Amanda L. Persons

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 15s 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.

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.

Enduring cortical alterations after a single in-vivo treatment of HIV-1 Tat.

HIV-1 proteins, including the transactivator of transcription (Tat), are believed to be involved in HIV-associated neurocognitive disorders by disrupting Ca2+ homeostasis, which leads to progressive dysregulation, damage, or death of neurons in the brain. We have found previously that bath-applied Tat abnormally increased Ca2+ influx through overactivated, voltage-sensitive L-type Ca2+ channels in pyramidal neurons within the rat medial prefrontal cortex (mPFC). However, it is unknown whether the Tat-induced Ca2+ dysregulation was mediated by increased activity and/or the number of the L-channels. This study tested the hypothesis that transient/early exposure to Tat in vivo promoted enduring L-channel dysregulation in the mPFC without neuron loss. Accordingly, rats were administered a single intracerebroventricular injection of recombinant Tat (80 &mgr;g/20 &mgr;l; diluted by cerebrospinal fluids to pathophysiological concentrations) or vehicle. Rats were killed 14 days after injection for immunohistochemical assessments of the mPFC, motor cortex, caudate–putamen, and nucleus accumbens. Stereological estimates for positively stained cells indicated a significant increase in the number of cells expressing the pore-forming Cav1.2-&agr;1c subunit of L-channels in the mPFC compared with other regions in Tat-treated or vehicle-treated rat brains. Optical density measurements showed a Tat-induced increase in glial fibrillary acidic protein expression, indicating astrogliosis in the cortical regions. There was no significant loss of neurons in any brain region investigated. These findings indicate that transient Tat exposure in vivo induced enduring L-channel dysregulation and astrogliosis in the mPFC without neuron loss. Such maladaptations may contribute toward dysregulated Ca2+ homeostasis and neuropathology in the PFC in the early stages of HIV infection.

The atypical antidepressant mirtazapine attenuates expression of morphine-induced place preference and motor sensitization

Opioid abuse and dependence remains prevalent despite having multiple FDA-approved medications to help maintain abstinence. Mirtazapine is an atypical antidepressant receiving attention for substance abuse pharmacotherapy, and its action includes alterations in monoaminergic transmission. As monoamines are indirectly altered by opioids, the current investigation assessed the ability of mirtazapine to ameliorate morphine-induced behaviors. Conditioned place preference (CPP) is a behavioral assay wherein a rewarding drug is paired with a distinct environmental context resulting in reward-related salience of cues through learning-related neuronal plasticity. A second behavioral assay involved motor sensitization (MSn), wherein repeated administration results in an enhanced motoric response to an acute challenge, also reflecting neuronal plasticity. Attenuation of CPP and/or MSn provides two behavioral measures to suggest therapeutic potential for addiction therapy, and the present study evaluated the effectiveness of mirtazapine to reduce both behaviors. To do so, morphine-induced CPP was established using an eight day conditioning paradigm, and expression of CPP was tested on day 10 following a 24h or 30min mirtazapine pretreatment. To determine if mirtazapine altered the expression of MSn, on day 11, rats received a pretreatment of mirtazapine, followed 30min later by a challenge injection of morphine. Pretreatment with mirtazapine 24h prior to the CPP test had no effect on CPP expression. In contrast, a 30min pretreatment of mirtazapine attenuated the expression of both CPP and MSn. Collectively, these results indicate that mirtazapine may help to maintain abstinence in opioid dependent patients.

Cortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine

The life span of individuals that are sero-positive for human immunodeficiency virus (HIV) has greatly improved; however, complications involving the central nervous system (CNS) remain a concern. While HIV does not directly infect neurons, the proteins produced by the virus, including HIV transactivator of transcription (Tat), are released from infected glia; these proteins can be neurotoxic. This neurotoxicity is thought to mediate the pathology underlying HIVassociated neurological impairments. Cocaine abuse is common among HIV infected individuals, and this abuse augments HIV-associated neurological deficits. The brain regions and pathophysiological mechanisms that are dysregulated by both chronic cocaine and Tat are the focus of the current review.

A new approach to assess gambling-like behavior in laboratory rats: using intracranial self-stimulation as a positive reinforcer

Pathological gambling is one manifestation of impulse control disorders. The biological underpinnings of these disorders remain elusive and treatment is far from ideal. Animal models of impulse control disorders are a critical research tool for understanding this condition and for medication development. Modeling such complex behaviors is daunting, but by its deconstruction, scientists have recapitulated in animals critical aspects of gambling. One aspect of gambling is cost/benefit decision-making wherein one weighs the anticipated costs and expected benefits of a course of action. Risk/reward, delay-based and effort-based decision-making all represent cost/benefit choices. These features are studied in humans and have been translated to animal protocols to measure decision-making processes. Traditionally, the positive reinforcer used in animal studies is food. Here, we describe how intracranial self-stimulation can be used for cost/benefit decision-making tasks and overview our recent studies showing how pharmacological therapies alter these behaviors in laboratory rats. We propose that these models may have value in screening new compounds for the ability to promote and prevent aspects of gambling behavior.

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.

Mirtazapine and ketanserin alter preference for gambling-like schedules of reinforcement in rats

ABSTRACT Drug and behavioral addictions have overlapping features, e.g., both manifest preference for larger, albeit costlier, reinforcement options in cost/benefit decision‐making tasks. Our prior work revealed that the mixed‐function serotonergic compound, mirtazapine, attenuates behaviors by rats motivated by abused drugs. To extend this work to behavioral addictions, here we determined if mirtazapine and/or ketanserin, another mixed‐function serotonin‐acting compound, can alter decision‐making in rats that is independent of drug (or food)‐motivated reward. Accordingly, we developed a novel variable‐ratio task in rats wherein intracranial self‐stimulation was used as the positive reinforcer. Using lever pressing for various levels of brain stimulation, the operant task provided choices between a small brain stimulation current delivered on a fixed‐ratio schedule (i.e., a predictable reward) and a large brain stimulation delivered following an unpredictable number of responses (i.e., a variable‐ratio schedule). This task allowed for demonstration of individualized preference and detection of shifts in motivational influences during a pharmacological treatment. Once baseline preference was established, we determined that pretreatment with mirtazapine or ketanserin significantly decreased preference for the large reinforcer presented after gambling‐like schedules of reinforcement. When the rats were tested the next day without drug, preference for the unpredictable large reinforcer option was restored. These data demonstrate that mirtazapine and ketanserin can reduce preference for larger, costlier reinforcement options, and illustrate the potential for these drugs to alter behavior. HIGHLIGHTSA novel model of cost/benefit decision‐making is described.Mirtazapine decreased preference for high effort/large reinforcers.Dose‐related effects of ketanserin in this task are revealed.

Self-administration of methamphetamine alters gut biomarkers of toxicity

Methamphetamine (METH) is a highly abused psychostimulant that is associated with an increased risk for developing Parkinsons disease (PD). This enhanced vulnerability likely relates to the toxic effects of METH that overlap with PD pathology, for example, aberrant functioning of α‐synuclein and parkin. In PD, peripheral factors are thought to contribute to central nervous system (CNS) degeneration. For example, α‐synuclein levels in the enteric nervous system (ENS) are elevated, and this precedes the onset of motor symptoms. It remains unclear whether neurons of the ENS, particularly catecholaminergic neurons, exhibit signs of METH‐induced toxicity as seen in the CNS. The aim of this study was to determine whether self‐administered METH altered the levels of α‐synuclein, parkin, tyrosine hydroxylase (TH), and dopamine‐β‐hydroxylase (DβH) in the myenteric plexus of the distal colon ENS. Young adult male Sprague‐Dawley rats self‐administered METH for 3 h per day for 14 days and controls were saline‐yoked. Distal colon tissue was collected at 1, 14, or 56 days after the last operant session. Levels of α‐synuclein were increased, while levels of parkin, TH, and DβH were decreased in the myenteric plexus in the METH‐exposed rats at 1 day following the last operant session and returned to the control levels after 14 or 56 days of forced abstinence. The changes were not confined to neurofilament‐positive neurons. These results suggest that colon biomarkers may provide early indications of METH‐induced neurotoxicity, particularly in young chronic METH users who may be more susceptible to progression to PD later in life.

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.