Neural firing in the prefrontal cortex during alcohol intake in alcohol preferring ‘P’ vs. Wistar rats

BACKGROUND: Neural activity within the prefrontal cortex (PFC) is altered by alcohol and alcohol-associated stimuli and is mediated by genetic susceptibility to alcoholism. However, very little is known about how genetic risk of excessive drinking might mediate neural firing in the PFC during alcohol consumption. METHODS: To determine how genetic risk influences alcohol seeking, intake, and neural activity, a Pavlovian alcohol consumption task was used-the 2-Way Cued Access Protocol (2CAP). Alcohol-preferring "P" rats and relatives of their (heterogeneous) founding Wistar population were used for these studies. After acquisition of 2CAP, extinction of responding for alcohol was evaluated by substituting water for alcohol. Following these experiments, in vivo electrophysiological recordings were obtained during 2CAP from the PFC in a separate cohort of Wistar and P rats implanted with moveable tetrode microdrives. RESULTS: P and Wistar rats increased daily alcohol seeking and intake with P rats consuming roughly twice as much alcohol as Wistar. Both rat populations decreased seeking behavior during extinction. However, P rats displayed persistent increases in seeking after controlling for intake versus Wistar. Higher firing rates (FRs) were observed in P rats prior to 2CAP and throughout alcohol and water consumption compared with Wistars that were matched for alcohol-drinking history. Differences in FR were driven, in part, by a larger percentage of neurons in P rats versus Wistars that increased FR compared with those that decreased, or did not change. CONCLUSIONS: These data provide additional evidence of increased alcohol consumption and persistent alcohol seeking in P versus Wistar rats. Differences in PFC neural firing observed in P rats prior to drinking could be heritable and/or related to an enhanced response to alcohol-associated contextual cues. FR differences observed during alcohol drinking might be related to an augmented sensitivity of PFC neurons to orally consumed alcohol

Impulsivity in rodents with a genetic predisposition for excessive alcohol consumption is associated with a lack of a prospective strategy

Increasing evidence supports the hypothesis that impulsive decision-making is a heritable risk factor for an alcohol use disorder (AUD). Clearly identifying a link between impulsivity and AUD risk, however, is complicated by the fact that both AUDs and impulsivity are heterogeneous constructs. Understanding the link between the two requires identifying the underlying cognitive factors that lead to impulsive choices. Rodent models have established that a family history of excessive drinking can lead to the expression of a transgenerational impulsive phenotype, suggesting heritable alterations in the decision-making process. In the present study, we explored the cognitive processes underlying impulsive choice in a validated, selectively bred rodent model of excessive drinking-the alcohol-preferring ("P") rat. Impulsivity was measured via delay discounting (DD), and P rats exhibited an impulsive phenotype as compared to their outbred foundation strain-Wistar rats. Steeper discounting in P rats was associated with a lack of a prospective behavioral strategy, which was observed in Wistar rats and was directly related to DD. To further explore the underlying cognitive factors mediating these observations, a drift diffusion model of DD was constructed. These simulations supported the hypothesis that prospective memory of the delayed reward guided choice decisions, slowed discounting, and optimized the fit of the model to the experimental data. Collectively, these data suggest that a deficit in forming or maintaining a prospective behavioral plan is a critical intermediary to delaying reward, and by extension, may underlie the inability to delay reward in those with increased AUD risk

Self-administration of edible Δ9-tetrahydrocannabinol and associated behavioral effects in mice

Background With increasing access to legal cannabis across the globe, it is imperative to more closely study its behavioral and physiological effects. Furthermore, with the proliferation of cannabis use, modes of consumption are changing, with edible formulations becoming increasingly popular. Nevertheless, there are relatively few animal models of self-administration of the primary psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), and almost all incorporate routes of administration other than those used by humans. The aim of the current study was to develop a model of edible THC self-administration and assess its impact on CB1 receptor-mediated behaviors in female and male mice. Methods Mice were given limited access to a palatable dough which occasionally contained THC in doses ranging from 1 to 10 mg/kg. Following dough consumption, mice were assessed for home cage locomotor activity, body temperature, or analgesia. Locomotor activity was also assessed in conjunction with the CB1 receptor antagonist SR141716A. Results Dough was well-consumed, but consumption decreased at the highest THC concentrations. Edible THC produced dose-dependent decreases in locomotor activity and body temperature in both sexes, and these effects were more pronounced in male mice. Hypolocomotion induced by edible THC was attenuated by SR141716A, indicating mediation by CB1 receptor activation. Conclusions In contrast to other cannabinoid self-administration models, edible THC is relatively low in stress and uses a route of administration analogous to one used by humans. Potential applications include chronic THC self-administration, determining THC reward/reinforcement, and investigating consequences of oral THC use

IS COGNITIVE FUNCTION IMPAIRED IN A RODENT MODEL OF ALCOHOLISM?

poster abstractAlcohol abuse is a major problem in society resulting in issues of health, family, and economics. The relationship between an individual’s genetic makeup and their environment is becoming a primary focus of preclinical and clinical research that seeks to understand the etiology of alcoholism. Ex-cessive drinking may be the result of the inability of advanced forms of cog-nition to properly govern behavior, and the current proposal explored this possibility. This study used Wistar and alcohol preferring rats (P-rats) to in-vestigate the relationship between the phenotypic vulnerability for alcohol-ism and its relationship to cognitive functions. Rats were given four weeks of intermittent alcohol access and completed a cognitively demanding task known as operant set-shifting. The effects of prior alcohol exposure in vul-nerable versus non-vulnerable phenotypes was examined. Thus far no dif-ferences between lines have been observed in the ability to learn a new task that gauges function of the prefrontal cortex. These data are inconclusive and require further analysis, but may indicate that the cognitive task is not demanding enough to show differences in prefrontal cortex functioning. Re-sults from the drinking study confirmed that alcohol drinking significantly in-creased over the four weeks of testing for P-rats, but not Wistars. P-rats also significantly increased ethanol consumption measured during the first 30 minutes of access throughout the drinking protocol. Results from this study show how future tests could improve our current understanding of the rela-tionship between alcohol abuse and cognition and can help guide future re-search to better understand this disease. School of Science Start-up funds and RSFG to C. Lapish. UROP to B. Tod

Dynamics of synchronized neural activity in prefrontal-hippocampal networks during behavioral sensitization

poster abstractNeural synchrony exhibits temporal variability, therefore the temporal patterns of synchronization and desynchronization may have functional relevance. This study employs novel time-series analysis to explore how neural signals become transiently phase locked and unlocked during repeated injections of the psychostimulant, D-Amphetamine (AMPH). Short (but frequent) desynchronized events dominate synchronized dynamics in each of the animals we examined. After the first AMPH injection, only increases in the relative prevalence of short desynchronization episodes (but not in average synchrony strength) were significant. Throughout sensitization both strength and the fine temporal structure of synchrony (measured as relative prevalence of short desynchronizations) were similarly altered with AMPH injections, with each measure decreasing in the pre-injection epoch and increasing after injection. Decoupling between locomotor activity and synchrony was observed in AMPH, but not saline, animals. The increase in numerous short desynchronizations (as opposed to infrequent, but long desynchronizations) in AMPH treated animals may indicate that synchrony is easy to form yet easy to break. These data yield novel insight into how synchrony is dynamically altered in cortical networks by AMPH and identify neurophysiological changes that may be important to understand the behavioral pathologies of addiction

Tolcapone suppresses ethanol intake in alcohol-preferring rats performing a novel cued access protocol

BACKGROUND: Dopamine (DA) has been shown to play a central role in regulating motivated behavior and encoding reward. Chronic drug abuse elicits a state of hypodopaminergia in the mesocorticolimbic (MCL) system in both humans and preclinical rodent models of addiction, including those modeling alcohol use disorders (AUD). METHODS: Working under the hypothesis that reductions in the bioavailability of DA play an integral role in the expression of the excessive drinking phenotype, the catechol-O-methyltransferase (COMT) inhibitor tolcapone was used as a means to amplify cortical DA concentration and drinking behaviors were then assessed. Sucrose and ethanol (EtOH) consumption were measured in P and Wistar rats in both a free choice drinking protocol and a novel cued access protocol. RESULTS: Tolcapone attenuated the consumption of EtOH, and to a lesser extent sucrose, in P rats in the cued access protocol, while no effect was observed in the free choice drinking protocol. Tolcapone also decreased EtOH consumption in high drinking Wistar rats. A follow-up experiment using the indirect DA agonist d-amphetamine showed no change in EtOH consumption. CONCLUSIONS: Collectively, these data suggest that COMT inhibitors may be capable of alleviating the extremely motivating or salient nature of stimuli associated with alcohol. The hypothesis is put forth that the relative specificity of tolcapone for cortical DA systems may mediate the suppression of the high seeking/drinking phenotype

Memory impairment and alterations in prefrontal cortex gamma band activity following methamphetamine sensitization

RATIONALE: Repeated methamphetamine (MA) use leads to increases in the incentive motivational properties of the drug as well as cognitive impairments. These behavioral alterations persist for some time following abstinence, and neuroadaptations in the structure and function of the prefrontal cortex (PFC) are particularly important for their expression. However, there is a weak understanding of the changes in neural firing and oscillatory activity in the PFC evoked by repeated drug use, thus complicating the development of novel treatment strategies for addiction. OBJECTIVES: The purpose of the current study was to assess changes in cognitive and brain function following MA sensitization. METHODS: Sensitization was induced in rats, then temporal and recognition memory were assessed after 1 or 30 days of abstinence. Electrophysiological recordings from the medial PFC were also acquired from rats whereupon simultaneous measures of oscillatory and spiking activity were examined. RESULTS: Impaired temporal memory was observed after 1 and 30 days of abstinence. However, recognition memory was only impaired after 1 day of abstinence. An injection of MA profoundly decreased neuronal firing rate and the anesthesia-induced slow oscillation (SO) in both sensitized (SENS) and control (CTRL) rats. Strong correlations were observed between the SO and gamma band power, which was altered in SENS animals. A decrease in the number of neurons phase-locked to the gamma oscillation was also observed in SENS animals. CONCLUSIONS: The changes observed in PFC function may play an integral role in the expression of the altered behavioral phenotype evoked by MA sensitization

Evaluating Differences in Cognitive Function after N-Acetyl-Cysteine Treatment in a Two-Hit Rat Model of Schizophrenia

poster abstractSchizophrenia (SZ) is a chronic mental disorder characterized by positive and negative symptoms both of which impair normal functioning. Effective treatment options for negative and cognitive symptoms are non-existent. Identifying translational biomarkers that can be applied across species could aid drug development. Remediation of cognitive impairments will be assessed after administering N-Acetyl-Cysteine (NAC) by the use of validated measures of cognitive performance in a “two-hit” model of SZ. Pups of Sprague Dawley dams were used. Each litter was split into two groups: maternally deprived (MD) or sham. The MD group (n= 9) were weighed and removed from their mothers for 24 hours on post-natal day 9. MD acts as an early-life stressor and may be linked with the development of SZ. The sham group (n= 9) served as controls. On post-natal day 75-88, MD rats (n= 9) received an injection of NAC (90.0 mg/kg; n= 5) or saline (n= 4). All sham rats received saline. Two days after NAC treatment, all rats received an acute injection of Phencyclidine (PCP) at 2.0 mg/kg, an N-Methyl-D-Aspartate antagonist. PCP alters glutamatergic signaling and is the second model used to induce SZ. The day after injection, short-term memory was assessed using temporal order and novel object recognition tasks. The same tasks were given to assess alterations of glutamatergic signaling after receiving chronic 2.0 mg/kg of PCP injections for six days. Preliminary results indicate no detectable differences in temporal order and novel object recognition tasks between the MD groups who received NAC from those who received saline. No significant differences were found between the MD and sham groups that received saline. Furthermore, there were no differences between any of the groups after chronic PCP administration. Additional animals are being tested to increase group sizes and to have larger power when running the analyses