Pilar Flores

Impulsivity Characterization in the Roman High- and Low-Avoidance Rat Strains: Behavioral and Neurochemical Differences

The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for rapid vs extremely poor acquisition of active avoidance behavior in a shuttle-box has generated two phenotypes with different emotional and motivational profiles. The phenotypic traits of the Roman rat lines/strains (outbred or inbred, respectively) include differences in sensation/novelty seeking, anxiety/fearfulness, stress responsivity, and susceptibility to addictive substances. We designed this study to characterize differences between the inbred RHA-I and RLA-I strains in the impulsivity trait by evaluating different aspects of the multifaceted nature of impulsive behaviors using two different models of impulsivity, the delay-discounting task and five-choice serial reaction time (5-CSRT) task. Previously, rats were evaluated on a schedule-induced polydipsia (SIP) task that has been suggested as a model of obsessive-compulsive disorder. RHA-I rats showed an increased acquisition of the SIP task, higher choice impulsivity in the delay-discounting task, and poor inhibitory control as shown by increased premature responses in the 5-CSRT task. Therefore, RHA-I rats manifested an increased impulsivity phenotype compared with RLA-I rats. Moreover, these differences in impulsivity were associated with basal neurochemical differences in striatum and nucleus accumbens monoamines found between the two strains. These findings characterize the Roman rat strains as a valid model for studying the different aspects of impulsive behavior and for analyzing the mechanisms involved in individual predisposition to impulsivity and its related psychopathologies.

Impulsivity differences in recreational cannabis users and binge drinkers in a university population

BACKGROUND Recreational cannabis use and alcohol binge drinking are the most common drug consumption patterns in young adults. Impulsivity and several psychopathological signs are increased in chronic drug users, but the implications of recreational use are still poorly understood. METHODS We evaluated impulsivity, sensation-seeking traits, impulsive decision-making, inhibitory control and possible symptoms of depression, anxiety and psychosis in three groups of young university adults: recreational cannabis users (N=20), alcohol binge drinkers (N=22) and non-drug users (N=26). RESULTS The cannabis and binge drinking groups had increased scores for impulsivity and sensation-seeking traits. Both groups also exhibited increased impulsive decision-making on the two-choice task and the Iowa gambling task; however, only the cannabis group was significantly different from the non-drug group regarding inhibitory control (go/no-go and stop tasks). The cannabis and binge drinking groups did not show differences in the psychopathological symptoms evaluated. CONCLUSIONS Our observations of this population of non-dependent drug users are consistent with the increased impulsivity traits and behaviors that have been described previously in chronic drug abusers. In this study, compared to no drug use, the recreational use of cannabis was associated with a major dysfunction of the different facets of impulsive behaviors. However, alcohol binge drinking was related only to impulsive decision-making. These results suggest that impulsivity traits and behaviors are present not only in chronic drug abusers but also in recreational drug users. Future work should continue to investigate the long-term effects of these common consumption patterns on various impulsive behaviors and psychopathological symptoms.

Effects of chlorpyrifos in the plus-maze model of anxiety.

The purpose of the present study was to determine the effect of two different doses of the organophosphate insecticide O, O′–diethyl‐O ‐3,5,6‐trichloro‐2‐pyridylphosphorothionate [chlorpyrifos (CPF)], a cholinesterase (ChE) inhibitor, in the plus‐maze test of anxiety in the rat, as well as on acetylcholinesterase (AChE) activity in the brain. In a first experiment, the behavioural methodology was validated by showing the anxiolytic and anxiogenic effects of diazepam and pentylenetetrazole (PTZ), respectively. Acute exposure to CPF (166 mg/kg and 250 mg/kg, s.c.) produced significant dose‐dependent inhibition (54% and 71%, respectively) of whole‐brain AChE 48 hours after treatment. Neither dose produced signs of acute cholinergic toxicity at any time following treatment, as was verified by a functional observational battery. Both doses of CPF were injected 48 h before testing in the plus‐maze and were shown to have anxiogenic effects as demonstrated by the significant decrease in the percentage of time spent and percentage of entries into open arms. This report thus shows clear behavioural alteration as an acute effect of an organophosphate in the absence of any classic sign of cholinergic toxicity. Our results are relevant to the understanding of both the pharmacology of anxiety and the behavioural toxicology of cholinesterase inhibitors.

Long-term monoamine changes in the striatum and nucleus accumbens after acute chlorpyrifos exposure.

This study examined the time-course effects (2, 7, 14 and 30 days) of acute chlorpyrifos (CPF) intoxication (250 mg/kg, s.c.) on monoamine systems and acetylcholinesterase (AChE) activity in the striatum and nucleus accumbens of adult male rats. We show that CPF produced significant long-term inhibition of AChE activity in the striatum and nucleus accumbens. In the striatum, CPF intoxication resulted in changes in dopamine (DA) metabolism after 2 days and changes in serotonin (5-HT) turnover after 7 and 15 days. Significant decreases in monoamine content including norepinephrine (NE), DA, 5-HT and their metabolites were found in the nucleus accumbens 30 days after CPF intoxication. These results suggest that acute exposure to CPF induces long-term changes in the monoamine systems (NE, DA and 5-HT) in adult animals. The lack of correlation between regional AChE activity and neurochemical outcomes points to independent mechanisms.

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

BackgroundSchedule-induced polydipsia (SIP), characterized by the development of excessive drinking under intermittent food-reinforcement schedules, has been proposed as a successful model for obsessive–compulsive disorder (OCD), schizophrenia, and alcohol abuse.ObjectivesThe purpose of this study was to review the main findings and current thinking regarding the use of SIP for compulsivity assessment and evaluate its contribution to improving our knowledge of the neurobehavioral mechanisms underlying the excessive behavior manifested in SIP relevant to compulsive behavior disorders.MethodsThe literature reviews SIP procedure and surveys main findings about its neurobehavioral basis and pharmacology relevant to its possible status as a model for compulsive disorders. Specifically, we reviewed effects of antipsychotics and serotoninergic drugs used in the treatment of OCD and schizophrenia. We also considered individual differences in SIP and its relevance as a possible compulsivity endophenotype.ConclusionsSIP represents an animal model of non-regulatory and excessive drinking that may be valid for studying the psychopharmacology of the compulsive phenotype and modeling different psychopathologies from compulsivity spectrum disorders.

5-HT2A and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains

The Roman Low- and High-Avoidance rat strains (RLA-I vs RHA-I) have been bidirectionally selected and bred according to their performance in the two-way active avoidance response in the shuttle-box test. Numerous studies have reported a pronounced divergence in emotionality between the two rat strains including differences in novelty seeking, anxiety, stress coping, and susceptibility to addictive substances. However, the underlying molecular mechanisms behind these divergent phenotypes are not known. Here, we determined impulsivity using the 5-choice serial reaction time task and levels of serotonin transporter (SERT), 5-HT(2A) and 5-HT(1A) receptor binding using highly specific radioligands ((3)H-escitalopram, (3)H-MDL100907 and (3)H-WAY100635) and mGlu2/3 receptor binding ((3)H-LY341495) using receptor autoradiography in fronto-cortical sections from RLA-I (n=8) and RHA-I (n=8) male rats. In the more impulsive RHA-I rats, 5-HT(2A), 5-HT(1A) and SERT binding in the frontal cortex was significantly higher compared to RLA-I rats. In contrast, mGlu2/3 receptor binding was decreased by 40% in RHA-I rats compared to RLA-I rats. To differentiate between mGlu2 and mGlu3 receptor protein levels, these were further studied using western blotting, which showed non-detectable levels of mGlu2 receptor protein in RHA rats, while no differences were observed for mGlu3 receptor protein levels. Collectively, these data show general congenital differences in the serotonergic system and a pronounced difference in mGlu2 receptor protein levels. We suggest that the differences in the serotonergic system may mediate some of the phenotypic characteristics in this strain such as hyper-impulsivity and susceptibility to drug addiction.

Individual differences in schedule-induced polydipsia and the role of gabaergic and dopaminergic systems

RationaleThe research of individual differences has opened new possibilities for better exploring the neurobiological basis of vulnerability to psychopathological disorders.ObjectiveWe extended this approach by using schedule-induced polydipsia (SIP).MethodsOutbred male Wistar rats were characterized as either high (HD) or low (LD) drinker according to their behavior in SIP. Subsequently, their performance in the elevated plus maze (EPM) was studied for possible differences in anxiety-like behaviors. Finally, the effects of pentylenetetrazol (PTZ), diazepam, d-amphetamine, and cocaine on individual differences in SIP were investigated.ResultsHD rats acquired SIP faster and reached higher asymptotic levels than LD. Nose pokes, however, were greater in LD. In the EPM, there were no differences between HD and LD animals. Gabaergic drug effects on SIP did not differ between HD and LD rats. Compared to saline, PTZ reduced and diazepam increased water SIP drinking. On the other hand, amphetamine dose-dependently reduced SIP in HD, whereas the highest dose was required to reduce SIP in LD. HD rats also showed reductions in SIP drinking after cocaine administration. However, the effects of these drugs on nose pokes did not differ between HD and LD.ConclusionThese data provide novel evidence that individual differences in SIP are not predictive of behavioral reactivity in animal models of anxiety and suggest an important role for the dopaminergic system in such individual differences. These findings point to SIP as a useful animal model for investigating the neurobiological basis of vulnerability to several psychopathologies in which the dopaminergic system is involved.

Rate-dependency hypothesis and the rate-decreasing effects of d-amphetamine on schedule-induced drinking.

The high levels of drinking induced by intermittent food-reinforcement schedules are dose-dependently reduced by acute doses of d-amphetamine. The present study evaluated whether the effects of d-amphetamine on this schedule-induced drinking reflect the reduction of high rates of responding. Twenty four rats were divided into six groups (n = 4) according to the interval and time durations of a multiple fixed-time (FT) fixed-interval (FI) schedule (15 s, 30 s, 60 s, 120 s, 240 s and 480 s). FT components were signalled by a tone and by lever withdrawal. Doses of 0.25 to 4.0 mg/kg of d-amphetamine were administered i.p. 10 min before test sessions, d-amphetamine produced similar dose-dependent reductions in rate of licking induced by FT and FI schedules. Rate-decreasing effects on operant lever pressing were also found after administrations of d-amphetamine. The dose-dependent decrements produced by d-amphetamine were a function of the infer-food interval length in both schedule-induced and operant behaviours. These rate-decreasing effects were rate-dependent, but d-amphetamine interacted differentially with control rates of adjunctive and operant behaviours, causing a greater suppression of the lower rates of adjunctive licking and the higher rates of operant lever pressing.

Antipunishment effects of diazepam on two levels of suppression of schedule-induced drinking in rats

Food-deprived Wistar rats were exposed to a fixed-time (FT) 60-s food delivery schedule until they developed schedule-induced drinking. Rats were matched in pairs according to their licking rates and were designated master or yoked at random. Every fifth lick by master rats was followed by an electric shock during two signalled 5-min periods, which ran concurrently with the food delivery schedule. For the master rats, shock intensities were adjusted to reduce licking to 5-30% (low suppression) or 50-75% (high suppression) of the unpunished licking rates. Yoked rats received the same shocks as master rats, but independently of their own licking. The drinking by yoked animals was not decreased by the presentation of these lick-independent shocks. Diazepam (0.3-10.0 mg/kg) was studied for its effects on punished and nonpunished schedule-induced drinking. Intermediate doses of the drug increased the punished behavior of master rats, but only when schedule-induced drinking was highly suppressed. Diazepam dose dependently decreased licking rates in all other conditions. The antipunishment effects of benzodiazepines may depend on the level of suppression of schedule-induced drinking, and this is in keeping with the results of other experimental preparations where behavior was under aversive control.

Strain-dependent differences in schedule-induced polydipsia: an assessment in Lewis and Fischer rats

Strain-dependent differences have been used to highlight unknown genetic contributions to important behavioral and physiological end points. In this regard, the Fischer (F344) and Lewis (LEW) rat strains have often been studied because they exhibit a myriad of behavioral and physiological differences. Recently, schedule-induced polydipsia (SIP), a potential model of stress and drug abuse, has been reported to differ between the two strains (see [Pharmacol. Biochem. Behav. 67 (2002) 809]) with F344 rats displaying greater levels of consumption than LEW rats. Given the importance of SIP as a behavioral model of stress and of drug abuse, the present study further explored SIP in F344 and LEW strains by assessing the acquisition and steady-state performance of SIP (under a fixed-time 30 schedule of food delivery; FT30), its characteristic postprandial temporal licking pattern and its modulation by variations in the food delivery schedule (FT15, FT30 and FT60). F344 rats acquired SIP at a faster rate and drank at a higher asymptotic level than LEW rats. Both strains displayed the typical inverted U-shaped post-pellet pattern of drinking and changes in levels of consumption (and displacement of the initiation of post-pellet drinking) with changes in the FT value, supporting the position that the increased drinking seen in both groups was schedule induced. These strain differences in SIP are consistent with the fact that the F344 and LEW strains differ on other behavioral and physiological indices of stress and raise the issue of the use of this model in the assessment of differential drug intake between the two strains.