Alcohol Preferring P Rats Exhibit Elevated Motor Impulsivity Concomitant with Operant Responding and Self-Administration of Alcohol

BACKGROUND: Increased levels of impulsivity are associated with increased illicit drug use and alcoholism. Previous research in our laboratory has shown that increased levels of delay discounting (a decision-making form of impulsivity) are related to appetitive processes governing alcohol self-administration as opposed to purely consummatory processes. Specifically, the high-seeking/high-drinking alcohol-preferring P rats showed increased delay discounting compared to nonselected Long Evans rats (LE) whereas the high-drinking/moderate-seeking HAD2 rats did not. The P rats also displayed a perseverative pattern of behavior such that during operant alcohol self-administration they exhibited greater resistance to extinction. METHODS: One explanation for the previous findings is that P rats have a deficit in response inhibition. This study followed up on this possibility by utilizing a countermanding paradigm (stop signal reaction time [SSRT] task) followed by operant self-administration of alcohol across increasing fixed ratio requirements (FR; 1, 2, 5, 10, and 15 responses). In separate animals, 24-hour access 2-bottle choice (10% EtOH vs. water) drinking was assessed. RESULTS: In the SSRT task, P rats exhibited an increased SSRT compared to both LE and HAD2 rats indicating a decrease in behavioral inhibition in the P rats. Also, P rats showed increased operant self-administration across all FRs and the greatest increase in responding with increasing FR requirements. Conversely, the HAD2 and LE had shorter SSRTs and lower levels of operant alcohol self-administration. However, for 2-bottle choice drinking HAD2s and P rats consumed more EtOH and had a greater preference for EtOH compared to LE. CONCLUSIONS: These data extend previous findings showing the P rats to have increased delay discounting (decision-making impulsivity) and suggest that P rats also have a lack of behavioral inhibition (motor impulsivity). This supports the notion that P rats are a highly impulsive as well as "high-seeking" model of alcoholism, and that the HAD2s' elevated levels of alcohol consumption are not mediated via appetitive processes or impulsivity

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

Alcohol-Preferring Rats Show Goal Oriented Behaviour to Food Incentives but Are Neither Sign-Trackers Nor Impulsive.

Drug addiction is often associated with impulsivity and altered behavioural responses to both primary and conditioned rewards. Here we investigated whether selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats show differential levels of impulsivity and conditioned behavioural responses to food incentives. P and NP rats were assessed for impulsivity in the 5-choice serial reaction time task (5-CSRTT), a widely used translational task in humans and other animals, as well as Pavlovian conditioned approach to measure sign- and goal-tracking behaviour. Drug-naïve P and NP rats showed similar levels of impulsivity on the 5-CSRTT, assessed by the number of premature, anticipatory responses, even when the waiting interval to respond was increased. However, unlike NP rats, P rats were faster to enter the food magazine and spent more time in this area. In addition, P rats showed higher levels of goal-tracking responses than NP rats, as measured by the number of magazine nose-pokes during the presentation of a food conditioned stimulus. By contrast, NP showed higher levels of sign-tracking behaviour than P rats. Following a 4-week exposure to intermittent alcohol we confirmed that P rats had a marked preference for, and consumed more alcohol than, NP rats, but were not more impulsive when re-tested in the 5-CSRTT. These findings indicate that high alcohol preferring and drinking P rats are neither intrinsically impulsive nor do they exhibit impulsivity after exposure to alcohol. However, P rats do show increased goal-directed behaviour to food incentives and this may be associated with their strong preference for alcohol.There are errors in the Funding section. The correct funding information is as follows: The present study was funded by the Wellcome Trust and the Medical Research Council Programme (MRC Ref: G1002231 awarded to BJE, JWD, TWR, Wellcome Trust Ref: 093875/Z/10/Z), and the R24 Alcohol Research Resource Award grant (R24 AA015512) from NIAAA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013101

Alcohol-preferring P rats emit spontaneous 22-28 kHz ultrasonic vocalizations that are altered by acute and chronic alcohol experience

BACKGROUND: Emotional states are often thought to drive excessive alcohol intake and influence the development of alcohol use disorders. To gain insight into affective properties associated with excessive alcohol intake, we utilized ultrasonic vocalization (USV) detection and analyses to characterize the emotional phenotype of selectively bred alcohol-preferring (P) rats; an established animal model of excessive alcohol intake. USVs emitted by rodents have been convincingly associated with positive (50-55 kHz frequency-modulated [FM]) and negative (22-28 kHz) affective states. Therefore, we hypothesized that 50-55 and 22-28 kHz USV emission patterns in P rats would reveal a unique emotional phenotype sensitive to alcohol experience. METHODS: 50-55 kHz FM and 22-28 kHz USVs elicited from male P rats were assessed during access to water, 15 and 30% EtOH (v/v). Ethanol (EtOH; n = 12) or water only (Control; n = 4) across 8 weeks of daily drinking-in-the-dark (DID) sessions. RESULTS: Spontaneous 22-28 kHz USVs are emitted by alcohol-naïve P rats and are enhanced by alcohol experience. During DID sessions when alcohol was not available (e.g., "EtOH OFF" intervals), significantly more 22-28 kHz than 50-55 kHz USVs were elicited, while significantly more 50-55 kHz FM than 22-28 kHz USVs were emitted when alcohol was available (e.g., "EtOH ON" intervals). In addition, USV acoustic property analyses revealed chronic effects of alcohol experience on 22-28 kHz USV mean frequency, indicative of lasting alcohol-mediated alterations to neural substrates underlying emotional response. CONCLUSIONS: Our findings demonstrate that acute and chronic effects of alcohol exposure are reflected in changes in 22-28 and 50-55 kHz FM USV counts and acoustic patterns. These data support the notion that initiation and maintenance of alcohol intake in P rats may be due to a unique, alcohol-responsive emotional phenotype and further suggest that spontaneous 22-28 kHz USVs serve as behavioral markers for excessive drinking vulnerability

Increased delay discounting tracks with a high ethanol-seeking phenotype and subsequent ethanol seeking but not consumption

BACKGROUND: Increased levels of delay discounting have been associated with alcoholism and problematic levels of drinking. Attempts to assess the directionality of this relationship by studying individuals with a family history of alcoholism as well as rodent lines selectively bred for high home cage alcohol preference have yielded discordant results. One possible reason for this discordance is that increased levels of delay discounting may only track with specific processes that lead to addiction vulnerability. This study investigated this possibility by assessing 3 strains of rats previously identified to exhibit heritable differences in ethanol (EtOH) seeking and consumption. METHODS: In an adjusting amount delay discounting task, alcohol-preferring (P) rats who display high levels of both EtOH seeking and consumption were compared to high alcohol-drinking (HAD2) rats who only exhibit moderate EtOH seeking despite high levels of consumption, and Long Evans (LE) rats who display moderate seeking and consumption. EtOH-seeking and consumption phenotypes were subsequently confirmed in an operant self-administration task with a procedural separation between EtOH seeking and drinking. RESULTS: P rats discounted delayed rewards to a greater extent than both HAD2s and LE who did not show differences in discounting. Moreover, the EtOH-seeking and drinking phenotypes were replicated with P rats displaying greater EtOH seeking compared to both the HAD2s and LE, and both the HAD2s and P rats consuming more EtOH than LEs. CONCLUSIONS: Only the high-seeking strain, the P rats, exhibited increased levels of delay discounting. This suggests that this measure of behavioral under-control is specifically associated with alcohol-related appetitive, but not consummatory, processes as the moderate seeking/high drinking line did not show increased levels of impulsivity. This finding supports the hypothesis that delay discounting is specifically associated with only certain processes which are sufficient but not necessary to confer addiction vulnerability and therefore also supports increased levels of delay discounting as a predisposing risk factor for alcoholism

Effects Of (R)-(-)-5-Methyl-1-Nicotinoyl-2-Pyrazoline On Glutamate Transporter 1 And Cysteine/Glutamate Exchanger As Well As Ethanol Drinking Behavior In Male, Alcohol-Preferring Rats

Alcohol consumption is largely associated with alterations in the extracellular glutamate concentrations in several brain reward regions. We recently showed that glutamate transporter 1 (GLT-1) is downregulated following chronic exposure to ethanol for 5 weeks in alcohol-preferring (P) rats and that upregulation of the GLT-1 levels in nucleus accumbens and prefrontal cortex results, in part, in attenuating ethanol consumption. Cystine glutamate antiporter (xCT) is also downregulated after chronic ethanol exposure in P rats, and its upregulation could be valuable in attenuating ethanol drinking. This study examines the effect of a synthetic compound, (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), on ethanol drinking and expressions of GLT-1 and xCT in the amygdala and the hippocampus of P rats. P rats were exposed to continuous free-choice access to water, 15% and 30% ethanol, and food for 5 weeks, after which they received treatments of MS-153 or vehicle for 5 days. The results show that MS-153 treatment significantly reduces ethanol consumption. It was revealed that GLT-1 and xCT expressions were downregulated in both the amygdala and the hippocampus of ethanol–vehicle-treated rats (ethanol–vehicle group) compared with water-control animals. MS-153 treatment upregulated GLT-1 and xCT expressions in these brain regions. These findings demonstrate an important role for MS-153 in these glutamate transporters for the attenuation of ethanol-drinking behavior

Effects of Alcohol and Saccharin Deprivations on Concurrent Ethanol and Saccharin Operant Self-Administration by Alcohol-Preferring (P) Rats

Consumption of sweet solutions has been associated with a reduction in withdrawal symptoms and alcohol craving in humans. The objective of the present study was to determine the effects of EtOH and saccharin (SACC) deprivations on operant oral self-administration. P rats were allowed to lever press concurrently self-administer EtOH (15% v/v) and SACC (0.0125% g/v) for 8 weeks. Rats were then maintained on daily operant access (non-deprived), deprived of both fluids (2 weeks), deprived of SACC and given 2 ml of EtOH daily, or deprived of EtOH and given 2 ml of SACC daily. All groups were then given two weeks of daily operant access to EtOH and SACC, followed by an identical second deprivation period. P rats responded more for EtOH than SACC. All deprived groups increased responding on the EtOH lever, but not on the SACC lever. Daily consumption of 2 ml EtOH decreased the duration of the ADE. Home cage access to 2 ml SACC also decreased the ADE but to a lesser extent than access to EtOH. A second deprivation period further increased and prolonged the expression of an ADE. These results show EtOH is a more salient reinforcer than SACC. With concurrent access to EtOH and SACC, P rats do not display a saccharin deprivation effect. Depriving P rats of both EtOH and SACC had the most pronounced effect on the magnitude and duration of the ADE, suggesting that there may be some interactions between EtOH and SACC in their CNS reinforcing effects