Janet Neisewander - Academia.edu (original) (raw)

Papers by Janet Neisewander

Frontiers in Systems Neuroscience, Nov 7, 2018

Frontiers in Systems Neuroscience, Oct 10, 2017

5-HT 1B receptors (5-HT 1B Rs) modulate behavioral effects of cocaine. Here we examined the effec... more 5-HT 1B receptors (5-HT 1B Rs) modulate behavioral effects of cocaine. Here we examined the effects of the 5-HT 1B R agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1Hpyrrolo[3,2-b]pyridine (CP94253) on spontaneous and cocaine-induced locomotion and on cocaine-primed reinstatement of conditioned place preference (CPP) in male mice given daily repeated injections of either saline or cocaine (15 mg/kg, IP) for 20 days. In the locomotor activity experiment, testing occurred both 1 and 20 days after the final injection. In the CPP experiment, mice underwent conditioning procedures while receiving the last of their daily injections, which were given either during or ≥2 h after CPP procedures. The CPP procedural timeline consisted of baseline preference testing (days 12-13 of the chronic regimen), conditioning (days 14-19, 2 daily 30-min sessions separated by 5 h), CPP test (day 21), extinction (days 22-34; no injections), CPP extinction test (day 35), and reinstatement test (day 36). Mice that had not extinguished received additional extinction sessions prior to reinstatement testing on day 42. On test days, mice were pretreated with either saline or CP94253 (10 mg/kg, IP). Testing began 30 min later, immediately after mice were primed with either saline or cocaine (5 mg/kg for locomotion; 15 mg/kg for reinstatement). We found that CP94253 increased spontaneous locomotion in mice receiving repeated injections of either saline or cocaine when tested 1 day after the last injection, but had no effect on spontaneous locomotion after 20 days abstinence from repeated injections. Surprisingly, cocaine-induced locomotion was sensitized regardless of whether the mice had received repeated saline or cocaine. CP94253 attenuated expression of the sensitized locomotion after 20 days abstinence. A control experiment in noninjected, drug-naïve mice showed that CP94253 had no effect on spontaneous or cocaineinduced locomotion. Mice reinstated cocaine-CPP when given a cocaine prime, and CP94253 pretreatment attenuated cocaine reinstatement. The findings suggest that stress from repeated saline injections and/or co-housing with cocaine-injected mice may cross-sensitize with cocaine effects on locomotion and that CP94253 attenuates these effects, as well as reinstatement of cocaine-CPP. This study supports the idea that 5-HT 1B R agonists may be useful anti-cocaine medications.

Behavioural Brain Research, Oct 1, 2016

Smoking initiation predominantly occurs during adolescence, often in the presence of peers. There... more Smoking initiation predominantly occurs during adolescence, often in the presence of peers. Therefore, understanding the neural mechanisms underlying the rewarding effects of nicotine and social stimuli is vital. Using the conditioned place preference (CPP) procedure, we measured immediate early gene (IEG) expression in animals following exposure either to a rewardconditioned environment or to the unconditioned stimuli (US). Adolescent, male rats were assigned to the following CPP US conditions: (1) Saline + Isolated, (2) Nicotine + Isolated, (3) Saline + Social, or (4) Nicotine + Social. For Experiment 1, brain tissue was collected 90 min following the CPP expression test and processed for Fos immunohistochemistry. We found that rats conditioned with nicotine with or without a social partner exhibited CPP; however, we found no group differences in Fos expression in any brain region analyzed, with the exception of the nucleus accumbens core that exhibited a social-induced attenuation in Fos expression. For Experiment 2, brain tissue was collected 90 min following US exposure during the last conditioning session. We found social reward-induced increases in IEG expression in striatal and amydalar subregions. In contrast, nicotine reduced IEG expression in prefrontal and striatal subregions. Reward interactions were also found in the dorsolateral striatum, basolateral amygdala, and ventral tegmental area where nicotine alone attenuated IEG expression and social reward reversed this effect. These results suggest that in general social rewards enhance, whereas nicotine attenuates, activation of mesocorticolimbic regions; however, the rewards given together interact to enhance activation in some regions. The findings contribute to knowledge of how a social environment influences nicotine effects.

Drug and Alcohol Dependence, Aug 1, 2019

Background:This study determined if a within-session dose-reduction design sufficiently captures ... more Background:This study determined if a within-session dose-reduction design sufficiently captures elasticity of demand for nicotine in male and female rats using environmental enrichment to manipulate demand elasticity.Methods:Male and female Sprague-Dawley rats were trained to self-administer nicotine (60 μg/kg/infusion). In Experiment 1, rats began daily dose-reduction for nine sessions following acquisition. Rats then underwent a minimum of five within-session dose-reduction sessions where each dose was available for 10 min. In Experiment 2, rats were reared in isolated, social, or enriched housing followed by acquisition of nicotine self-administration. Rats then underwent within-session dose-reduction. Housing environments were then switched, followed by additional testing sessions. Consumption was calculated for each dose and exponential demand curves were fit.Results:No sex differences in acquisition of nicotine self-administration were detected for either experiment. In experiment 1, demand intensity (Q0; estimated intake if nicotine were freely available), was higher with between- compared to within-session dose-reduction, although elasticity of demand (α; rate of decline in nicotine intake as a function of increasing unit price), was lower. In Experiment 2, animals reared in enrichment had fewer infusions during acquisition compared to animals in isolation. Enriched males had reduced demand intensity compared to both isolated and social males, whereas isolated females had reduced intensity compared to enriched females.Conclusions:The within-session dose-reduction procedure for nicotine self-administration replicated effects of environmental enrichment on consumption behaviors. Additionally, this procedure captured differences in nicotine demand due to sex, laying important groundwork for future translational research on mechanisms of nicotine dependence.

Neuropharmacology, Oct 1, 2016

Highlights: • VTA BDNF overexpression enhanced cocaine binge intake in socially-defeated rats. • ... more Highlights: • VTA BDNF overexpression enhanced cocaine binge intake in socially-defeated rats. • VTA BDNF overexpression in the absence of stress had no effect on cocaine self-administration. • VTA BDNF overexpression enhanced ∆FosB expression in the nucleus accumbens, but not the dorsal striatum.

Genes, Brain and Behavior, Jan 26, 2018

The neuronal RNA-binding protein HuD is involved in synaptic plasticity and learning and memory m... more The neuronal RNA-binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD-mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuD OE). When this set was further limited to genes in the Knowledgebase of Addiction Related Genes database (KARG) that contains predicted HuDbinding sites in their 3′ untranslated regions (3′ UTR), we found that HuD regulates networks that have been associated with addiction-like behavior. These genes included Bdnf and Camk2a, two previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction-related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens (NAc) of wild type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuD OE and wild type mice in CPP and found that HuD OE mice showed increased cocaine CPP compared to controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKIIα and BDNF. These findings suggest HuD involvement in addiction-related behaviors such as cocaine conditioning and seeking, through increased plasticity-related gene expression.

ACS Chemical Neuroscience, May 1, 2019

5-HT1B receptors (5-HT1BRs) modulate psychostimulant reward and incentive motivation in rodents. ... more 5-HT1B receptors (5-HT1BRs) modulate psychostimulant reward and incentive motivation in rodents. Here we investigated the effects of the 5-HT1BR agonist CP94253 (10 mg/kg, IP) on the acquisition and expression of methamphetamine (Meth) conditioned place preference (CPP) in C57BL/6 male mice. We subsequently examined the potential brain regions involved in CP94253 effects using FOS as a marker of neural activity. In the acquisition experiment, mice received the agonist 30 min before each of the Meth injections given during conditioning. In the expression experiment, mice that had acquired Meth-CPP were given either saline or CP94253 and were tested for CPP 30 min later. We found that CP94253 attenuated the expression of Meth-CPP, but had no effect on acquisition. Mice expressing Meth-CPP had elevated numbers of FOS+ cells in the ventral tegmental area (VTA) and basolateral amygdala (BlA) and reduced FOS+ cells in the central amygdala (CeA) compared to saline controls. CP94253 given before the expression test, but not acutely in drug-naive mice, enhanced FOS+ cells in the VTA, the nucleus accumbens (NAc) shell and core, and the dorsomedial striatum and reversed the Meth-conditioned changes in FOS in the BlA and CeA. Approximately 50-70% of FOS+ cells in the NAc and VTA were GABAergic regardless of group. By contrast, we did not observe FOS-labeling in dopamine neurons in the VTA. The findings suggest that CP94253 attenuates the motivational effects of the Meth-associated environment and highlight the amygdala, VTA, NAc, and dorsomedial striatum as potential regions involved in this effect.

Medicine and Science in Sports and Exercise, Sep 1, 2022

Research Square (Research Square), Apr 18, 2022

RNA-sequencing (RNA-seq) technology has led to a surge of neuroscience research using animal mode... more RNA-sequencing (RNA-seq) technology has led to a surge of neuroscience research using animal models to probe the complex molecular mechanisms underlying brain function and behavior, including substance use disorders (SUDs). However, ndings from rodent studies often fail to be translated into clinical treatments. Here, we developed a novel pipeline for narrowing candidate genes from preclinical studies by translational potential and demonstrated utility of this model in three RNA-seq studies of rodent self-administration. This pipeline uses evolutionary conservation and preferential expression of genes across brain tissues to prioritize candidate genes, increasing the translational utility of RNA-seq in model organisms. We found only 1 differentially-expressed gene (DEG) in any dataset after correcting for multiple testing (FDR < 0.05 or < 0.1), raising concerns about false positives and low statistical power that may impact these and other RNA-seq datasets. Thus, we demonstrate the utility of our prioritization pipeline using an uncorrected p-value. Curiously, even with an uncorrected p-value of 0.05 we saw low overlap of DEGs across the 3 selected datasets. Thus, we also advocate for improved RNA-seq data collection, statistical testing, and metadata reporting that will bolster the eld's ability to identify reliable candidate genes and compare results across studies.

Medicine and Science in Sports and Exercise, Jul 1, 2020

Drug and Alcohol Dependence, Feb 1, 2017

Aims: Compounds selective for dopamine D3 receptors (D3R) may have therapeutic effects for cocain... more Aims: Compounds selective for dopamine D3 receptors (D3R) may have therapeutic effects for cocaine dependence. We have previously shown that D3R partial agonists are effective in decreasing cocaine self-administration (SA) on a high, but not a low, effort schedule of reinforcement. Here, we investigated the effects of a 168-fold selective partial D3R agonist, LS-3-134 (LS) on locomotor activity and cocaine and sucrose reinforcement rates on a multiple variable-interval (VI) 60-second schedule. Methods: Male Sprague Dawley rats (N = 15) were injected on separate days with either LS (0, 1.0, 3.2, 5.6 mg/kg) or LS + coc (15 mg/kg IP). 5 min post injection, locomotor activity was recorded for 1 h. Rats were then trained on a VI-60 schedule that alternated components of coc (0.75 mg/kg/0.1 mL IV) and sucrose reinforcement. Rats were then given separate tests 5 min after pretreatment with varying doses of LS on the VI-60 multiple schedule with coc dose reduced to 0.375 mg/kg, IV. Stable reinforcement rates were reestablished between tests. Results: A paired t-test (vehicle + coc vs. drug pretreatment + coc) found that the highest dose of LS (5.6 mg/kg) decreased coc-induced locomotion. In contrast, LS had no effect on spontaneous locomotion nor on reinforcement rates on the multiple schedule of reinforcement. Conclusions: The highest dose of LS tested (5.6 mg/kg) reversed cocaine-induced locomotion but had no effect on spontaneous locomotion nor on cocaine or sucrose reinforcement rates on the low effort multiple schedule of reinforcement. We are currently examining the effect of the compound on extinction of responding as a measure of cocaine seeking. An effect of LS on cocaine seeking would be consistent with the selective effect of other D3R drugs on motivation for cocaine. Financial support: Supported by DA023957.

Drug and Alcohol Dependence, Nov 1, 2015

Addiction neuroscience, Mar 1, 2023

Brain Behavior and Immunity, May 1, 2022

Chronic drug self-administration and withdrawal are associated with distinct neuroimmune adaptati... more Chronic drug self-administration and withdrawal are associated with distinct neuroimmune adaptations that may increase drug craving and relapse vulnerability in humans. The nuclear factor kappa-B (NF-κB) pathway is a critical regulator of many immune- and addiction-related genes such as the extracellular matrix enzyme matrix metalloproteinase-9 (MMP-9), which is a known modulator of learning, memory, and synaptic plasticity. While some studies suggest striatal NF-κB signaling may regulate drug-conditioned behavior, no studies to date have examined whether NF-κB signaling within the nucleus accumbens core (NAc core) alters downstream neuroimmune function and cue-motivated cocaine seeking following a period of forced abstinence, whether any effects are specific to cocaine over other reinforcers, or whether sex differences exist. Here, we examined whether viral-mediated knockdown of the p65 subunit of NF-κB within the NAc core would alter MMP-9 expression and cue-induced cocaine- and sucrose-seeking behavior following a period of forced abstinence in male and female rats. We demonstrate that NAc core p65 knockdown results in a significant decrease in cue-induced cocaine seeking in males but not females. This effect was specific to cocaine, as p65 knockdown did not significantly affect cue-induced sucrose seeking in either males or females. Moreover, we demonstrate that males express higher levels of MMP-9 within the NAc core and nucleus accumbens shell (NAcSh) compared to females, and that p65 knockdown significantly decreases MMP-9 in the NAc core of males but not females among cocaine cue-exposed animals. Altogether, these results suggest that NAc core NF-κB signaling exerts modulatory control over cue-motivated drug-seeking behavior and downstream neuroimmune function in a sex-specific manner. These findings highlight the need to consider sex as an important biological variable when examining immunomodulatory mechanisms of cocaine seeking.

Translational Psychiatry, Aug 3, 2020

Serotonin 1B receptor (5-HT 1B R) agonists enhance cocaine intake in rats during daily self-admin... more Serotonin 1B receptor (5-HT 1B R) agonists enhance cocaine intake in rats during daily self-administration but attenuate cocaine intake after prolonged abstinence. Here we investigated whether the less selective but clinically available 5-HT 1D/1B R agonist, zolmitriptan, produces similar effects. Male and free-cycling female Sprague-Dawley rats were trained to lever press for cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg pellet) reinforcement until performance rates stabilized. Rats then received zolmitriptan (3.0, 5.6, and 10 mg/kg, s.c.) prior to testing for its effects on response and reinforcement rates. Under cocaine testing conditions, rats had access to the training dose for the first hour followed by a lower cocaine dose (0.075 mg/kg, i.v.) for the second hour. Zolmitriptan decreased cocaine intake at both cocaine doses and in both sexes even without a period of abstinence and without altering sucrose intake. A separate group of rats underwent identical training procedures and were tested for effects of the selective 5-HT 1B and 5-HT 1D receptor antagonists, SB224289 (3.2, 5.6, and 10 mg/kg, s.c.) and BRL15572 (0.3, 1.0, and 3.0 mg/kg, i.p.), respectively, alone or in combination with zolmitriptan (5.6 mg/kg, s.c.) under identical cocaine testing procedures as above. The zolmitriptaninduced decrease in cocaine intake was reversed by SB224289 and to a lesser extent by BRL15572, suggesting that the effects of zolmitriptan involve both 5-HT 1B and 5-HT 1D receptors. Neither zolmitriptan, SB224289, or BRL15572 altered locomotor activity at the doses effective for modulating cocaine intake. These findings suggest that zolmitriptan has potential for repurposing as a treatment for cocaine use disorders.

Frontiers in Pharmacology, Feb 14, 2019

Alpha6-containing nicotinic acetylcholine receptors are primarily found in neurons of the midbrai... more Alpha6-containing nicotinic acetylcholine receptors are primarily found in neurons of the midbrain dopaminergic (DA) system, suggesting these receptors are potentially involved in drug reward and dependence. Here, we report a novel effect that cocaine directly inhibits α6N/α3Cβ2β3-nAChR (α6*-nAChRs) function. Human α6*-nAChRs were heterologously expressed within cells of the SH-EP1 cell line for functional characterization. Mechanically dissociated DA neurons from mouse ventral tegmental area (VTA) were used as a model of presynaptic α6*-nAChR activation since this method preserves terminal boutons. Patch-clamp recordings in whole-cell configuration were used to measure α6*-nAChR function as well as evaluate the effects of cocaine. In SH-EP1 cells containing heterologously expressed human α6*-nAChRs, cocaine inhibits nicotineinduced inward currents in a concentration-dependent manner with an IC 50 value of 30 μM. Interestingly, in the presence of 30 μM cocaine, the maximal current response of the nicotine concentration-response curve is reduced without changing nicotine's EC 50 value, suggesting a noncompetitive mechanism. Furthermore, analysis of wholecell current kinetics demonstrated that cocaine slows nAChR channel activation but accelerates whole-cell current decay time. Our findings demonstrate that cocaineinduced inhibition occurs solely with bath application, but not during intracellular administration, and this inhibition is not use-dependent. Additionally, in Xenopus oocytes, cocaine inhibits both α6N/α3Cβ2β3-nAChRs and α6M211L/α3ICβ2β3-nCAhRs similarly, suggesting that cocaine may not act on the α3 transmembrane domain of chimeric α6N/α3Cβ2β3-nAChR. In mechanically isolated VTA DA neurons, cocaine abolishes α6*-nAChR-mediated enhancement of spontaneous inhibitory postsynaptic currents (sIPSCs). Collectively, these studies provide the first evidence that cocaine directly inhibits the function of both heterologously and naturally expressed α6*-nAChRs. These findings suggest that α6*-nAChRs may provide a novel pharmacological target mediating the effects of cocaine and may underlie a novel mechanism of cocaine reward and dependence.

Journal of Psychopharmacology, 2021

Background: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during mainte... more Background: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. Aims: We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. Methods: Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21–60 days) and ...

Drug and Alcohol Dependence, 2021

BACKGROUND MicroRNAs (miRNAs) are "master post-transcriptional regulators" of gene expr... more BACKGROUND MicroRNAs (miRNAs) are "master post-transcriptional regulators" of gene expression. Here we investigate miRNAs involved in the incentive motivation for cocaine elicited by exposure to cocaine-associated cues. METHODS We conducted NanoString nCounter analyses of microRNA expression in the nucleus accumbens shell of male rats that had been tested for cue reactivity in a previous study. These rats had been trained to self-administer cocaine while living in isolate housing, then during a subsequent 21-day forced abstinence period they either stayed under isolate housing or switched to environmental enrichment (EE), as this EE intervention is known to decrease cocaine seeking. This allowed us to create groups of "high" and "low" cocaine seekers using a median split of cocaine-seeking behavior. RESULTS Differential expression analysis across high- and low-seekers identified 33 microRNAs that were differentially expressed in the nucleus accumbens shell. Predicted mRNA targets of these microRNAs are implicated in synaptic plasticity, neuronal signaling, and neuroinflammation signaling, and many are known addiction-related genes. Of the 33 differentially-expressed microRNAs, 8 were specifically downregulated in the low-seeking group and another set of 8 had expression levels that were significantly correlated with cocaine-seeking behavior. CONCLUSION These findings not only confirm the involvement of previously identified microRNAs (e.g., miR-212, miR-495) but also reveal novel microRNAs (e.g., miR-3557, miR-377) that alter, or are altered by, processes associated with cocaine-seeking behavior. Further research examining the mechanisms involved in these microRNA changes and their effects on signaling may reveal novel therapeutic targets for attenuating drug craving.

Biological Psychiatry, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Pharmacology, biochemistry, and behavior, 2018

The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have succe... more The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic. Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-...