Cocaine Self-Administration Influences Central Nervous System Immune Responses in Male HIV-1 Transgenic Rats.

Cocaine use increases the neurotoxic severity of human immunodeficiency virus-1 (HIV-1) infection and the development of HIV-associated neurocognitive disorders (HAND). Among the studied cellular mechanisms promoting neurotoxicity in HIV-1 and cocaine use, central nervous system (CNS) immunity, such as neuroimmune signaling and reduced antiviral activity, are risk determinants; however, concrete evidence remains elusive. In the present study, we tested the hypothesis that cocaine self-administration by transgenic HIV-1 (HIV-1Tg) rats promotes CNS inflammation. To test this hypothesis, we measured cytokine, chemokine, and growth factor protein levels in the frontal cortex (fCTX) and caudal striatum (cSTR). Our results demonstrated that cocaine self-administration significantly increased fCTX inflammation in HIV-1Tg rats, but not in the cSTR. Accordingly, we postulate that cocaine synergizes with HIV-1 proteins to increase neuroinflammation in a region-selective manner, including the fCTX. Given the fCTX role in cognition, this interaction may contribute to the hyperimmunity and reduced antiviral activity associated with cocaine-mediated enhancement of HAND.

Impaired verbal memory in individuals living with HIV and cocaine dependence.

INTRODUCTION: Our study aimed to understand the independent and combined effects of cocaine dependence and HIV status across aspects of verbal memory. METHOD: Our sample consisted of a total of 102 individuals: 28 individuals living with HIV and cocaine dependence (HIV+/CD), 28 individuals who are HIV-negative with cocaine dependence (HIV-/CD), 20 individuals living with HIV without cocaine dependence (HIV+/ND), and 26 individuals who are HIV-negative without cocaine dependence (HIV-/ND). We utilized the Hopkins Verbal Learning Test-Revised Version (HVLT-R) to assess components of verbal memory, including encoding, recall, and recognition. A 2 (HIV: Yes/No) × 2 (Cocaine: Yes/No) MANCOVA on Total and Delayed Recall while controlling for premorbid intelligence was conducted. We used a Kruskal-Wallis H test to examine retrieval and recognition. RESULTS: The combination of HIV and cocaine dependence amplified deficits on Total Recall. We found comparably poor performance across Delayed Recall between all three clinical groups. People living with HIV without cocaine dependence demonstrated intact recognition, whereas those with cocaine dependence had poor recognition. CONCLUSIONS: HIV and cocaine both impacted verbal memory. However, there are potential subtle differences in the role cocaine versus HIV has on the memory process. People living with HIV without cocaine dependence recognized significantly more words than they could freely recall. In contrast, cocaine dependence impacted recognition in HIV and non-HIV groups. These performance patterns suggest HIV may be associated with retrieval deficits, whereas cocaine dependence may be associated with encoding deficits. Further research assessing these specific components of the memory process will help clarify these potential differences.

Gut and brain profiles that resemble pre-motor and early-stage Parkinson's disease in methamphetamine self-administering rats.

INTRODUCTION: Methamphetamine is a potent psychomotor stimulant, and methamphetamine abusers are up to three times more likely to develop Parkinson's disease (PD) later in life. Prodromal PD may involve gut inflammation and the accumulation of toxic proteins that are transported from the enteric nervous system to the central nervous system to mediate, in part, the degeneration of dopaminergic projections. We hypothesized that self-administration of methamphetamine in rats produces a gut and brain profile that mirrors pre-motor and early-stage PD. METHODS: Rats self-administered methamphetamine in daily 3 h sessions for two weeks. Motor function was assessed before self-administration, during self-administration and throughout the 56 days of forced abstinence. Assays for pathogenic markers (tyrosine hydroxylase, glial fibrillary acidic protein (GFAP), α-synuclein) were conducted on brain and gut tissue collected at one or 56 days after cessation of methamphetamine self-administration. RESULTS: Motor deficits emerged by day 14 of forced abstinence and progressively worsened up to 56 days of forced abstinence. In the pre-motor stage, we observed increased immunoreactivity for GFAP and α-synuclein within the ganglia of the myenteric plexus in the distal colon. Increased α-synuclein was also observed in the substantia nigra pars compacta. At 56 days, GFAP and α-synuclein normalized in the gut, but the accumulation of nigral α-synuclein persisted, and the dorsolateral striatum exhibited a significant loss of tyrosine hydroxylase. CONCLUSION: The pre-motor profile is consistent with gut inflammation and gut/brain α-synuclein accumulation associated with prodromal PD and the eventual development of the neurological disease.

HIV-1 Tat and morphine decrease murine inter-male social interactions and associated oxytocin levels in the prefrontal cortex, amygdala, and hypothalamic paraventricular nucleus.

Many persons infected with HIV-1 (PWH) and opioid-dependent individuals experience deficits in sociability that interfere with daily living. Sociability is regulated by the prefrontal cortico-hippocampal-amygdalar circuit. Within this circuit HIV-1 trans-activator of transcription (HIV-1 Tat) and opioids can increase dendritic pathology and alter neuronal firing. Changes in sociability are also associated with dysregulation of hypothalamic neuropeptides such as oxytocin or corticotropin releasing factor (CRF) in the prefrontal cortico-hippocampal-amygdalar circuit. Accordingly, we hypothesized that the interaction of HIV-1 Tat and morphine would impair inter-male social interactions and disrupt oxytocin and CRF within the PFC and associated circuitry. Male mice were exposed to HIV-1 Tat for 8 weeks and administered saline or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of HIV-1 Tat exposure. Tat attenuated aggressive interactions with an unknown intruder, whereas morphine decreased both non-aggressive and aggressive social interactions in the resident-intruder test. However, there was no effect of Tat or morphine on non-reciprocal interactions in the social interaction and novelty tests. Tat, but not morphine, decreased oxytocin levels in the PFC and amygdala, whereas both Tat and morphine decreased the percentage of oxytocin-immunoreactive neurons in the hypothalamic paraventricular nucleus (PVN). In Tat(+) or morphine-exposed mice, regional levels of CRF and oxytocin correlated with alterations in behavior in the social interaction and novelty tests. Overall, decreased expression of oxytocin in the prefrontal cortico-hippocampal-amygdalar circuit is associated with morphine- and HIV-Tat-induced deficits in social behavior.

Mitochondrial function influences expression of methamphetamine-induced behavioral sensitization.

Repeated methamphetamine use leads to long lasting brain and behavioral changes in humans and laboratory rats. These changes have high energy requirements, implicating a role for mitochondria. We explored whether mitochondrial function underpins behaviors that occur in rats months after stopping methamphetamine self-administration. Accordingly, rats self-administered intravenous methamphetamine for 3 h/day for 14 days. The mitochondrial toxin rotenone was administered as (1 mg/kg/day for 6 days) via an osmotic minipump starting at 0, 14 or 28 days of abstinence abstinence. On abstinence day 61, expression of methamphetamine-induced behavioral sensitization was obtained with an acute methamphetamine challenge in rotenone-free rats. Rotenone impeded the expression of sensitization, with the most robust effects obtained with later abstinence exposure. These findings verified that self-titration of moderate methamphetamine doses results in behavioral (and thus brain) changes that can be revealed months after exposure termination, and that the meth-initiated processes progressed during abstinence so that longer abstinence periods were more susceptible to the consequences of exposure to a mitochondrial toxin.

Hippocampal blood-brain barrier of methamphetamine self-administering HIV-1 transgenic rats.

Combined antiretroviral therapy for HIV infection reduces plasma viral load and prolongs life. However, the brain is a viral reservoir, and pathologies such as cognitive decline and blood-brain barrier (BBB) disruption persist. Methamphetamine abuse is prevalent among HIV-infected individuals. Methamphetamine and HIV toxic proteins can disrupt the BBB, but it is unclear if there exists a common pathway by which HIV proteins and methamphetamine induce BBB damage. Also unknown are the BBB effects imposed by chronic exposure to HIV proteins in the comorbid context of chronic methamphetamine abuse. To evaluate these scenarios, we trained HIV-1 transgenic (Tg) and non-Tg rats to self-administer methamphetamine using a 21-day paradigm that produced an equivalency dose range at the low end of the amounts self-titrated by humans. Markers of BBB integrity were measured for the hippocampus, a brain region involved in cognitive function. Outcomes revealed that tight junction proteins, claudin-5 and occludin, were reduced in Tg rats independent of methamphetamine, and this co-occurred with increased levels of lipopolysaccharide, albumin (indicating barrier breakdown) and matrix metalloproteinase-9 (MMP-9; indicating barrier matrix disruption); reductions in GFAP (indicating astrocytic dysfunction); and microglial activation (indicating inflammation). Evaluations of markers for two signaling pathways that regulate MMP-9 transcription, NF-κB and ERK/∆FosB revealed an overall genotype effect for NF-κB. Methamphetamine did not alter measurements from Tg rats, but in non-Tg rats, methamphetamine reduced occludin and GFAP, and increased MMP-9 and NF-κB. Study outcomes suggest that BBB dysregulation resulting from chronic exposure to HIV-1 proteins or methamphetamine both involve NF-κB/MMP-9.

The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease.

Addictions involve a spectrum of behaviors that encompass features of impulsivity and compulsivity, herein referred to as impulsive-compulsive spectrum disorders (ICSDs). The etiology of ICSDs likely involves a complex interplay among neurobiological, psychological and social risk factors. Neurobiological risk factors include the status of the neuroanatomical circuits that govern ICSDs. These circuits can be altered by disease, as well as exogenous influences such as centrally-acting pharmacologics. The 'poster child' for this scenario is Parkinson's disease (PD) medically managed by pharmacological treatments. PD is a progressive neurodegenerative disease that involves a gradual loss of dopaminergic neurons largely within nigrostriatal projections. Replacement therapy includes dopamine receptor agonists that directly activate postsynaptic dopamine receptors (bypassing the requirement for functioning presynaptic terminals). Some clinically useful dopamine agonists, e.g., pramipexole and ropinirole, exhibit high affinity for the D2/D3 receptor subtypes. These agonists provide excellent relief from PD motor symptoms, but some patients exhibit debilitating ICSD. Teasing out the neuropsychiatric contribution of PD-associated pathology from the drugs used to treat PD motor symptoms is challenging. In this review, we posit that modern clinical and preclinical research converge on the conclusion that dopamine replacement therapy can mediate addictions in PD and other neurological disorders. We provide five categories of evidences that align with this position: (i) ICSD prevalence is greater with D2/D3 receptor agonist therapy vs PD alone. (ii) Capacity of dopamine replacement therapy to produce addiction-like behaviors is independent of disease for which the therapy is being provided. (iii) ICSD-like behaviors are recapitulated in laboratory rats with and without PD-like pathology. (iv) Behavioral pathology co-varies with drug exposure. (v) ICSD Features of ICSDs are consistent with agonist pharmacology and neuroanatomical substrates of addictions. Considering the underpinnings of ICSDs in PD should not only help therapeutic decision-making in neurological disorders, but also apprise ICSDs in general.

Using Modern Neuroscience to Inform Opioid Use and Abuse Liability in Adolescents.

Opioid abuse and overdosing have reached epidemic status in the United States, and this epidemic has profound negative effects on the lives of adolescents and their families. A combination of readily available opioids (including illicit opioids, such as heroin, and overprescribed prescription opioid-based painkillers) and an abuse vulnerability inherent to adolescence drives the problem. The pharmacology of opioids in the context of adolescent brain neurobiology helps explain the enhanced vulnerability to drug abuse experienced by the young. This report overviews these topics as they relate to orthopaedic procedures employed for adolescent patients.

Pharmacological insights into impulsive-compulsive spectrum disorders associated with dopaminergic therapy.

Impulsive-compulsive spectrum disorders are associated with dopamine agonist therapy in some patients. These untoward outcomes occur with direct-acting, full and partial agonists at D2 dopamine family receptors. The disorders typically emerge during chronic treatment, and exhibit common features that are independent of the neurological or psychiatric pathology for which the initial therapy was indicated. It is well-documented that the brain is 'plastic', changing in response to alterations to internal factors (e.g., disease processes), as well as external factors (e.g., therapies). The complexities of these clinical scenarios have eluded a clear depiction of the neurobiology for impulsive-compulsive spectrum disorders and engendered considerable debate regarding the mechanistic underpinnings of the disorders. In this opinion, we use pharmacological concepts related to homeostatic compensation subsequent to chronic receptor activation to provide a unifying construct. This construct helps explain the occurrence of impulsive-compulsive spectrum disorders across disease states, and during therapy with full and partial agonists.

Integrating Addiction into the Neuroscience Curriculum.

Addiction is a relevant and fascinating topic that can be readily taught within undergraduate neuroscience curricula. Modern research has afforded tremendous insights into the neuroscience of addictions, including substance use disorders, behavioral addictions, and disorders of impulse control and compulsivity. Building on the neuroscience of plasticity associated with learning and memory, we now understand a great deal about the temporal and spatial progression of these disorders in adult and developing brains. Addictions have considerable health and social consequences to modern society, particularly with legalization of marijuana, the increasing popularity of numerous gambling/gaming venues, and the surge of methamphetamine and opioid abuse. To guide healthy medical practices and help inform policy makers, there is an increasing need for neuroscientists informed on addiction topics. Undergraduate education for students with an interest in the neurosciences is an excellent venue to achieve this goal. Key to this education is what modern neuroscience informs us on addiction processes and making these concepts relevant to the undergraduate student. Toward that end, this editorial will illustrate how addiction neuroscience can be integrated into ongoing curricula at the undergraduate level.

Region-specific changes in markers of neuroplasticity revealed in HIV-1 transgenic rats by low-dose methamphetamine.

Methamphetamine abuse co-occurring with HIV infection presents neuropathology in brain regions that mediate reward and motivation. A neuronal signaling cascade altered acutely by meth and some HIV-1 proteins is the mitogen-activated protein kinase (MAPK) pathway. It remains unknown if chronic co-exposure to meth and HIV-1 proteins converge on MAPK in vivo. To make this determination, we studied young adult Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats that self-administered meth (0.02-0.04 mg/kg/0.05 ml iv infusion, 2 h/day for 21 days) and their saline-yoked controls. One day following the operant task, rats were killed. Brain regions involved in reward-motivation [i.e., nucleus accumbens (NA) and ventral pallidum (VP)], were assayed for a MAPK cascade protein, extracellular signal-regulated kinase (ERK), and a downstream transcription factor, ΔFosB. In the NA, activated (phosphorylated; p) ERK-to-ERK ratio (pERK/ERK) was increased in meth-exposed Tg rats versus saline Tg controls, and versus meth non-Tg rats. ΔFosB was increased in meth Tg rats versus saline and meth non-Tg rats. Assessment of two targets of ΔFosB-regulated transcription revealed (1) increased dopamine D1 receptor (D1R) immunoreactivity in the NA shell of Tg-meth rats versus saline Tg controls, but (2) no changes in the AMPA receptor subunit, GluA2. No changes related to genotype or meth occurred for ERK, ΔFosB or D1R protein in the VP. Results reveal a region-specific activation of ERK, and increases in ΔFosB and D1R expression induced by HIV-1 proteins and meth. Such effects may contribute to the neuronal and behavioral pathology associated with meth/HIV comorbidity.

OPQRST(U): Integrating substance use disorders or "Use" into the medical history.

Substance use disorders (SUDs) are pervasive in the United States, with 20.1 million cases in 2016, of which only 19% receive treatment. SUDs permeate all medical specialties and should be considered in the differential diagnosis of every chief complaint. Acknowledging the salience of SUDs provides a unique opportunity for early identification and intervention. Thus, SUDs should be reflected prominently in the history of the present illness rather than in the social history. To this effect, we propose the inclusion of Use (U) in the history of present illness and incorporating "U" into the pedagogical mnemonic of OPQRST that is commonly used in medical training. Obtaining this history will help determine if and which abused substances may be contributing to the chief complaint. We also suggest the incorporation of an additional acronym, SORTED, to account for the various domains of Use, including Street (illicit drugs), OTCs (over-the-counter medications), Rx (prescriptions, including nonmedicinal use of pharmaceutical drugs), Tobacco (including e-cigarettes), EtOH (alcohol), and Dietary (caffeine, vitamins, and herbal supplements) agents. We discuss how utilizing OPQRSTU will help reshape the way medical students think about SUDs and will facilitate detection and diagnosis of all domains of SUDs.

Colon dysregulation in methamphetamine self-administering HIV-1 transgenic rats.

The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not known. To shed light on this scenario, we evaluated colon barrier pathology in a rat model of the human comorbid condition. Intestinal barrier integrity and permeability were assessed in drug-naïve Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats, and in Tg and non-Tg rats instrumented with jugular cannulae trained to self-administer methamphetamine or serving as saline-yoked controls. Intestinal permeability was determined by measuring the urine content of orally gavaged sugars. Intestinal barrier integrity was evaluated by immunoblotting or immunofluorescence of colon claudin-1 and zonula occludens-1 (ZO-1), two major tight junction proteins that regulate gut epithelial paracellular permeability. Both non-Tg and Tg rats self-administered moderate amounts of methamphetamine. These amounts were sufficient to increase colon permeability, reduce protein level of claudin-1, and reduce claudin-1 and ZO-1 immunofluorescence in Tg rats relative to non-Tg rats. Methamphetamine decreased tight junction immunofluorescence in non-Tg rats, with a similar, but non-significant trend observed in Tg rats. However, the effect of methamphetamine on tight junction proteins was subthreshold to gut leakiness. These findings reveal that both HIV-1 proteins and methamphetamine alter colon barrier integrity, and indicate that the gut may be a pathogenic site for these insults.

Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update.

Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.

Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease.

Pramipexole and ropinirole are dopamine agonists that are efficacious in treating motor disturbances of neuropathologies, e.g., Parkinson's disease and restless legs syndrome. A significant portion of treated patients develop impulsive/compulsive behaviors. Current treatment is dose reduction or switching to an alternative dopamine replacement, both of which can undermine the motor benefits. Needed is a preclinical model that can assist in identifying adjunct treatments to dopamine agonist therapy that reduce impulsive/compulsive behaviors without interfering with motor benefits of the dopamine agonist. Toward that objective, the current study implemented a rat model of Parkinson's disease to behaviorally profile chronically administered pramipexole. This was accomplished with male Sprague-Dawley rats wherein (i) 6-hydroxydopamine-induced lesions of the dorsolateral striatum produced Parkinson's disease-like akinesia, measured in the forelimbs, (ii) intracranial self-stimulation-mediated probability discounting indicated impulsivity/risk-taking, and (iii) two doses of pramipexole were continuously administered for 14-28days via osmotic minipumps to mirror the chronic, stable exposure achieved with extended release formulations. The atypical antidepressant, mirtazapine, is known to reduce behaviors associated with drug addiction in rats; thus, we demonstrated model utility here by determining the effects of mirtazapine on pramipexole-induced motor improvements versus probability discounting. We observed that forelimb akinesia subsequent to striatal lesions was attenuated by both pramipexole doses tested (0.3 and 1.2mg/kg/day) within 4h of pump implant dispensing 0.3mg/kg/day and 1h by 1.2mg/kg/day. By contrast, 12-14days of infusion with 0.3mg/kg/day did not alter discounting, but increases were obtained with 1.2mg/kg/day pramipexole, with 67% of 1.2mg/kg/day-treated rats meeting categorical criteria for 'high risk-taking'. Insertion of a second minipump delivering mirtazapine did not alter motor function during 14days of co-administration with pramipexole, but was sufficient to attenuate risk-taking. These outcomes revealed distinct probability discounting and anti-akinesia profiles for pramipexole, indicating that pharmacotherapy, (e.g., mirtazapine treatments), can be developed that reduce risk-taking while leaving motor benefits intact.

HIV-1 Transgenic Rat Prefrontal Cortex Hyper-Excitability is Enhanced by Cocaine Self-Administration.

The medial prefrontal cortex (mPFC) is dysregulated in HIV-1-infected humans and the dysregulation is enhanced by cocaine abuse. Understanding mPFC pathophysiology in this comorbid state has been hampered by the dearth of relevant animal models. To help fill this knowledge gap, electrophysiological assessments were made of mPFC pyramidal neurons (PN) from adult male HIV-1 transgenic (Tg) F344 rats (which express seven of the nine HIV-1 toxic proteins) and non-Tg F344 rats that self-administered cocaine for 14 days (COC-SA), as well as saline-yoked controls (SAL-Yoked) and experimentally naive Tg and non-Tg rats. Forebrain slices were harvested and prepared for whole-cell patch-clamp recording, and in treated rats, this occurred after 14-18 days of forced abstinence. Aged-matched rats were used for immunohistochemical detection of the L-channel protein, Cav1.2-α1c. We determined that: (i) the two genotypes acquired the operant task and maintained similar levels of COC-SA, (ii) forced abstinence from COC-SA enhanced mPFC PN excitability in both genotypes, and neurons from Tg rats exhibited the greatest pathophysiology, (iii) neurons from SAL-Yoked Tg rats were more excitable than those from SAL-Yoked non-Tg rats, and in Tg rats (iv) blockade of L-type Ca(2+) channels reduced the enhanced excitability, and (v) Cav1.2-immunoreactivity was increased. These findings provide the first assessment of the mPFC pathophysiology in a rodent model of HIV-1-mediated neuropathology with and without cocaine self-administration. Outcomes reveal an enhanced cortical excitability during chronic exposure to HIV-1 proteins that is excessively exacerbated with cocaine abuse. Such neuropathophysiology may underlie the cognitive dysregulation reported for comorbid humans.

Dopaminergic lesions of the dorsolateral striatum in rats increase delay discounting in an impulsive choice task.

Dysregulated dopamine transmission in striatal circuitry is associated with impulsivity. The current study evaluated the influence of dopaminergic inputs to the dorsolateral striatum on impulsive choice, one aspect of impulsive behavior. We implemented an operant task that measures impulsive choice in rats via delay discounting wherein intracranial self-stimulation (ICSS) was used as the positive reinforcer. To do so, rats were anesthetized to allow implanting of a stimulating electrode within the lateral hypothalamus of one hemisphere and bilateral dorsal striatal injections of the dopaminergic toxin, 6-OHDA (lesioned) or its vehicle (sham). Following recovery, rats were trained in a delay discounting task wherein they selected between a small ICSS current presented immediately after lever pressing, and a large ICSS current presented following a 0 to 15 s delay upon pressing the alternate lever. Task acquisition and reinforcer discrimination were similar for lesioned and sham rats. All rats exhibited an initial preference for the large reinforcer, and as the delay was increased, preference for the large reinforcer was decreased indicating that the subjective value of the large reinforcer was discounted as a function of delay time. However, this discounting effect was significantly enhanced in lesioned rats for the longer delays. These data reveal a contribution of dopaminergic inputs to the dorsolateral striatum on impulsive choice behavior, and provide new insights into neural substrates underlying discounting behaviors.

Choice impulsivity: Definitions, measurement issues, and clinical implications.

Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, and steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.