The Neural Basis of Addiction : A Pathology of Motivation and Choice Am J Psychiatry 162 : , August 2005

Introduction Addiction Addiction : recurring desire & compromised : recurring desire & compromised ability to suppress that desire ability to suppress that desire  where pharmacotherapeutic intervention may be most effectively employed  where pharmacotherapeutic intervention may be most effectively employed

Introduction Neural basis of addiction requires understanding Neural basis of addiction requires understanding (1) the neurobiological basis of (1) the neurobiological basis of motivation and choice for motivation and choice for ① biological rewards( food, sex) + ② more cognitively and experientially ① biological rewards( food, sex) + ② more cognitively and experientially based rewards (friendship, family, based rewards (friendship, family, social status) social status)  motivationally relevant events(MRE)  motivationally relevant events(MRE)

Introduction (2)Physiological mechanisms of enduring neuroplasticity (reorganization) neuroplasticity (reorganization)  After outlining the neurobiology of motivated behavior, the neurobiology of motivated behavior, we will describe the we will describe the pathological dysregulation of cellular and circuitry functions produced by addiction pathological dysregulation of cellular and circuitry functions produced by addiction

Introduction Encoding of learned associations Encoding of learned associations (necessary for development of addiction ) ☞ dopamine projections to ☞ dopamine projections to the basal ganglia and cortex the basal ganglia and cortex Uncontrollable urge to obtain drugs and relapse Uncontrollable urge to obtain drugs and relapse ☞ pathological form of the plasticity ☞ pathological form of the plasticity in excitatory transmission in excitatory transmission

The Neurobiology of Adaptive Behavior Motivated adaptive behaviors Motivated adaptive behaviors (e.x - seeking food &companionship, (e.x - seeking food &companionship, avoiding physical &psychological discomfort) avoiding physical &psychological discomfort) (1) Activation of Behavior ① Dopamine and the ventral tegmental area ① Dopamine and the ventral tegmental area ② Amygdala ② Amygdala ③ Prefrontal cortex ③ Prefrontal cortex ④ Nucleus accumbens ④ Nucleus accumbens (2) Direction of Behavior (choice)  only marginally effective at understanding

(1) Activation of Behavior

① Dopamine and the ventral tegmental area 2 functions in the circuit 2 functions in the circuit (1) alert the organism to the appearance of novel salient stimuli, and thereby promote neuroplasticity (learning) (2) alert the organism to the pending appearance of a familiar MRE

② Amygdala Glutamatergic projections to the prefrontal cortex & accumbens Glutamatergic projections to the prefrontal cortex & accumbens are required are required for learned associations to influence more complex behavioral responses for learned associations to influence more complex behavioral responses

③ Prefrontal cortex (1) recruited by MRE & stimuli that predict such MRE predict such MRE (2) contribute to ① Whether a behavioral response will be emitted be emitted ② Relative intensity of that response

④ Nucleus accumbens Shell Shell Core Core (1) Primary site mediating the expression of learned behaviors the expression of learned behaviors in response to stimuli predicting MRE in response to stimuli predicting MRE (2) Expressing adaptive behavior depends not on dopaminergic afferents depends not on dopaminergic afferents,rather, on glutamatergic afferents from,rather, on glutamatergic afferents from the prefrontal cortex the prefrontal cortex

(2) Direction of Behavior – ‘choice’ Glutamatergic efferents from the prefrontal cortex stimulate Glutamatergic efferents from the prefrontal cortex stimulate behavioral output by accessing behavioral output by accessing accumbens - thalamocortical circuitry accumbens - thalamocortical circuitry Only recently it was demonstrated that different subsets of neurons in the accumbens respond differentially to cues associated with distinct MRE ( water vs. cocaine) Only recently it was demonstrated that different subsets of neurons in the accumbens respond differentially to cues associated with distinct MRE ( water vs. cocaine)

(2) Direction of Behavior – ‘choice’ However, the intensity and quality of behavioral output are strongly influenced by However, the intensity and quality of behavioral output are strongly influenced by both dopaminergic & glutamatergic input to the accumbens, both dopaminergic & glutamatergic input to the accumbens, activity at these synapses produces morphological changes in the dendrites of accumbens spiny cells activity at these synapses produces morphological changes in the dendrites of accumbens spiny cells

(2) Direction of Behavior – ‘choice’ Recent studies demonstrate that addiction is associated with neuroplasticity in these cellular mechanisms of synaptic organization, Recent studies demonstrate that addiction is associated with neuroplasticity in these cellular mechanisms of synaptic organization, and we will discuss them in detail. and we will discuss them in detail.

Addiction : Dysregulation in the Motive Circuit

3 general principles emerge from the circuit in figure 2. 3 general principles emerge from the circuit in figure 2. (1) Final Common Pathway (2) Modality-Dependent Subcircuits (3) Requirement for Dopamine Transmission

(1) Final Common Pathway  evidence ① Inactivation of the prefrontal cortex ② AMPA glutamate R. antagonists in the accumbens ☞ prevention the reinstatement of drug seeking ☞ prevention the reinstatement of drug seeking ③ Neuroimaging- The change in metabolic activity in both the orbitofrontal & anterior cingulate cortices correlates with the the self-reported cue-induced craving

(2) Modality-Dependent Subcircuits ① Cue-primed drug seeking requires involvement of requires involvement of the basolateral amygdala, the basolateral amygdala, while stress- & drug-primed drug while stress- & drug-primed drug seeking don’t. seeking don’t. ② Stress-induced drug seeking selectively engages selectively engages nuclei in the extended amygdala nuclei in the extended amygdala

( 3) Requirement for Dopamine Transmission evidence evidence (1) Inactivation of the ventral tegmental area ☞ drug seeking is inhibited, area ☞ drug seeking is inhibited, regardless of the stimulus modality regardless of the stimulus modality (2) But, the reinstatement of drug seeking requires dopamine release seeking requires dopamine release in the prefrontal cortex and amygdala, in the prefrontal cortex and amygdala, not in the nucleus accumbens core not in the nucleus accumbens core

Stages of Addiction The switch from dopamine- to The switch from dopamine- to glutamate-based behavior reveals that glutamate-based behavior reveals that the development of addiction occurs the development of addiction occurs in a chronological sequence in a chronological sequence ① acute drug effects ② transition from recreational use to patterns of use characteristic of addiction patterns of use characteristic of addiction ③ end-stage addiction

Stage 1: Acute Drug Effects

① The induction of Fos and other immediate early genes promotes immediate early genes promotes short-term neuroplastic changes short-term neuroplastic changes in response to the acute drug injection in response to the acute drug injection ② persist for a few hours or days after drug administration. after drug administration. ③ don’t mediate the enduring behavioral consequences of addiction.

Stage 2: Transition to Addiction (1) D1 R.-mediated, long term stimulation of proteins with long t(1/2) (ex. ᅀ FosB - transcriptional regulator ) regulator ) (2) GluR1 glutamate R. subunit ↑ in the ventral tegmental area in the ventral tegmental area for a few days after discontinuation for a few days after discontinuation

Stage 3: End-stage addiction ① Vulnerability to relapse in end-stage addiction endures for years & addiction endures for years & results from equally enduring results from equally enduring cellular changes cellular changes ② Changes in protein content and/or function in this category correlate with increasing periods of withdrawal function in this category correlate with increasing periods of withdrawal

Cellular Adaptations in Glutamatergic Projection From Prefrontal Cortex to Accumbens That Mediate Drug Seeking

Prefrontal Cortex Cell signaling through Cell signaling through transmitter R. coupled to Gi ↓ transmitter R. coupled to Gi ↓  AGS3 (G protein binding protein ) ↑  D2 R. signaling ↓  D1 R. signaling ↑  D1 R. blockade in the prefrontal cortex prevents the reinstatement of drug seeking

Nucleus Accumbens : Presynaptic Adaptations Increased release of glutamate induce Increased release of glutamate induce (1)adaptations that reduce inhibitory presynaptic regulation by inhibitory presynaptic regulation by mGluR2/3 inhibitory auto R. mGluR2/3 inhibitory auto R. (2)alterations in the organization of vesicles in presynaptic terminals

Nucleus Accumbens: Postsynaptic Adaptations enduring adaptations in postsynaptic R. associated proteins enduring adaptations in postsynaptic R. associated proteins  alter Glu. R. intracellular signaling  PSD-95 and Homer ↓ (scaffolding proteins) (scaffolding proteins)  dendritic dysmorphisms in the accumbens

Potential New Targets for Pharmacotherapeutic Amelioration of Addiction

pharmacotherapies could target other components of the circuit in figure 2 pharmacotherapies could target other components of the circuit in figure 2 (1) motivational value of the drug ↓ (2) salience and motivational value of nondrug reinforcers ↑ nondrug reinforcers ↑ (3) inhibit conditioned responses to stimuli predicting drug availability.

Summary Recently identified pathology in the prefrontal-accumbens glutamate projection Recently identified pathology in the prefrontal-accumbens glutamate projection (1) alterations in G protein signaling in the prefrontal cortex that increase the excitability of neurons projecting to the accumbens, (1) alterations in G protein signaling in the prefrontal cortex that increase the excitability of neurons projecting to the accumbens,

Summary (2) augmented presynaptic glutamate release in the accumbens due to release in the accumbens due to ① inhibitory presynaptic regulation ↓ & ② releasability of synaptic vesicles ↑ (3) alterations in postsynaptic proteins that result in rigid dendritic that result in rigid dendritic morphology and signaling morphology and signaling