Developmental Differences in the Accumbal Dopaminergic Response to Repeated Ethanol Exposure

Recent research indicates that alcohol use/abuse is often initiated during the adolescent period and that brain reinforcement pathways (e.g., the mesolimbic dopamine [DA] pathway) are undergoing developmental transition. Our research focuses on the effects of ethanol administration on neural mechanisms associated with addiction in preadolescent (postnatal day [PND] 25), adolescent (PND 35, PND 45), and young adult (PND 60) animals. Using conditioned place preference (CPP) testing, we have shown that adolescent animals are unique in their responses to ethanol. Since CPP has been associated with contextually conditioned incentive motivation, our results suggest that younger animals may be more vulnerable to addiction. The present data reveal that adolescent animals are neurochemically distinct in response to ethanol\u27s effects. Using in vivo microdialysis within the nucleus accumbens septi (NAcc), we have determined the DAergic response across development. Results reveal that basal levels of DA transition during the adolescent period and differ from preadolescent or adult animals. Specifically, PND 45 animals exhibited significantly higher, and PND 25 significantly lower, basal DA levels than all other ages examined. Further, repeated exposure to ethanol elevated basal DA levels significantly regardless of age or dose. Basal 3,4‐dihydroxyphenylacetic acid (DOPAC)/DA ratio also differed as a function of age, with PND 35 and PND 60 animals demonstrating the highest ratios, and PND 45 animals producing the lowest baseline levels. Repeated ethanol exposure produced significant changes in basal ratios as a function of age. Interestingly, PND 45 animals exhibited no change in ratios with repeated exposure, while all other ages demonstrated a dose‐dependent rise in DOPAC/DA ratios. These data indicate an age‐dependent difference in the homeostatic alterations of mesolimbic systems in response to repeated ethanol treatment, an effect that may manifest itself as differences in behavioral responsivity and conditionability to the drug and the drug\u27s effects

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

Substance abuse is a major issue in today’s 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

The Effects of Repeated Alcohol Exposure on the Neurochemistry of the Periadolescent Nucleus Accumbens Septi

Substance abuse is a major issue in today\u27s 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 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

Grid Crossing: Inability to Compare Activity Levels between Adolescent and Adult Rats

Traditionally, studies measuring behavioral activity have used male adult animals and grid crossings (GCs) as a representative measure of activity in lieu of total distance moved (TDM). However, using GCs as the dependent measure may not be effective for comparing the activity of animals during development, as they vary significantly in size. The present study examines the reliability of GCs as opposed to TDM as an indicator of locomotor activity for comparisons during ontogeny using a computerized behavioral tracking system (Noldus). Rats (postnatal day[PND] 35, PND 60) were tracked for a period of 3 minutes inside a closed runway. GCs and TDM were measured for the recorded tracks. It was determined that GCs were positively correlated with TDM in the behavioral apparatus, suggesting that GCs is a reliable measure of an individual animal\u27s activity. Using GCs as the dependent measure, no significant differences in activity were observed across age or sex. However, using TDM indicates adolescent rats are significantly more active than their adult counterparts. These data indicate that although the number of GCs is predictive of total activity, the slope of the relationship varies significantly with age, therefore making it inappropriate to use GCs when comparing across ages. Studies that use animals of differing age must be sensitive to baseline differences in locomotor activity

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

An Animal Model of Sensation Seeking: The Adolescent Rat

Previous research has established a strong relationship between a rodent\u27s 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

Developmental Differences in Nicotine Place Conditioning

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