Drug addiction, dysregulation of reward, and allostasis.

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.

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The Neural Basis of Addiction: A Pathology of Motivation and Choice

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...

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Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex

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...

Psychiatric aspects of impulsivity

https://www.thelancet.com/pdfs/journals/lanpsy/PIIS2215-0366(16)00104-8.pdf

Neurobiology of addiction: A neurocircuitry analysis.

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.

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

Acute administration of phencyclidine to rats potently activates mesocorticolimbic dopaminergic neurons. The activation of dopamine release and utilization in the prefrontal cortex and nucleus accumbens are associated with profound cognitive impairment and hyperlocomotion, respectively. This dopaminergic activation by phencyclidine is not mediated by direct effects on the cell body regions of the dopamine neurons; however, phencyclidine augments dopamine release locally in the terminal fields. In the present study, the possible involvement of the prefrontal cortex in mediating activation of the mesolimbic dopamine system by phencyclidine was examined. Ibotenic acid lesions of the prefrontal cortex attenuated the biochemical activation of the mesolimbic dopamine neurons by PCP, and prefrontal lesions sharply blunted phencyclidine-, but not amphetamine- or novelty-, induced hyperlocomotion. In addition, injection of phencyclidine directly into the prefrontal cortex increased dopamine utilization in the nucleus accumbens and induced hyperlocomotion. In summary, these studies show that phencyclidine activates the mesolimbic pathway through a mechanism in the prefrontal cortex, possibly by disinhibiting the cortical circuit and activating corticofugal glutamatergic release in the ventral tegmental area.

Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence

Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits

D4 dopamine receptors (DRs) are enriched in the primate prefrontal cortex, a brain region implicated in cognitive processes, and mesoprefrontal dopaminergic systems appear to be involved in modulating some cognitive functions of the prefrontal cortex. Despite anatomical localization of D4 DRs within the frontal cortex, the role of these receptors, specifically, in the regulation of cognition or behavior in primates is unknown. In these studies, we sought to learn whether specific antagonism of D4 DRs would affect performance of a task dependent on the frontostriatal system. The effects of NGD94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole dimaleate), a potent and selective D4 DR antagonist and haloperidol, a non-specific D2-like DR antagonist, on the performance of an object retrieval/detour task by monkeys were examined. The effects of these antagonists on the object retrieval task were evaluated in normal control monkeys and in subjects repeatedly exposed to phencyclidine (PCP), to induce frontal cortical dopaminergic and cognitive dysfunction. NGD94-1 (1–5 mg/kg) reversed the cognitive deficits of PCP pre-treated monkeys, whereas haloperidol (25 μg/kg) exacerbated PCP-induced performance impairments. A low dose of NGD94-1 failed to affect performance of control subjects, while both haloperidol and a high dose of NGD94-1 impaired control performance. These data show, for the first time, that D4 DRs modulate the cognitive functions of the frontostriatal system.

Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys.

Publisher Summary Phencyclidine (PCP) induces several distinct behavioral effects in humans and animals that appear to represent schizophrenia-like symptomatology. In humans, acute PCP exposure can induce both positive and negative symptoms of schizophrenia. In contrast, repeated exposure to PCP in humans can lead to enduring presentation of both negative and positive symptoms of schizophrenia. Thus, repeated PCP administration may induce neurobiological defects that mimic those present in the brain of patients with schizophrenia. This chapter discusses some of the recent studies on the effects of acute and repeated PCP administration on the rodent and nonhuman primate dopamine (DA) systems and how these neurobiological effects may underlie the psychotomimetic properties of PCP. The chapter also evaluates the relevance of DAergic dysfunction for the hypoglutamatergic and neuropathological hypotheses of PCP's effects. In the primate, acute PCP administration causes a selective activation of DA metabolism in the frontal cortex, while sparing subcortical DA systems. It is suggested that activation of DA systems by PCP may be involved in the development of neuropathology after acute PCP administration. Taken together, these studies indicate that repeated PCP administration may model the cognitive dysfunction of schizophrenia and suggest that this dysfunction may be because of an inhibition of DAergic function in the PFC. Further, this paradigm may represent a step forward in biological psychiatric research by offering a tool for evaluating the pathophysiology of the deficits of schizophrenia and a mechanism for the evaluation of novel agents that may be able to ameliorate the typically treatment-refractory negative symptoms in this debilitating disorders.

Dysregulation of Mesoprefrontal Dopamine Neurons Induced by Acute and Repeated Phencyclidine Administration in the Nonhuman Primate: Implications for Schizophrenia

J. D. Jentsch

Papers

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

Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence

Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits

Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys.

Dysregulation of Mesoprefrontal Dopamine Neurons Induced by Acute and Repeated Phencyclidine Administration in the Nonhuman Primate: Implications for Schizophrenia