Rex M. Philpot

Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression.

Polygenic factors play important roles in animal models of substance abuse and susceptibility to dopaminergic neurodegeneration. Genetic factors are also likely to contribute to the etiology of human drug abuse disorders, and may alter human vulnerabilities to Parkinsonian neurodegeneration. The dopamine transporter (DAT; SLC6A3) is densely expressed by the dopaminergic midbrain neurons that play central roles in drug reward and is believed to be a primary site of action for cocaine reward. This transporter is necessary for the action of selective dopaminergic neurotoxins, and is uniquely expressed on neurons that are the primary targets of Parkinsonian neurodegeneration. To study possible influences of variant DAT expression on these processes, we have constructed transgenic mice (THDAT) in which tyrosine hydroxylase (TH) promoter sequences drive expression of a rat DAT cDNA variant, increase striatal DAT expression by 20-30%, and provide modest alterations in striatal levels of dopamine and its metabolites. THDAT mice habituate more rapidly to a novel environment than wildtype littermates. These animals display enhanced reward conferred by cocaine, as measured by conditioned place preference. However, locomotor responses to cocaine administration are similar to those of wildtype mice, except at high cocaine doses. THDAT mice display more than 50% greater losses of dopaminergic neurons following a course of MPTP treatment than do wildtype control mice. These results document a model for allelic variation at a gene locus that can exert significant effects in murine models of human substance abuse vulnerability and dopaminergic neurodegeneration.

Repeated ethanol exposure during adolescence alters the developmental trajectory of dopaminergic output from the nucleus accumbens septi

Individuals who begin using alcohol prior to 14 years of age are 4 times more likely to progress to addiction than those who do not initiate use until 21 years of age. The nucleus accumbens septi undergoes dramatic developmental transitions during the adolescent period, and dopaminergic activity within this region has been identified as a central neurochemical mediator of drug reward, addiction and dependence. Thus, alcohol‐induced neurochemical alterations in dopaminergic activity within this brain region likely mediate the heightened vulnerability to addiction observed in adolescent alcohol users. To investigate this idea, Sprague–Dawley rats were exposed to intraperitoneal injections of either saline or ethanol (0.5, 1.0 or 2.0 g/kg) twice daily over four days beginning on postnatal day 21, 31, 41 or 56. Cannulas were implanted toward the nucleus accumbens septi, subsequent in vivo microdialysis was used to collect samples, and both basal and ethanol‐stimulated dopamine overflow was measured using high performance liquid chromatography with electrochemical detection. A developmental transition in basal levels of dopamine in the nucleus accumbens septi was apparent with peak levels at postnatal day 45. An ethanol challenge produced unique responses across ages, with greater peak effects relative to baseline in younger animals (postnatal day 25 and 35). Following repeated exposure to ethanol, a significant increase in basal dopamine was apparent for all ages, and when these animals were challenged with ethanol, peak effects relative to baseline were decreased in younger animals, but unchanged in older animals (postnatal day 45 and 60). Results indicate that there is a key developmental transition in the ability of rats to adapt to the effects of repeated ethanol exposure, which occurs between postnatal day 35 and 45. This alteration may explain the increased addiction vulnerability observed in individuals who initiate alcohol use during early adolescence.

Developmental Differences in Nicotine Place Conditioning

Abstract: To understand the motivations and implications of the prevalence of smoking, studies have compared the behavioral effects of nicotine, the psychoactive drug in tobacco, in adolescent and adult animals. The present study used a biased three‐chambered conditioned‐place preference procedure without prior habituation to examine the potential rewarding and anxiolytic effects of nicotine across adolescence and adulthood to assess the presence of age‐dependent differences in response to nicotine.

An Animal Model of Sensation Seeking: The Adolescent Rat

Abstract: Previous research has established a strong relationship between a rodents preference for novelty and sensitivity to psychomotor stimulants. Rats with greater sensitivity to the motoric effects of amphetamine exhibit higher preferences for novelty. Additionally, animals with high novelty preference scores are more easily drug conditioned and are more sensitive to, and can more accurately discriminate, amphetamine doses. Novelty preference in animals has been compared to sensation seeking in humans and is strongly correlated with drug use and addiction vulnerability. Thus, the present studies employed a playground maze procedure to measure changes in novelty preference across age following either four or eight habituation trials using eight distinct objects. Early‐adult (postnatal day [PND] 59) animals did not exhibit a significant preference for a novel object regardless of total number of habituation trials. Early‐adolescent animals (PND 34) exhibited a preference for the novel object in fewer than four habituation trials, but exhibited no preference with increased habituation trials. These results are counterintuitive and may demonstrate an overgeneralization of the habituation trials specific to adolescent animals. Given that adolescence is a period of heightened exploration, one would expect adolescent animals to demonstrate an enhanced preference for novel stimuli using this paradigm. However, it is possible that the complexity of the task, as presented, reveals differences in the establishment and behavioral manifestation of associations during adolescence. To address this issue, a separate novelty paradigm was implemented using an open‐field habituation procedure followed by the introduction of a single novel object during the testing period. This revised design provides the foundation needed to better assess novelty‐induced locomotor activity and novelty preference in adolescent rats.

Dependence of Adolescent Novelty-Seeking Behavior on Response Phenotype and Effects of Apparatus Scaling

Adult rats have been phenotyped as high (HRs) or low (LRs) responders to novelty, the former associated with high-risk behaviors. Data indicating that adolescent rodents exhibit increased novelty-seeking relative to adults are equivocal, and phenotypic variations in adolescent novel stimulus reactivity are unknown. To determine whether novelty-seeking differs between adolescent and adult rats, reflecting phenotypic variations within each age, activities in an inescapable novel environment and novel object exploration were measured. Adolescents moved further, faster, and more continuously than adults, and exhibited a greater variability and range of activity in the novel environment. Both adolescent and adult LRs habituated to the environment by the second trial, but HRs maintained increased activity throughout 8 trials. In the free-choice paradigm, adolescents approached the novel object more frequently and spent more time in proximity to the object than adults. Similar results were obtained using arenas and objects of the same size or scaled to animal size. Results confirm that novelty-seeking by adolescents is greater than by adults, a behavior attributed primarily to the response magnitude exhibited by adolescents with the HR phenotype.

The effects of repeated alcohol exposure on the neurochemistry of the periadolescent nucleus accumbens septi.

SUBSTANCE abuse is a major issue in todays society and is an issue of critical importance in the adolescent population. Research indicates that substance use is often initiated during the adolescent period and that brain reward areas are still undergoing changes during this time. Despite this, little research has investigated the effects of repeated drug use on the reward mechanisms of periadolescent animals. For this reason, the present study examined the effects of repeated ethanol (EtOH) administration on the responsiveness of the nucleus accumbens septi (NAcc) to either EtOH or saline challenge. The data indicate that repeated exposure to EtOH produces temporal shifts in the dopaminergic (DAergic) activity of the NAcc, with peak activity occurring earlier. Importantly, following repeated injections of EtOH, saline injections alone elicit DA increases in the NAcc suggesting that the context of alcohol administration produces fundamental changes in the way that neuro-chemical reinforcement mechanisms respond. The expectancy of the drug alone elicits reward-related activity within the NAcc.

Repeated Cocaine Exposure: Effects on Catecholamines in the Nucleus Accumbens Septi of Periadolescent Animals

Substance abuse is a major issue in todays society, and is an issue of critical importance in the adolescent population. Research indicates that substance use is often initiated during the adolescent period, and that brain reward areas are still undergoing changes during this time. Despite this, little research has investigated the effects of repeated drug use on the reward mechanisms of periadolescent animals. For this reason, the present study examined the effects of repeated cocaine administration on the responsiveness of the nucleus accumbens septi (NAcc) to either cocaine or saline challenge. The data indicate that repeated exposure to cocaine produces temporal shifts in the dopaminergic (DAergic) activity of the NAcc, with peak activity occurring earlier. Importantly, following repeated injections of cocaine, saline injections alone elicit increases followed by a subsequent suppression in DA overflow in the NAcc. These results suggest that the context of cocaine administration produces fundamental changes in the way that neurochemical reinforcement mechanisms respond. The expectancy of the drug alone elicits reward-related activity within the NAcc, which may play a critical role in the development of addiction.

An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome

BackgroundMinocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug’s effect on the cognitive and behavioral manifestations of the disorder.MethodsParticipants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η2) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett’s post hoc testing.ResultsSignificant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period.ConclusionThe clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted.Trial registrationNCT01531582 – clinicaltrials.gov

Stereotaxic localization of the developing nucleus accumbens septi

The nucleus accumbens septi (NAcc) has been implicated as a mediator of a variety of disorders, most notably substance abuse. The development of this system is a critical area for investigation, and has been largely overlooked. Specifically, few studies have focussed on dopamine (DA), its neurochemical pathways and the long-term consequences of manipulating the dopaminergic (DAergic) system in the developing animal. Important insight into the establishment of addiction, its development and time course, may be found by examining the development of the periadolescent DA system, specifically the mesocorticolimbic system. Recent developmental studies demonstrate dramatic changes in DAergic levels, receptor concentrations and transporter levels during periadolescent development. These ontogenetic changes, as well as drug exposure during development, may predispose the adolescent animal to addiction. Given that humans typically experiment with and initiate drug use during the adolescent period it is proposed that developmental alterations in the mesolimbic DA projection areas, specifically the NAcc, are an essential area for investigation in drug addiction. The present paper presents formulas for the weight-based calculation of stereotaxic coordinates for the NAcc in rats across development to facilitate further research in the area.

Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia

Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.