Neural Activity in the Anterior Insula at Drinking Onset and Licking Relates to Compulsion-Like Alcohol Consumption.

Much remains unknown about the etiology of compulsion-like alcohol drinking, where consumption persists despite adverse consequences. The role of the anterior insula (AIC) in emotion, motivation, and interoception makes this brain region a likely candidate to drive challenge-resistant behavior, including compulsive drinking. Indeed, subcortical projections from the AIC promote compulsion-like intake in rats and are recruited in heavy-drinking humans during compulsion for alcohol, highlighting the importance of and need for more information about AIC activity patterns that support aversion-resistant responding. Single-unit activity was recorded in the AIC from 15 male rats during alcohol-only and compulsion-like consumption. We found three sustained firing phenotypes, sustained-increase, sustained-decrease, and drinking-onset cells, as well as several firing patterns synchronized with licking. While many AIC neurons had session-long activity changes, only neurons with firing increases at drinking onset had greater activity under compulsion-like conditions. Further, only cells with persistent firing increases maintained activity during pauses in licking, suggesting roles in maintaining drive for alcohol during breaks. AIC firing was not elevated during saccharin drinking, similar to lack of effect of AIC inhibition on sweet fluid intake in many studies. In addition, we observed subsecond changes in AIC neural activity tightly entrained to licking. One lick-synched firing pattern (determined for all licks in a session) predicted compulsion-like drinking, while a separate lick-associated pattern correlated with greater consumption across alcohol intake conditions. Collectively, these data provide a more integrated model for the role of AIC firing in compulsion-like drinking, with important relevance for how the AIC promotes sustained motivated responding more generally.

Sex differences in neural networks recruited by frontloaded binge alcohol drinking.

Frontloading is an alcohol drinking pattern where intake is skewed towards the onset of access. This study aimed to identify brain regions involved in frontloading. Whole brain imaging was performed in 63 C57Bl/6J (32 female, 31 male) mice that underwent 8 days of binge drinking using drinking-in-the-dark (DID). On Days 1-7 mice received 20% (v/v) alcohol or water for 2 h. Intake was measured in 1-min bins using volumetric sippers. On Day 8 mice were perfused 80 min into the DID session and brains were extracted. Brains were processed to stain for Fos protein using iDISCO+. Following light sheet imaging, ClearMap2.1 was used to register brains to the Allen Brain Atlas and detect Fos+ cells. For network analyses, Day 8 drinking patterns were used to characterize mice as frontloaders or non-frontloaders using a change-point analysis. Functional correlation matrices were calculated for each group from log10 Fos values. Euclidean distances were calculated from these R values and clustering was used to determine modules (highly connected groups of brain regions). In males, alcohol access decreased modularity (three modules in both frontloaders and non-frontloaders) as compared to water (seven modules). In females, an opposite effect was observed. Alcohol access (nine modules for frontloaders) increased modularity as compared to water (five modules). Further, different brain regions served as hubs in frontloaders as compared to control groups. In conclusion, alcohol consumption led to fewer, but more densely connected, groups of brain regions in males but not females and we identify several brain-wide signatures of frontloading.

Male and female impairments in odor span are observed in a rat model of PTSD.

Posttraumatic stress disorder (PTSD) is associated with neural and behavioral alterations in response to trauma exposure, including working memory impairments. Rodent models of PTSD have not fully investigated chronic or reactive working memory deficits, despite clinical relevance. The present study uses footshock to induce a posttraumatic stress state in male and female rats and evaluates the effect of footshock and trauma-paired odor cues on working memory performance in the odor span task. Results demonstrate the emergence of chronic deficits in working memory among animals exposed to footshock by 3 wk after traumatic stress. The presentation of a trauma-paired odor cue was associated with further decrement in working memory performance for male animals. Furthermore, anxiety-like behaviors associated with the PTSD-like phenotype could predict the degree of working memory impairment in response to the trauma-paired odor cue. This study enhances validation of an existing rodent model of PTSD through replication of the clinical observations of working memory deficits associated with PTSD and provides novel insight into effects in female rodents. This will facilitate work to probe underlying mechanistic dysregulation of working memory following footshock trauma exposure and future development of novel treatment strategies.

A critical review of front-loading: A maladaptive drinking pattern driven by alcohol's rewarding effects.

Front-loading is a drinking pattern in which alcohol intake is skewed toward the onset of reward access. This phenomenon has been reported across several different alcohol self-administration protocols in a wide variety of species, including humans. The hypothesis of the current review is that front-loading emerges in response to the rewarding effects of alcohol and can be used to measure the motivation to consume alcohol. Alternative or additional hypotheses that we consider and contrast with the main hypothesis are that: (1) front-loading is directed at overcoming behavioral and/or metabolic tolerance and (2) front-loading is driven by negative reinforcement. Evidence for each of these explanations is reviewed. We also consider how front-loading has been evaluated statistically in previous research and make recommendations for defining this intake pattern in future studies. Because front-loading may predict long-term maladaptive alcohol drinking patterns leading to the development of alcohol use disorder (AUD), several future directions are proposed to elucidate the relationship between front-loading and AUD.

Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala.

BACKGROUND: Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. METHODS: Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. RESULTS: Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region-specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. CONCLUSIONS: These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

Impaired cognitive flexibility and heightened urgency are associated with increased alcohol consumption in rodent models of excessive drinking.

Alcohol use disorder (AUD) is characterized by impairments in decision-making that can exist as stable traits or transient states. Cognitive inflexibility reflects an inability to update information that guides decision-making and is thought to contribute to the inability to abstain from drinking. While several studies have reported evidence of impaired cognitive flexibility following chronic alcohol exposure, evidence that a pre-existing impairment in cognitive flexibility is a heritable risk factor for AUD is scarce. Here, we found that cognitive flexibility was impaired in rodents selectively bred for excessive alcohol consumption (alcohol preferring (P) rats), on the attentional set-shifting task (ASST). Further, the degree of impairment is predictive of future ethanol consumption, thus suggesting that cognitive inflexibility is a stable trait capable of predisposing one for drinking. In a second set of experiments, we observed an impairment in the ability of P rats to use a previously learned rule to guide foraging in a simple discrimination task. Convergence across several behavioral measures suggested that this impairment reflected a state of heightened urgency that interfered with decision-making. A similar impairment on a simple discrimination task was observed in Wistar rats with a history of alcohol consumption. These findings indicate how trait and state variables-in this case, impaired cognitive flexibility and heightened urgency, respectively-may influence the risk for excessive drinking. Furthermore, our results suggest that cognitive inflexibility and urgency can exist as both risk factors for and the result of alcohol exposure.

Ethanol Alters Variability, But Not Rate, of Firing in Medial Prefrontal Cortex Neurons of Awake-Behaving Rats.

BACKGROUND: The medial prefrontal cortex (mPFC) is a brain region involved in the evaluation and selection of motivationally relevant outcomes. Neural activity in mPFC is altered following acute ethanol (EtOH) use and, in rodent models, doses as low as 0.75 g/kg yield cognitive deficits. Deficits in decision making following acute EtOH are thought to be mediated, at least in part, by decreases in mPFC firing rates (FRs). However, the data leading to this conclusion have been generated exclusively in anesthetized rodents. The present study characterizes the effects of acute EtOH injections on mPFC neural activity in awake-behaving rodents. METHODS: Awake-behaving and anesthetized in vivo electrophysiological recordings were performed. We utilized 3 groups: the first received 2 saline injections, the second received a saline injection followed by 1.0 g/kg EtOH, and the last received saline followed by 2 g/kg EtOH. One week later, an anesthetized recording occurred where a saline injection was followed by an injection of 1.0 g/kg EtOH. RESULTS: The anesthetized condition showed robust decreases in neural activity and differences in up-down states (UDS) dynamics. In the awake-behaving condition, FRs were grouped according to behavioral state: moving, not-moving, and sleep. The differences in median FRs were found for each treatment and behavioral state combination. A FR decrease was only found in the 2.0 g/kg EtOH treatment during not-moving states. However, robust decreases in FR variability were found across behavioral state in both the 1.0 and 2.0 g/kg EtOH treatment. Sleep was separately analyzed. EtOH modulated the UDS during sleep producing decreases in FRs. CONCLUSIONS: In conclusion, the changes in neural activity following EtOH administration in anesthetized animals are not conserved in awake-behaving animals. The most prominent difference following EtOH was a decrease in FR variability suggesting that acute EtOH may be affecting decision making via this mechanism.

High Alcohol-Preferring Mice Show Reaction to Loss of Ethanol Reward Following Repeated Binge Drinking.

BACKGROUND: Beyond yielding high blood ethanol (EtOH) concentrations (BECs), binge-drinking models allow examination of drinking patterns which may be associated with EtOH's rewarding effects, including front-loading and consummatory successive negative contrast (cSNC), a decrease in intake when only water is available to subjects expecting EtOH. The goals of the current study were to broaden our understanding of these reward-related behaviors during binge EtOH access in high alcohol-preferring (HAP) replicate lines (HAP2 and HAP3) of mice selectively bred to prefer alcohol. We hypothesized that both lines would show evidence of front-loading during binge EtOH access and that we would find a cSNC effect in groups where EtOH was replaced with water, as these results have been shown previously in HAP1 mice. METHODS: HAP replicate 2 and replicate 3 female and male mice were given 2 hours of EtOH or water access in the home cage for 15 consecutive days using "drinking in the dark" (DID) procedures. Mice received the same fluid (either 20% unsweetened EtOH or water) for the first 14 days. However, on the 15th day, half of the mice from these 2 groups were provided with the opposite assigned fluid (EtOH groups received water and vice versa). Intake was measured in 1-minute bins using specialized sipper tubes, which allowed within-session analyses of binge-drinking patterns. RESULTS: EtOH front-loading was observed in both replicates. HAP3 mice displayed front-loading on the first day of EtOH access, whereas front-loading developed following alcohol experience in HAP2 mice, which may suggest differences in initial sensitivity to EtOH reward. Consummatory SNC, which manifests as lower water intake in mice expecting EtOH as compared to mice expecting water, was observed in both replicates. CONCLUSIONS: These findings increase confidence that defined changes in home cage consummatory behavior are driven by the incentive value of EtOH. The presence of cSNC across HAP replicates indicates that this reaction to loss of reward is genetically mediated, which suggests that there is a biological mechanism that might be targeted.

A Method to Present and Analyze Ensembles of Information Sources.

Information theory is a powerful tool for analyzing complex systems. In many areas of neuroscience, it is now possible to gather data from large ensembles of neural variables (e.g., data from many neurons, genes, or voxels). The individual variables can be analyzed with information theory to provide estimates of information shared between variables (forming a network between variables), or between neural variables and other variables (e.g., behavior or sensory stimuli). However, it can be difficult to (1) evaluate if the ensemble is significantly different from what would be expected in a purely noisy system and (2) determine if two ensembles are different. Herein, we introduce relatively simple methods to address these problems by analyzing ensembles of information sources. We demonstrate how an ensemble built of mutual information connections can be compared to null surrogate data to determine if the ensemble is significantly different from noise. Next, we show how two ensembles can be compared using a randomization process to determine if the sources in one contain more information than the other. All code necessary to carry out these analyses and demonstrations are provided.

Dynamical ventral tegmental area circuit mechanisms of alcohol-dependent dopamine release.

A large body of data has identified numerous molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms interact to result in dysregulated dopamine (DA) release under the influence of alcohol in vivo remains unclear. In this manuscript, we delineate potential circuit-level mechanisms responsible for EtOH-dependent dysregulation of DA release from the ventral tegmental area (VTA) into its projection areas. For this purpose, we constructed a circuit model of the VTA that integrates realistic Glutamatergic (Glu) inputs and reproduces DA release observed experimentally. We modelled the concentration-dependent effects of EtOH on its principal VTA targets. We calibrated the model to reproduce the inverted U-shape dose dependence of DA neuron activity on EtOH concentration. The model suggests a primary role of EtOH-induced boost in the Ih and AMPA currents in the DA firing-rate/bursting increase. This is counteracted by potentiated GABA transmission that decreases DA neuron activity at higher EtOH concentrations. Thus, the model connects well-established in vitro pharmacological EtOH targets with its in vivo influence on neuronal activity. Furthermore, we predict that increases in VTA activity produced by moderate EtOH doses require partial synchrony and relatively low rates of the Glu afferents. We propose that the increased frequency of transient (phasic) DA peaks evoked by EtOH results from synchronous population bursts in VTA DA neurons. Our model predicts that the impact of acute ETOH on dopamine release is critically shaped by the structure of the cortical inputs to the VTA.

Temporal Dynamics of Hippocampal and Medial Prefrontal Cortex Interactions During the Delay Period of a Working Memory-Guided Foraging Task.

Connections between the hippocampus (HC) and medial prefrontal cortex (mPFC) are critical for working memory; however, the precise contribution of this pathway is a matter of debate. One suggestion is that it may stabilize retrospective memories of recently encountered task-relevant information. Alternatively, it may be involved in encoding prospective memories, or the internal representation of future goals. To explore these possibilities, simultaneous extracellular recordings were made from mPFC and HC of rats performing the delayed spatial win-shift on a radial maze. Each trial consisted of a training-phase (when 4 randomly chosen arms were open) and test phase (all 8 arms were open but only previously blocked arms contained food) separated by a 60-s delay. Theta power was highest during the delay, and mPFC units were more likely to become entrained to hippocampal theta as the delay progressed. Training and test phase performance were accurately predicted by a linear classifier, and there was a transition in classification for training-phase to test-phase activity patterns throughout the delay on trials where the rats performed well. These data suggest that the HC and mPFC become more strongly synchronized as mPFC circuits preferentially shift from encoding retrospective to prospective information.

Rich-Club Organization in Effective Connectivity among Cortical Neurons.

The performance of complex networks, like the brain, depends on how effectively their elements communicate. Despite the importance of communication, it is virtually unknown how information is transferred in local cortical networks, consisting of hundreds of closely spaced neurons. To address this, it is important to record simultaneously from hundreds of neurons at a spacing that matches typical axonal connection distances, and at a temporal resolution that matches synaptic delays. We used a 512-electrode array (60 µm spacing) to record spontaneous activity at 20 kHz from up to 500 neurons simultaneously in slice cultures of mouse somatosensory cortex for 1 h at a time. We applied a previously validated version of transfer entropy to quantify information transfer. Similar to in vivo reports, we found an approximately lognormal distribution of firing rates. Pairwise information transfer strengths also were nearly lognormally distributed, similar to reports of synaptic strengths. Some neurons transferred and received much more information than others, which is consistent with previous predictions. Neurons with the highest outgoing and incoming information transfer were more strongly connected to each other than chance, thus forming a "rich club." We found similar results in networks recorded in vivo from rodent cortex, suggesting the generality of these findings. A rich-club structure has been found previously in large-scale human brain networks and is thought to facilitate communication between cortical regions. The discovery of a small, but information-rich, subset of neurons within cortical regions suggests that this population will play a vital role in communication, learning, and memory. Significance statement: Many studies have focused on communication networks between cortical brain regions. In contrast, very few studies have examined communication networks within a cortical region. This is the first study to combine such a large number of neurons (several hundred at a time) with such high temporal resolution (so we can know the direction of communication between neurons) for mapping networks within cortex. We found that information was not transferred equally through all neurons. Instead, ∼70% of the information passed through only 20% of the neurons. Network models suggest that this highly concentrated pattern of information transfer would be both efficient and robust to damage. Therefore, this work may help in understanding how the cortex processes information and responds to neurodegenerative diseases.

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.

Dopamine Neurons Change the Type of Excitability in Response to Stimuli.

The dynamics of neuronal excitability determine the neuron's response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance-based biophysical model, and its regulation by intrinsic and synaptic currents. Calibrating the model to reproduce low frequency tonic firing results in N-methyl-D-aspartate (NMDA) excitation balanced by γ-Aminobutyric acid (GABA)-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency "balanced" state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II characterized by the abrupt onset of repetitive firing. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized γ-Aminobutyric acid receptor (GABAR) reversal potential or co-activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of N-methyl-D-aspartate receptors (NMDARs) together with AMPARs and GABARs shifts the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I excitability in dopamine neurons might be important for low firing rates and fine-tuning basal dopamine levels, while switching excitability to type II during NMDAR and AMPAR activation may facilitate a transient increase in dopamine concentration, as type II neurons are more amenable to synchronization by mutual excitation.

Amphetamine Exerts Dose-Dependent Changes in Prefrontal Cortex Attractor Dynamics during Working Memory.

Modulation of neural activity by monoamine neurotransmitters is thought to play an essential role in shaping computational neurodynamics in the neocortex, especially in prefrontal regions. Computational theories propose that monoamines may exert bidirectional (concentration-dependent) effects on cognition by altering prefrontal cortical attractor dynamics according to an inverted U-shaped function. To date, this hypothesis has not been addressed directly, in part because of the absence of appropriate statistical methods required to assess attractor-like behavior in vivo. The present study used a combination of advanced multivariate statistical, time series analysis, and machine learning methods to assess dynamic changes in network activity from multiple single-unit recordings from the medial prefrontal cortex (mPFC) of rats while the animals performed a foraging task guided by working memory after pretreatment with different doses of d-amphetamine (AMPH), which increases monoamine efflux in the mPFC. A dose-dependent, bidirectional effect of AMPH on neural dynamics in the mPFC was observed. Specifically, a 1.0 mg/kg dose of AMPH accentuated separation between task-epoch-specific population states and convergence toward these states. In contrast, a 3.3 mg/kg dose diminished separation and convergence toward task-epoch-specific population states, which was paralleled by deficits in cognitive performance. These results support the computationally derived hypothesis that moderate increases in monoamine efflux would enhance attractor stability, whereas high frontal monoamine levels would severely diminish it. Furthermore, they are consistent with the proposed inverted U-shaped and concentration-dependent modulation of cortical efficiency by monoamines.

Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting.

In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+ current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally.

Neural Firing in the Prefrontal Cortex During Alcohol Intake in Alcohol-Preferring "P" Versus 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.

Stability of avoidance behaviour following repeated intermittent treatment with clozapine, olanzapine or D,L-govadine.

Most antipsychotic drugs act as dopamine D2 receptor antagonists within the basal ganglia. These compounds have efficacy in the treatment of positive symptoms of schizophrenia but do not address the cognitive deficits that define this disorder. D,L-Govadine, a recently synthesized tetrahydroprotoberberine, shows efficacy on preclinical tests of antipsychotic action, as well as procognitive properties. We sought to compare D,L-govadine with two atypical antipsychotics, clozapine and olanzapine, on repeated conditioned avoidance responding (CAR), a task that has recently been utilized to model the effects of repeated antipsychotic treatment. After acquisition of two-way avoidance, rats were given D,L-govadine, clozapine, olanzapine or a vehicle control before repeated testing on CAR. Daily sessions were conducted, with 'drug-on' days spaced by a 'drug-off' test day and a rest day, for a total of five drug administrations. Consistent with previous research, the lower dose of olanzapine showed a modest but progressive increase in disruption of avoidance behaviour as observed with many antipsychotics. In contrast, repeated administration of clozapine led to tolerance, and the novel compound D,L-govadine produced a consistent effect across administrations. This stable effect of D,L-govadine on CAR may indicate a desirable preclinical profile for a candidate antipsychotic compound.

Methamphetamine-induced deficits in social interaction are not observed following abstinence from single or repeated exposures.

The purpose of the current study was to assess social interaction (SI) following acute and repeated methamphetamine (MA) administration. Rats were injected with 5.0 mg/kg of MA and SI was tested 30 min or 24 h later. In another group of animals, MA sensitization was induced using 5.0 mg/kg of MA, and SI was assessed after 1 or 30 days of abstinence. SI was reduced in rats injected with MA 30 min, but not 24 h, before testing, compared with saline controls. Impaired SI was observed in combination with active avoidance of the conspecific animal. Repeated injections of MA progressively reduced locomotor activity and increased stereotypy, indicating that animals were sensitized. However, no differences in SI were observed 24 h or 30 days following the induction of sensitization. The absence of detectable differences in SI following MA sensitization may be attributable to the relatively short regimen used to induce sensitization. However, the current series of experiments provides evidence that an acute injection of MA decreases SI and simultaneously increases avoidance behavior, which supports a link between psychostimulant use and impaired social functioning. These data suggest that the acute injection model may provide a useful model to explore the neural basis of impaired social functioning and antisocial behavior.

Dynamical reorganization of synchronous activity patterns in prefrontal cortex-hippocampus networks during behavioral sensitization.

Neural synchrony exhibits temporal variability and, 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 in the theta frequency band in prefrontal cortex and hippocampus of awake, behaving rats 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 the relative prevalence of short desynchronizations) were similarly altered with AMPH injections, with each measure decreasing in the preinjection epoch and increasing after injection. Sensitization also induced decoupling between locomotor activity and synchrony. 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 a 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.