Cocaine Seeking And Taking Are Oppositely Regulated By Dopamine (original) (raw)
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Increased Occupancy of Dopamine Receptors in Human Striatum during Cue-Elicited Cocaine Craving
Neuropsychopharmacology, 2007
In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [ 11 C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.
Phasic dopamine release in appetitive behaviors and drug addiction
Current drug abuse reviews, 2009
Although dopamine is implicated in the development of addiction, it is unclear how specific dopamine release patterns are involved with drug seeking. Addictive drugs increase tonic dopamine levels on the order of minutes, as well as phasic dopamine release events that occur on a subsecond time scale. Phasic dopamine release is associated with the initiation of goal-directed behaviors, and has been shown to promote drug seeking. Prior experience with addictive drugs modulates the synaptic and intrinsic properties of dopamine neurons, affects the pattern of dopamine neuron firing and release, and alters dopamine-dependent behaviors related to drug addiction. In this review, we synthesize the known drugdependent changes to the dopamine system along with the established functions of phasic dopamine release in order to provide a framework for conceptualizing the role of phasic dopamine release in drug addiction. Because drug addiction is commonly thought to involve changes in brain circuits important for natural reinforcement, we first present the role of phasic dopamine release in appetitive and goal-directed behaviors in the context of contemporary theories regarding the function of dopamine. Next, we discuss the known drug-induced changes to dopamine neurons and phasic release in both in vitro and in vivo preparations. Finally, we offer a simple model that chronic drug experience increases the contrast, or 'signal to noise', of phasic dopamine release to basal dopamine levels in response to drug-related stimuli, which could result in aberrant associations between cues and reinforcers that contribute to the development of addiction.
Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.
Excessive cocaine use results from decreased phasic dopamine signaling in the striatum
Nature Neuroscience, 2014
Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum (DLS) is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased; with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating the causal relationship between diminished dopamine transmission and excessive drug use. Thus, together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use.
Cocaine cue-induced dopamine release in the human prefrontal cortex
Journal of psychiatry & neuroscience : JPN, 2016
Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown. We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence. Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical ...
Proceedings of the National Academy of Sciences of the United States of America, 2012
Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine. D rug use often begins as a recreational behavior driven by the rewarding properties of the abused drug. However, addiction is characterized by habitual and compulsive drug use in which other factors, such as withdrawal symptoms, stress, and drug-associated conditioned stimuli (CS), also contribute to the motivation to consume drugs, and drug taking becomes increasingly prioritized over other behaviors (1). A wealth of evidence shows that the mesolimbic dopamine projection from the ventral tegmental area to the ventromedial striatum (VMS) is central to drug reinforcement (2). The ambient concentration of dopamine in the VMS is increased when animals self-administer drugs of abuse, including cocaine (3), and animals maintain this elevated dopamine level by regulating their rate of responding for drug (4). In addition, with repeated pairing of environmental stimuli with the drug, these CS also gain the propensity to elicit changes in dopamine concentration in the VMS (5-8); and even though these phasic neurochemical responses last only a few seconds, they are capable of controlling drug-seeking and -taking behavior (5). Together, these results implicate dopamine release in the VMS as a critical substrate in the control of drug use .
American Journal of Psychiatry, 2007
Objective: Dopamine is an important mediator of the reinforcing effects of cocaine, and alterations in dopamine function might be involved in cocaine dependence. The goals of the present study were to characterize pre-and postsynaptic dopamine function in recently detoxified cocaine-dependent subjects. Specifically, dopamine response to an acute amphetamine challenge was assessed in striatal subregions in cocaine-dependent and healthy comparison participants using positron emission tomography (PET). Furthermore, the relationship between this dopamine response and the choice to self-administer cocaine in a laboratory model of relapse was investigated.
Dopamine, behavior, and addiction
Journal of Biomedical Science
Addictive drugs are habit-forming. Addiction is a learned behavior; repeated exposure to addictive drugs can stamp in learning. Dopamine-depleted or dopamine-deleted animals have only unlearned reflexes; they lack learned seeking and learned avoidance. Burst-firing of dopamine neurons enables learning—long-term potentiation (LTP)—of search and avoidance responses. It sets the stage for learning that occurs between glutamatergic sensory inputs and GABAergic motor-related outputs of the striatum; this learning establishes the ability to search and avoid. Independent of burst-firing, the rate of single-spiking—or “pacemaker firing”—of dopaminergic neurons mediates motivational arousal. Motivational arousal increases during need states and its level determines the responsiveness of the animal to established predictive stimuli. Addictive drugs, while usually not serving as an external stimulus, have varying abilities to activate the dopamine system; the comparative abilities of different...