Dynamics of neuronal circuits in addiction: reward, antireward, and emotional memory

Abstract

Drug addiction is conceptualized as chronic, relapsing compulsive use of drugs with significant dysregulation of brain hedonic systems. Compulsive drug use is accompanied by decreased function of brain substrates for drug positive reinforcement and recruitment of brain substrates mediating the negative reinforcement of motivational withdrawal. The neural substrates for motivational withdrawal ("dark side" of addiction) involve recruitment of elements of the extended amygdala and the brain stress systems, including corticotropin-releasing factor and norepinephrine. These changes, combined with decreased reward function, are hypothesized to persist in the form of an allostatic state that forms a powerful motivational background for relapse. Relapse also involves a key role for the basolateral amygdala in mediating the motivational effects of stimuli previously paired with drug seeking and drug motivational withdrawal. The basolateral amygdala has a key role in mediating emotional memories in general. The hypothesis argued here is that brain stress systems activated by the motivational consequences of drug withdrawal can not only form the basis for negative reinforcement that drives drug seeking, but also potentiate associative mechanisms that perpetuate the emotional state and help drive the allostatic state of addiction.

Figure 1

Neural circuitry associated with the three stages of the addiction cycle, the drugs that are currently in use for the treatment focused on these stages, and the targets identified in this review relevant to these stages. Binge/intoxication stage: Reinforcing effects of drugs may engage associative mechanisms and reward neurotransmitters in the nucleus accumbens shell and core and then engage stimulus-response habits that depend on the dorsal striatum. Withdrawal/negative affect stage: The negative emotional state of withdrawal may engage the activation of the extended amygdala. The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, central nucleus of the amygdala, and possibly the medial portion (or shell) of the nucleus accumbens. A major neurotransmitter in the extended amygdala is corticotropin-releasing factor, projecting to the brainstem where noradrenergic neurons provide a major projection reciprocally to the extended amygdala. Preoccupation/anticipation (“craving”) stage: This stage involves the processing of conditioned reinforcement in the basolateral amygdala and the processing of contextual information by the hippocampus. Executive control depends on the prefrontal cortex and includes representation of contingencies, representation of outcomes, and their value and subjective states (i.e., craving and, presumably, feelings) associated with drugs. The subjective effects, called drug craving in humans, involves activation of the orbital and anterior cingulate cortex and temporal lobe, including the amygdala, in functional imaging studies. For each stage of the addiction process, also shown in the diagram are the existing medications and future targets for addiction treatment particularly relevant to that stage. Green/blue arrows, glutamatergic projections; Orange arrows, dopaminergic projections; Pink arrows, GABAergic projections; Acb, nucleus accumbens; BLA, basolateral amygdala; VTA, ventral tegmental area; SNc, substantia nigra pars compacta. VGP, ventral globus pallidus; DGP, dorsal globus pallidus; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; NE, norepinephrine; CRF, corticotropin-releasing factor; PIT, Pavlovian instrumental transfer. Modified with permission from [39].

Figure 2

(A) Relationship between elevations in intracranial self-stimulation (ICSS) reward thresholds and cocaine intake escalation. (Left) Percent change from baseline ICSS thresholds. (Right) Number of cocaine injections earned during the first hour of each session. Rats were first prepared with bipolar electrodes in either the right or left posterior lateral hypothalamus. One week post-surgery, they were trained to respond for electrical brain stimulation. Reward thresholds measured in microamps were assessed according to a modified discrete-trial current-threshold procedure [51]. During the screening phase, the 22 rats that were tested for self-administration were allowed to self-administer cocaine during only 1 h on a fixed-ratio 1 schedule of reinforcement, after which two balanced groups with the same weight, cocaine intake, and reward thresholds were formed. During the escalation phase, one group had access to cocaine self-administration for only 1 h per day (short-access, ShA) and the other group for 6 h per day (long-access, LgA). The remaining eight rats were exposed to the same experimental manipulations as the other rats, with the exception that they were not exposed to cocaine (not shown). Reward thresholds were measured in all rats two times per day, 3 h and 17-22 h after each daily self-administration session (ShA and LgA rats) or the control procedure (drug-naive rats; data not shown). Each reward threshold session lasted about 30 min. *p < 0.05, compared with drug-naive and/or ShA rats (tests of simple main effects). Taken with permission from [1]. (B) Unlimited daily access to heroin escalated heroin intake and decreased the excitability of brain reward systems. Heroin intake (± SEM; 20 mg per infusion) in rats during limited (1 h) or unlimited (23 h) self-administration sessions. ***p < 0.001, main effect of access (1 or 23 h), two-way repeated-measures analysis of variance. Also presented is the percent change from baseline reward thresholds (± SEM) in 23 h rats. Reward thresholds, assessed immediately after each daily 23 h self-administration session, became progressively more elevated as exposure to self-administered heroin increased across sessions. *p < 0.05, main effect of heroin on reward thresholds (two-way repeated-measures analysis of variance). Taken with permission from [31].

Figure 2

(A) Relationship between elevations in intracranial self-stimulation (ICSS) reward thresholds and cocaine intake escalation. (Left) Percent change from baseline ICSS thresholds. (Right) Number of cocaine injections earned during the first hour of each session. Rats were first prepared with bipolar electrodes in either the right or left posterior lateral hypothalamus. One week post-surgery, they were trained to respond for electrical brain stimulation. Reward thresholds measured in microamps were assessed according to a modified discrete-trial current-threshold procedure [51]. During the screening phase, the 22 rats that were tested for self-administration were allowed to self-administer cocaine during only 1 h on a fixed-ratio 1 schedule of reinforcement, after which two balanced groups with the same weight, cocaine intake, and reward thresholds were formed. During the escalation phase, one group had access to cocaine self-administration for only 1 h per day (short-access, ShA) and the other group for 6 h per day (long-access, LgA). The remaining eight rats were exposed to the same experimental manipulations as the other rats, with the exception that they were not exposed to cocaine (not shown). Reward thresholds were measured in all rats two times per day, 3 h and 17-22 h after each daily self-administration session (ShA and LgA rats) or the control procedure (drug-naive rats; data not shown). Each reward threshold session lasted about 30 min. *p < 0.05, compared with drug-naive and/or ShA rats (tests of simple main effects). Taken with permission from [1]. (B) Unlimited daily access to heroin escalated heroin intake and decreased the excitability of brain reward systems. Heroin intake (± SEM; 20 mg per infusion) in rats during limited (1 h) or unlimited (23 h) self-administration sessions. ***p < 0.001, main effect of access (1 or 23 h), two-way repeated-measures analysis of variance. Also presented is the percent change from baseline reward thresholds (± SEM) in 23 h rats. Reward thresholds, assessed immediately after each daily 23 h self-administration session, became progressively more elevated as exposure to self-administered heroin increased across sessions. *p < 0.05, main effect of heroin on reward thresholds (two-way repeated-measures analysis of variance). Taken with permission from [31].

Figure 3

Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of dependence and how it changes in the transition from nondependent drug taking to dependent drug taking. Key elements of the reward circuit are dopamine (DA) and opioid peptide neurons that intersect at both the ventral tegmental area (VTA) and nucleus accumbens and are activated during initial use and the early binge/intoxication stage. Key elements of the stress circuit are corticotropin-releasing factor (CRF) and noradrenergic (norepinephrine, NE) neurons that converge on γ-aminobutyric acid (GABA) interneurons in the central nucleus of the amygdala that are activated during the development of dependence. Taken with permission from [45].

Figure 4

Schematic diagram summarizing the hypothesized relationship between motivational dependence and emotional memory. Emotional states are well known to trigger relapse, and a mechanism may be a parallel action in which the negative emotional state of drug withdrawal and the emotional memories of protracted abstinence are hypothesized to combine to exacerbate relapse and the addiction process. The conceptual framework for such changes involves a break from emotional homeostasis, termed allostasis (stability through change), in neurobiological mechanisms in the extended amygdala.