbens (nacc) 1 output of vta projections. nucleus accumbens consists of gabaergic medium spiny neurons (msns). nacc associated acquiring , eliciting conditioned behaviors, , involved in increased sensitivity drugs addiction progresses. overexpression of Δfosb in nucleus accumbens necessary common factor in known forms of addiction; Δfosb strong positive modulator of positively reinforced behaviors.
the prefrontal cortex, including anterior cingulate , orbitofrontal cortices, vta output in mesocorticolimbic pathway; important integration of information helps determine whether behavior elicited. critical forming associations between rewarding experience of drug use , cues in environment. importantly, these cues strong mediators of drug-seeking behavior , can trigger relapse after months or years of abstinence.

other brain structures involved in addiction include:

the basolateral amygdala projects nacc , thought important motivation.
the hippocampus involved in drug addiction, because of role in learning , memory. of evidence stems investigations showing manipulating cells in hippocampus alters dopamine levels in nacc , firing rates of vta dopaminergic cells.

role of dopamine , glutamate

dopamine primary neurotransmitter of reward system in brain. plays role in regulating movement, emotion, cognition, motivation, , feelings of pleasure. natural rewards, eating, recreational drug use cause release of dopamine, , associated reinforcing nature of these stimuli. addictive drugs, directly or indirectly, act upon brain s reward system heightening dopaminergic activity.

excessive intake of many types of addictive drugs results in repeated release of high amounts of dopamine, in turn affects reward pathway directly through heightened dopamine receptor activation. prolonged , abnormally high levels of dopamine in synaptic cleft can induce receptor downregulation in neural pathway. downregulation of mesolimbic dopamine receptors can result in decrease in sensitivity natural reinforcers.

drug seeking behavior induced glutamatergic projections prefrontal cortex nucleus accumbens. idea supported data experiments showing drug seeking behavior can prevented following inhibition of ampa glutamate receptors , glutamate release in nucleus accumbens.

reward sensitization

reward sensitization process causes increase in amount of reward (specifically, incentive salience) assigned brain rewarding stimulus (e.g., drug). in simple terms, when reward sensitization specific stimulus (e.g., drug) occurs, individual s wanting or desire stimulus , associated cues increases. reward sensitization occurs following chronically high levels of exposure stimulus. Δfosb (deltafosb) expression in d1-type medium spiny neurons in nucleus accumbens has been shown directly , positively regulate reward sensitization involving drugs , natural rewards.

cue-induced wanting or cue-triggered wanting , form of craving occurs in addiction, responsible majority of compulsive behavior addicts exhibit. these cues create overwhelming short-term urges engage addictive stimulus acting conditioned reinforcers addictive stimulus (a primary reinforcer) assigned pathologically high levels of incentive salience ( want ).

research on interaction between natural , drug rewards suggests dopaminergic psychostimulants (e.g., amphetamine) , sexual behavior act on similar biomolecular mechanisms induce Δfosb in nucleus accumbens , possess bidirectional reward cross-sensitization effect mediated through Δfosb.

in contrast Δfosb s reward-sensitizing effect, creb transcriptional activity decreases user s sensitivity rewarding effects of substance. creb transcription in nucleus accumbens implicated in psychological dependence , symptoms involving lack of pleasure or motivation during drug withdrawal.

the set of proteins known regulators of g protein signaling (rgs), particularly rgs4 , rgs9-2, have been implicated in modulating forms of opioid sensitization, including reward sensitization.

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