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.

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.

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.

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.

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.

Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat.

The medial prefrontal cortex (mPFC) plays a critical role in reward-motivated behaviors. Repeated cocaine exposure dysregulates the dorsal mPFC, and this is thought to contribute to cocaine-seeking and relapse of abstinent abusers. Neuropathology of the mPFC also occurs in human immunodeficiency virus (HIV)-positive individuals, and this is exaggerated in those who also abuse cocaine. The impact of the comorbid condition on mPFC neuronal function is unknown. To fill this knowledge gap, we performed a behavioral and electrophysiological study utilising adult male rats that self-administered cocaine by pressing a lever for 14 once-daily operant sessions. Saline-yoked (SAL-yoked) rats served as controls. Cue reactivity (CR) was used to indicate drug-seeking, assessed by re-exposing the rats to cocaine-paired cues wherein non-reinforced lever pressing was quantified 1 day (CR1) and 18-21 days (CR2) after the 14th operant session. Only cocaine self-administration (COC-SA) rats showed CR. One day after CR2, brain slices were prepared for electrophysiological assessment. Whole-cell patch-clamp recordings of dorsal (prelimbic) mPFC pyramidal neurons from COC-SA rats showed a significant increase in firing evoked by depolarizing currents as compared with those from SAL-yoked control rats. Bath application of the toxic HIV-1 protein transactivator of transcription (Tat) also depolarized neuronal membranes and increased evoked firing. The Tat-induced excitation was greater in the neurons from withdrawn COC-SA rats than in controls. Tat also reduced spike amplitude, and this co-varied with cocaine-seeking during CR2. Taken together, these novel findings provide support at the neuronal level for the concept that the increased excitability of mPFC pyramidal neurons following cocaine self-administration drives drug-seeking and augments the neuropathophysiology caused by HIV-1 Tat.

Linking neuroscience with modern concepts of impulse control disorders in Parkinson's disease.

Patients with Parkinson's disease (PD) may experience impulse control disorders (ICDs) when on dopamine agonist therapy for their motor symptoms. In the last few years, a rapid growth of interest for the recognition of these aberrant behaviors and their neurobiological correlates has occurred. Recent advances in neuroimaging are helping to identify the neuroanatomical networks responsible for these ICDs, and together with psychopharmacological assessments are providing new insights into the brain status of impulsive behavior. The genetic associations that may be unique to ICDs in PD are also being identified. Complementing human studies, electrophysiological and biochemical studies in animal models are providing insights into neuropathological mechanisms associated with these disorders. New animal models of ICDs in PD patients are being implemented that should provide critical means to identify efficacious therapies for PD-related motor deficits while avoiding ICD side effects. Here, we provide an overview of these recent advances, with a particular emphasis on the neurobiological correlates reported in animal models and patients along with their genetic underpinnings.

Methamphetamine self-administration results in persistent dopaminergic pathology: implications for Parkinson's disease risk and reward-seeking.

Methamphetamine (Meth) abuse may be a risk factor for Parkinson's disease (PD); a problematic event as approximately 33 million people abuse Meth worldwide. The current study determined if a mild form of PD-like nigrostriatal pathology occurred following forced abstinence in Meth self-administering rats. The average daily intake of self-administered Meth was 3.6 ± 0.2 mg/kg/3 h over 14 sessions. Subsequently, animals were killed and the brains harvested at 1, 7, 28 or 56 days of abstinence. Post mortem, tyrosine hydroxylase (TH) immunostaining in the dorsal striatum progressively decreased throughout abstinence, reaching a 50% loss at 56 days. In the substantia nigra, there was marked reduction of TH+ cells, and Fluorogold (retrograde tracer) transport from the striatum to the nigra, at 28 and 56 days after Meth. Thus, Meth-induced progressive nigrostriatal damage occurred retrogradely, similar to PD pathology. The mesolimbic dopamine pathway [i.e. ventral tegmental area (VTA) and nucleus accumbens (NAc)], critical for Meth-induced reward, was also evaluated. TH immunostaining was decreased in the NAc-core at 28 and 56 days of forced abstinence, while staining in the dorsomedial NAc-shell was preserved. Accordingly, TH+ cell loss was evident in the lateral VTA, the origin of projections to the NAc-core, but not the medial VTA where NAc-shell projections originate. Thus, after Meth-taking ceased, a time-dependent, progressive degeneration occurred within nigrostriatal projections that eventually engulfed lateral mesolimbic projections. This pathological pattern is consistent with a trajectory for developing PD; therefore, these findings provide preclinical support for Meth abuse to increase vulnerability to developing PD.

Dopamine receptors and the persistent neurovascular dysregulation induced by methamphetamine self-administration in rats.

Recently abstinent methamphetamine (Meth) abusers showed neurovascular dysregulation within the striatum. The factors that contribute to this dysregulation and the persistence of these effects are unclear. The current study addressed these knowledge gaps. First, we evaluated the brains of rats with a history of Meth self-administration following various periods of forced abstinence. Micro-computed tomography revealed a marked reduction in vessel diameter and vascular volume uniquely within the striatum between 1 and 28 days after Meth self-administration. Microvessels showed a greater impairment than larger vessels. Subsequently, we determined that dopamine (DA) D2 receptors regulated Meth-induced striatal vasoconstriction via acute noncontingent administration of Meth. These receptors likely regulated the response to striatal hypoxia, as hypoxia inducible factor 1α was elevated. Acute Meth exposure also increased striatal levels of endothelin receptor A and decreased neuronal nitric oxide synthase. Collectively, the data provide novel evidence that Meth-induced striatal neurovascular dysregulation involves DA receptor signaling that results in vasoconstriction via endothelin receptor A and nitric oxide signaling. As these effects can lead to hypoxia and trigger neuronal damage, these findings provide a mechanistic explanation for the selective striatal toxicity observed in the brains of Meth-abusing humans.

Cellular distribution of AMPA receptor subunits and mGlu5 following acute and repeated administration of morphine or methamphetamine.

Ionotropic AMPA receptors (AMPAR) and metabotropic glutamate group I subtype 5 receptors (mGlu5) mediate neuronal and behavioral effects of abused drugs. mGlu5 stimulation increases expression of striatal-enriched tyrosine phosphatase isoform 61 (STEP61 ) which internalizes AMPARs. We determined the rat brain profile of these proteins using two different classes of abused drugs, opiates, and stimulants. STEP61 levels, and cellular distribution/expression of AMPAR subunits (GluA1, GluA2) and mGlu5, were evaluated via a protein cross-linking assay in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP) harvested 1 day after acute, or fourteen days after repeated morphine (8 mg/kg) or methamphetamine (1 mg/kg) (treatments producing behavioral sensitization). Acute morphine decreased GluA1 and GluA2 surface expression in mPFC and GluA1 in NAc. Fourteen days after repeated morphine or methamphetamine, mGlu5 surface expression increased in VP. In mPFC, mGlu5 were unaltered; however, after methamphetamine, STEP61 levels decreased and GluA2 surface expression increased. Pre-treatment with a mGlu5-selective negative allosteric modulator, blocked methamphetamine-induced behavioral sensitization and changes in mPFC GluA2 and STEP61 . These data reveal (i) region-specific distinctions in glutamate receptor trafficking between acute and repeated treatments of morphine and methamphetamine, and (ii) that mGlu5 is necessary for methamphetamine-induced alterations in mPFC GluA2 and STEP61 .

SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats.

BACKGROUND: Methamphetamine (meth) dependence presents a substantial socioeconomic burden. Despite the need, there is no FDA-approved pharmacotherapy for psychostimulant dependence. We consider 5-HT2C receptors as viable therapeutic targets. We recently revealed that the atypical antidepressant, mirtazapine, attenuates meth-seeking in a rodent model of human substance abuse. Mirtazapine historically has been considered to be an antagonist at 5-HT2C receptors, but more recently shown to exhibit inverse agonism at constitutively active 5-HT2C receptors. To help distinguish the roles for antagonism vs. inverse agonism, here we explored the ability of a more selective 5-HT2C inverse agonist, SB 206553 to attenuate meth-seeking behavior, and compared its effects to those obtained with 5-HT2C antagonists, SDZ Ser 082 and SB 242084. To do so, rats were trained to self-administer meth and tested for seeking-like behavior in cue reactivity sessions consisting of contingently presenting meth-associated cues without meth reinforcement. We also explored motor function to determine the influence of SB 206553 and SDZ Ser 082 on motor activity in the presence and absence of meth. RESULTS: Like mirtazapine, pretreatment with SB 206553 (1.0, 5.0, and 10.0 mg/kg), attenuated meth-seeking. In contrast, the antagonists, SDZ Ser 082 (0.1, 0.3, and 1.0 mg/kg) and SB 242084 (3.0 mg/kg) had no effect on cue reactivity (CR). SB 242084 (3.0 mg/kg) failed to attenuate the effects of 5.0 and 10 mg/kg SB 206553 on CR. Motor function was largely unaltered by the 5-HT2C ligands; however, SB 206553, at the highest dose tested (10.0 mg/kg), attenuated meth-induced rearing behavior. CONCLUSIONS: The lack of effect by 5-HT2C antagonists suggests that meth-seeking and meth-evoked motor activity are independent of endogenous 5-HT acting at 5-HT2C receptors. While SB 206553 dramatically impacted meth-evoked behaviors it is unclear whether the observed effects were 5-HT2C receptor mediated. Thus, SB 206553 deserves further attention in the study of psychostimulant abuse disorders.

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.

Repeated exposure to morphine alters surface expression of AMPA receptors in the rat medial prefrontal cortex.

Behavioral sensitization describes the intensification of motor activity that results from repeated exposure to drugs of misuse, and the underlying neuronal adaptations are hypothesized to model aspects of the brain changes that occur in humans misusing such drugs. The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor is an ionotropic glutamate receptor involved in the neuroplasticity that accompanies acute and repeated drug administration. Changing surface expression is one means to regulate AMPA receptor function, and the present study tested the hypothesis that behavioral sensitization to the µ-opioid receptor agonist morphine is accompanied by changes in the subcellular distribution of AMPA receptors in limbic brain regions. To test this hypothesis, we used a protein cross-linking assay to assess cell surface and intracellular levels of GluA1 and GluA2 subunits in the nucleus accumbens, medial prefrontal cortex and ventral pallidum. Repeated morphine treatment decreased surface expression of GluA1 in the medial prefrontal cortex without affecting levels of GluA2. In contrast, surface levels of GluA1 or GluA2 were unchanged in the nucleus accumbens and ventral pallidum, demonstrating that although AMPA receptors in accumbal and pallidal regions are critical mediators of behaviors induced by repeated opiate exposure, these effects are not accompanied by changes in surface expression. The findings reveal that the involvement of AMPA receptor trafficking in opiate-induced behavioral sensitization is relegated to selective regions and that AMPA receptors in the medial prefrontal cortex may be particularly sensitive to these actions.

Brain region-selective cellular redistribution of mGlu5 but not GABA(B) receptors following methamphetamine-induced associative learning.

Alterations in receptor expression and distribution between cell surface and cytoplasm are means by which psychostimulants regulate neurotransmission. Metabotropic glutamate receptor group I, subtype 5 (mGluR5) and GABA(B) receptors (GABA(B) R) are critically involved in the development and expression of stimulant-induced behaviors, including conditioned place preference (CPP), an index of drug-seeking. However, it is not known if psychostimulant-induced CPP alters the trafficking of these receptors. To fill this gap, this study used methamphetamine (Meth)-induced CPP in rats to ascertain if receptor changes occur in limbic brain regions that regulate drug-seeking, the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP). To do so, ex vivo tissue was assessed for changes in expression and surface vs. intracellular distribution of mGluR5 and GABA(B) Rs. There was a decrease in the surface to intracellular ratio of mGluR5 in the mPFC in Meth-conditioned rats, commensurate with an increase in intracellular levels. mGluR5 levels in the NAc or the VP were unaltered. There were no changes for GABA(B) R in any brain region assayed. This ex vivo snapshot of metabotropic glutamate and GABA receptor cellular distribution following induction of Meth-induced CPP is the first report to determine if these receptors are differentially altered after Meth-induced CPP. The results suggest that this Meth treatment paradigm likely induced a compensatory change in mGluR5 surface to intracellular ratio such that the surface remains unaltered while an increase in intracellular protein occurred.

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.

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.

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.

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.