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Journal ArticleDOI

Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli.

21 Oct 1999-Psychopharmacology (Psychopharmacology (Berl))-Vol. 146, Iss: 4, pp 373-390
TL;DR: The neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking are considered and an integrative hypothesis for compulsive reward-seeking in drug abuse is presented.
Abstract: Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behaviors. These phenomena have been linked with dopamine function within the ventral striatum and amygdala and have been described specifically in terms of motivational and incentive learning processes. New data are emerging that suggest that regions of the frontal cortex involved in inhibitory response control are directly affected by long-term exposure to drugs of abuse. The result of chronic drug use may be frontal cortical cognitive dysfunction, resulting in an inability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs, by related stimuli or by internal drive states. Drug-seeking behavior may thus be due to two related phenomena: (1) augmented incentive motivational qualities of the drug and associated stimuli (due to limbic/amygdalar dysfunction) and (2) impaired inhibitory control (due to frontal cortical dysfunction). In this review, we consider the neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking. The evidence for cognitive impulsivity in drug abuse associated with dysfunction of the frontostriatal system will be discussed, and an integrative hypothesis for compulsive reward-seeking in drug abuse will be presented.
Citations
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Journal ArticleDOI
TL;DR: The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.

2,678 citations


Cites background from "Impulsivity resulting from frontost..."

  • ...…with hypothalamic and brain-stem regions included in autonomic and consummatory responses, while the cortico- striatal-thalamic circuitry is comprised of regions implicated in motor learning, reinforcer evaluation (nucleus accumbens) or stimulus-reward associations (Jentsch and Taylor 1999)....

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  • ...Note that the central nucleus of the amygdala is connected with hypothalamic and brain-stem regions included in autonomic and consummatory responses, while the corticostriatal-thalamic circuitry is comprised of regions implicated in motor learning, reinforcer evaluation (nucleus accumbens) or stimulus-reward associations (Jentsch and Taylor 1999)....

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Journal ArticleDOI
TL;DR: Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control (choice), and enhancing glutamatorgic drive in response to drug-associated stimuli.
Abstract: Objective: A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. Method: Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking.

2,496 citations


Cites background from "Impulsivity resulting from frontost..."

  • ...The prefrontal cortex is less involved in establishing whether a stimulus is positive or negative (valence); rather, it regulates the overall motivational salience and determines the intensity of behavioral responding (13, 14)....

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Journal ArticleDOI
TL;DR: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed, and results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervalued of alternative rein forcers, and deficits in inhibitory control for drug responses.
Abstract: OBJECTIVE: Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. METHOD: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. RESULTS: The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to tr...

2,415 citations


Cites background from "Impulsivity resulting from frontost..."

  • ...For a review of the role of the mesolimbic and mesocortical dopamine system in inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking, see Jentsch and Taylor (63)....

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Journal ArticleDOI
TL;DR: Before treatment studies on impulsivity can move forward, measures of impulsivity that capture the core aspects of this behavior need to be refined and tested on the basis of an ideologically neutral model of impulsiveness.
Abstract: OBJECTIVE: The authors discuss the relationship of impulsivity to psychiatric disorders and present selected hypotheses regarding the reasons for these relationships. METHOD: Previous research has shown significantly higher levels of impulsivity among patients with conduct disorder, personality disorders, substance use disorders, and bipolar disorder, compared to other psychiatric patients or healthy comparison subjects. A literature review of the theoretical bases of the relationship between these disorders and impulsivity is presented. Measurements of impulsivity and treatment options are discussed in relation to the physiology of impulsivity and the disorders in which it is a prominent feature. RESULTS: Impulsivity, as defined on the basis of a biopsychosocial approach, is a key feature of several psychiatric disorders. Behavioral and pharmacological interventions that are effective for treating impulsivity should be incorporated into treatment plans for these disorders. CONCLUSIONS: The high comorbidi...

2,277 citations

Journal ArticleDOI
TL;DR: Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.

1,985 citations

References
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Journal ArticleDOI
14 Mar 1997-Science
TL;DR: Findings in this work indicate that dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events can be understood through quantitative theories of adaptive optimizing control.
Abstract: The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.

8,163 citations

Journal ArticleDOI
TL;DR: S sensitization of incentive salience can produce addictive behavior even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family.

6,783 citations

Journal ArticleDOI
TL;DR: The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis as mentioned in this paper.
Abstract: The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.

4,610 citations

Journal ArticleDOI
TL;DR: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP and the findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia.
Abstract: Objective: Phencyclidine (PCP, “angel dust”) induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding ofschizophrenic pathophysiology. Methoc�: Twenty-five papers were identified that described the clinicaldose and serum and CSF levelsat which PCP induces its psychotomimetic effects. The dose range ofPCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. Results: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation ofits receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. Conclusions: These findings suggestthat endogenous dysfunction ofNMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models ofschizophrenia are discussedin relationship to the diagnosis and etiology of schizophrenia. (Am J Psychiatry1991;148:1301-1308)

2,883 citations

Journal ArticleDOI
TL;DR: The hypothesis rejects attempts to limit human reasoning and decision making to mechanisms relying, in an exclusive and unrelated manner, on either conditioning alone or cognition alone.
Abstract: In this article I discuss a hypothesis, known as the somatic marker hypothesis, which I believe is relevant to the understanding of processes of human reasoning and decision making. The ventromedial sector of the prefrontal cortices is critical to the operations postulated here, but the hypothesis does not necessarily apply to prefrontal cortex as a whole and should not be seen as an attempt to unify frontal lobe functions under a single mechanism. The key idea in the hypothesis is that 'marker' signals influence the processes of response to stimuli, at multiple levels of operation, some of which occur overtly (consciously, 'in mind') and some of which occur covertly (non-consciously, in a non-minded manner). The marker signals arise in bioregulatory processes, including those which express themselves in emotions and feelings, but are not necessarily confined to those alone. This is the reason why the markers are termed somatic: they relate to body-state structure and regulation even when they do not arise in the body proper but rather in the brain's representation of the body. Examples of the covert action of 'marker' signals are the undeliberated inhibition of a response learned previously; the introduction of a bias in the selection of an aversive or appetitive mode of behaviour, or in the otherwise deliberate evaluation of varied option-outcome scenarios. Examples of overt action include the conscious 'qualifying' of certain option-outcome scenarios as dangerous or advantageous. The hypothesis rejects attempts to limit human reasoning and decision making to mechanisms relying, in an exclusive and unrelated manner, on either conditioning alone or cognition alone.

2,487 citations