Barry J. Everitt

Neural systems of reinforcement for drug addiction: from actions to habits to compulsion

Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use—when a drug is voluntarily taken because it has reinforcing, often hedonic, effects—through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.*Note: In the version of this article initially published, there is an error in Figure 1. Please see the PDF for details.

Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex.

Emotions are multifaceted, but a key aspect of emotion involves the assessment of the value of environmental stimuli. This article reviews the many psychological representations, including representations of stimulus value, which are formed in the brain during Pavlovian and instrumental conditioning tasks. These representations may be related directly to the functions of cortical and subcortical neural structures. The basolateral amygdala (BLA) appears to be required for a Pavlovian conditioned stimulus (CS) to gain access to the current value of the specific unconditioned stimulus (US) that it predicts, while the central nucleus of the amygdala acts as a controller of brainstem arousal and response systems, and subserves some forms of stimulus-response Pavlovian conditioning. The nucleus accumbens, which appears not to be required for knowledge of the contingency between instrumental actions and their outcomes, nevertheless influences instrumental behaviour strongly by allowing Pavlovian CSs to affect the level of instrumental responding (Pavlovian-instrumental transfer), and is required for the normal ability of animals to choose rewards that are delayed. The prelimbic cortex is required for the detection of instrumental action-outcome contingencies, while insular cortex may allow rats to retrieve the values of specific foods via their sensory properties. The orbitofrontal cortex, like the BLA, may represent aspects of reinforcer value that govern instrumental choice behaviour. Finally, the anterior cingulate cortex, implicated in human disorders of emotion and attention, may have multiple roles in responding to the emotional significance of stimuli and to errors in performance, preventing responding to inappropriate stimuli.

Neurobehavioural mechanisms of reward and motivation

The analysis of the behavioural and neural mechanisms of reinforcement and motivation has benefited from the recent application of learning theory and better anatomical knowledge of the connectivity of certain key neural structures, such as the nucleus accumbens. This progress has enabled the dissection of motivational processes into components that can begin to be related to the functioning of specific limbic cortical structures that project to different compartments of the ventral striatum.

Differential co-existence of neuropeptide Y (NPY)-like immunoreactivity with catecholamines in the central nervous system of the rat

The distribution of neuropeptide Y immunoreactive cell bodies in relation to various types of catecholamine-containing cell bodies in the rat brain was analyzed immunohistochemically using antisera to tyrosine hydroxylase, dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase. Coexistence of the peptide in catecholamine cell bodies was established by using an elution-restaining procedure. Neuropeptide Y-like immunoreactivity was observed in most noradrenergic cell bodies of the Al/Cl cell groups in the ventro lateral medulla oblongata. Similarly this peptide immunoreactivity was also observed in the majority of the adrenergic cell bodies of the C2 group. In the dorsal and dorsal-lateral part of the nucleus of the solitary tract, where a group of small adrenergic cells is present, several small neuropeptide Y immunoreactive cells were also observed. The possibility of coexistence of adrenaline and neuropeptide Y in these cells remains to be established. The majority of the noradrenergic cell bodies of the A2 group, as well as the presumptive dopaminergic cells within its ventromedial part, seemed to lack neuropeptide Y-like immunoreactivity. Many noradrenergic cell bodies of the A6 group in the locus coeruleus proper were neuropeptide Y-immunoreactive, whereas the peptide could not be observed in the subcoeruleus group. Neither the A5 and A7 noradrenergic cells in the pons, nor any of the dopaminergic cell groups in the mesencephalon and forebrain (A8-A15) seemed to contain a neuropeptide Y-like peptide. The findings indicate that central catecholamine neurons can be subdivided into distinct sub-groups based upon the coexistence of a specific peptide.

Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement

Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms.

We used a novel computerized decision-making task to compare the decision-making behavior of chronic amphetamine abusers, chronic opiate abusers, and patients with focal lesions of orbital prefrontal cortex (PFC) or dorsolateral/medial PFC. We also assessed the effects of reducing central 5-hydroxytryptamine (5-HT) activity using a tryptophan-depleting amino acid drink in normal volunteers. Chronic amphetamine abusers showed sub-optimal decisions (correlated with years of abuse), and deliberated for significantly longer before making their choices. The opiate abusers exhibited only the second of these behavioral changes. Importantly, both sub-optimal choices and increased deliberation times were evident in the patients with damage to orbitofrontal PFC but not other sectors of PFC. Qualitatively, the performance of the subjects with lowered plasma tryptophan was similar to that associated with amphetamine abuse, consistent with recent reports of depleted 5-HT in the orbital regions of PFC of methamphetamine abusers. Overall, these data suggest that chronic amphetamine abusers show similar decision-making deficits to those seen after focal damage to orbitofrontal PFC. These deficits may reflect altered neuromodulation of the orbitofrontal PFC and interconnected limbic-striatal systems by both the ascending 5-HT and mesocortical dopamine (DA) projections.

Impulsivity, Compulsivity, and Top-Down Cognitive Control

Impulsivity is the tendency to act prematurely without foresight. Behavioral and neurobiological analysis of this construct, with evidence from both animal and human studies, defines several dissociable forms depending on distinct cortico-striatal substrates. One form of impulsivity depends on the temporal discounting of reward, another on motor or response disinhibition. Impulsivity is commonly associated with addiction to drugs from different pharmacological classes, but its causal role in human addiction is unclear. We characterize in neurobehavioral and neurochemical terms a rodent model of impulsivity based on premature responding in an attentional task. Evidence is surveyed that high impulsivity on this task precedes the escalation subsequently of cocaine self-administration behavior, and also a tendency toward compulsive cocaine-seeking and to relapse. These results indicate that the vulnerability to stimulant addiction may depend on an impulsivity endophenotype. Implications of these findings for the etiology, development, and treatment of drug addiction are considered.

Independent Cellular Processes for Hippocampal Memory Consolidation and Reconsolidation

The idea that new memories undergo a time-dependent consolidation process after acquisition has received considerable experimental support. More controversial has been the demonstration that established memories, once recalled, become labile and sensitive to disruption, requiring “reconsolidation” to become permanent. By infusing antisense oligodeoxynucleotides into the hippocampus of rats, we show that consolidation and reconsolidation are doubly dissociable component processes of memory. Consolidation involves brain-derived neurotrophic factor (BDNF) but not the transcription factor Zif268, whereas reconsolidation recruits Zif268 but not BDNF. These findings confirm a requirement for BDNF specifically in memory consolidation and also resolve the role of Zif268 in brain plasticity, learning, and memory.

Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.

High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking

Both impulsivity and novelty-seeking have been suggested to be behavioral markers of the propensity to take addictive drugs. However, their relevance for the vulnerability to compulsively seek and take drugs, which is a hallmark feature of addiction, is unknown. We report here that, whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration, high impulsivity predicts the development of addiction-like behavior in rats, including persistent or compulsive drug-taking in the face of aversive outcomes. This study shows experimental evidence that a shift from impulsivity to compulsivity occurs during the development of addictive behavior, which provides insights into the genesis and neural mechanisms of drug addiction.