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Early-life adversities during development (e.g., child abuse and neglect) are linked to multiple behavioral and cognitive dysfunctions, such as attention deficit/hyperactivity disorder (ADHD) and anxiety disorders, which have high comorbidity. However, the impact of adversities during adolescence, a crucial period in early life for these disorders, is understudied. Using a chronic unpredictable stress (CUS) model in rats, we investigated whether adversities in adolescence could lead to increased anxiety and ADHD-like symptoms in adulthood.Mid- to late-adolescent (5-7-week-old) male and female Sprague-Dawley rats underwent a mild CUS procedure for 2 weeks. Various stressors were applied in an unpredictable way. Rats of both sexes were then trained with a 2-choice reaction time (2-CRT) task during adulthood, which are designed to detect ADHD-like symptoms, including increased impulsivity and lapse of attention. In addition, an open field test was conducted to examine if CUS resulted in a persistent increase in anxiety-like behavior during adulthood.Both male and female rats with CUS exposure travelled shorter distances in the open field and spent less time in the center zone, indicating increased anxiety. In the 2-CRT task, rats of both sexes with CUS exposure showed increased impulsivity. Augmented lapses of attention were observed in female but not male rats.Chronic unpredictable stress during adolescence increases anxiety and leads to ADHD-like symptoms in both male and female rats in adulthood. The deficits are more severe in females than in males. These observations support that adversities during adolescence persistently increase anxiety, which is comorbid with attention deficits.

BACKGROUND. Individuals with fetal alcohol spectrum disorders (FASD) often show sensory processing deficits in all sensory modalities. Using an operant light reinforcement model, we tested if prenatal ethanol exposure (PE) could alter operant responding to elicit a contingent sensory stimulus - light onset (turning on light) and habituation of this behavior in rats. We also explored if postnatal environmental enrichment could ameliorate PE-induced deficits. METHODS. Pregnant Sprague Dawley rats were gavaged twice/day with 0 or 3 g/kg/treatment ethanol (15% w/v) during gestational days 8–20, mimicking second-trimester heavy PE in humans. The offspring were reared in the standard housing condition or an enriched condition. Adult male and female offspring underwent an operant light reinforcement experiment with either a short-access or a long-access procedure. A dishabituation test was also conducted to further characterize the habituation process. RESULTS. In the short-access procedure, PE led to increased operant responding to the contingent light-onset in both sexes reared in the standard housing condition. Such an effect was not observed in rats reared in enriched condition due to an overall decrease in responding. Moreover, rats reared in enriched condition showed greater short-term habituation. In the long access procedure, PE rats showed increased responding and impaired long-term habituation. The long-access procedure facilitated both short-term and long-term habituation in control and PE rats. CONCLUSION. Prenatal ethanol exposure increases responding to contingent light-onset and impairs the long-term habituation process. The PE-induced deficits could be ameliorated by rearing in the enriched environment and increasing the duration and frequency of exposure to light-onset. The PE-induced effects are similar to increased sensation-seeking, a subtype of sensory-processing deficits, which is often observed in individuals with FASD. Our findings could inform a suitable animal model for investigating the underlying mechanisms as well as possible intervention strategies for these deficits in FASD.

Author(s): Chitre, Apurva S; Polesskaya, Oksana; Holl, Katie; Gao, Jianjun; Cheng, Riyan; Bimschleger, Hannah; Garcia Martinez, Angel; George, Tony; Gileta, Alexander F; Han, Wenyan; Horvath, Aidan; Hughson, Alesa; Ishiwari, Keita; King, Christopher P; Lamparelli, Alexander; Versaggi, Cassandra L; Martin, Connor; St Pierre, Celine L; Tripi, Jordan A; Wang, Tengfei; Chen, Hao; Flagel, Shelly B; Meyer, Paul; Richards, Jerry; Robinson, Terry E; Palmer, Abraham A; Solberg Woods, Leah C | Abstract: ObjectiveObesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits.MethodsThis study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers.ResultsThis study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci.ConclusionsThis study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing.

Background Attention deficits caused by prenatal ethanol exposure (PE) are a prevalent condition in fetal alcohol spectrum disorders (FASD). Importantly, the deficits are observed in individuals with FASD who have normal IQs and show no dysmorphic facial features caused by heavy PE. These observations suggest that even moderate PE could lead to attention deficits. This possibility was investigated using a rat model in the present study. Methods Pregnant Sprague Dawley rats were administered with ethanol (3 g/kg/day) or vehicle via intragastric gavage on gestational days 8 - 20. The blood ethanol concentration (BEC) in ethanol-treated rats was 87.7 ± 1.2 mg/dL (1 h after the gavage), similar to the BEC levels reported in other moderate PE studies in rodents. Moderate PE did not produce teratogenic effects on birth weight or litter size. The adult offspring underwent a 2-choice reaction time task. Results Moderate PE led to augmented action impulsivity in both sexes, indicated by more rapid response initiation and increased premature responses. More marked deficits were observed in males than in females. No increases in lapse of attention, assessed by incorrect or relatively slow responses, were observed in rats of either sex with moderate PE. In addition, no deficits in learning or motor function were detected after moderate PE. Interestingly, rats with moderate PE completed more trials than controls. Conclusions Our results confirm that moderate PE indeed leads to attention deficits in both sexes, which is demonstrated by greater action impulsivity, but not increased lapses of attention. This effect is different from that of heavy PE observed in our previous study, which is manifested as impaired action impulsivity and lapses of attention in both sexes.

Previous research has shown that rats reared in simple/impoverished environments demonstrate greater repetitive responding for sensory reinforcers (e.g., light onset). Moreover, the brains of these rats are abnormally developed, compared to brains of rats reared in more complex/enriched environments. Repetitive behaviors are commonly observed in individuals with developmental disorders. Some of these repetitive behaviors could be maintained by the reinforcing effects of the sensory stimulation that they produce. Therefore, rearing rats in impoverished conditions may provide an animal model for certain repetitive behaviors associated with developmental disorders. We hypothesize that in rats reared in simple/impoverished environments, the normal habituation process to sensory reinforcers is impaired, resulting in high levels of repetitive behaviors. We tested the hypothesis using an operant sensory reinforcement paradigm in rats reared in simple/impoverished (IC), standard laboratory (SC), and complex/enrichened conditions (EC, treatments including postnatal handling and environmental enrichment). Results show that the within-session habituation of the reinforcer effectiveness of light onset was slower in the IC and SC rats than in the EC rats. A dishabituation challenge indicated that within-session decline of responses was due to habituation and not motor fatigue or sensory adaptation. In conclusion, rearing rats in simple/impoverished environments, and comparing them to rats reared in more complex/enriched environments, may constitute a useful approach for studying certain repetitive behaviors associated with developmental disorders.

Genome-wide association studies in humans have suggested that variants of the cadherin-13 (CDH13) gene are associated with substance use disorder, subjective response to amphetamine, and attention deficit hyperactivity disorder. To examine the role of the Cdh13 and its peptide ligand adiponectin (AdipoQ) in addiction-related behaviors, we assessed Cdh13 knock-out rats and AdipoQ knock-out mice using intravenous cocaine self-administration and conditioned place preference paradigms. During intravenous cocaine self-administration, male Cdh13 heterozygous (+/−) and knock-out (−/−) rats showed increased cue-induced reinstatement compared to wild-type rats when presented with a cocaine-paired stimulus, whereas female Cdh13 rats showed no differences across genotype. Cdh13 −/− rats showed higher responding for a saccharin reinforcer and learned the choice reaction time task more slowly than wild-types. However, we found no differences between Cdh13 −/− and +/+ rats in responding for sensory reinforcement, number of premature responses in the reaction time task, tendency to approach a Pavlovian food cue, conditioned place preference and locomotor activation to cocaine (10 or 20 mg/kg). In AdipoQ −/− mice there was a significant increase in conditioned place preference to methamphetamine (1 mg/kg) but not to a range of d-amphetamine doses (0.5, 1, 2 and 4 mg/kg). Taken together, these data suggest that Cdh13 and AdipoQ regulate sensitivity to psychomotor stimulants and palatable rewards without producing major changes in other behaviors. In humans, these two genes may regulate sensitivity to natural and drug rewards, thus influencing susceptibility to the conditioned drug effects and relapse.

Background Multiple factors contribute to the etiology of addiction, including genetics, sex, and a number of addiction-related behavioral traits. One behavioral trait where individuals assign incentive salience to food stimuli (“sign-trackers”, ST) are more impulsive compared to those that do not (“goal-trackers”, GT), as well as more sensitive to drugs and drug stimuli. Furthermore, this GT/ST phenotype predicts differences in other behavioral measures. Recent studies have implicated the gut microbiota as a key regulator of brain and behavior, and have shown that many microbiota-associated changes occur in a sex-dependent manner. However, few studies have examined how the microbiome might influence addiction-related behaviors. To this end, we sought to determine if gut microbiome composition was correlated with addiction-related behaviors determined by the GT/ST phenotype. Methods Outbred male (N=101) and female (N=101) heterogeneous stock rats underwent a series of behavioral tests measuring impulsivity, attention, reward-learning, incentive salience, and locomotor response. Cecal microbiome composition was estimated using 16S rRNA gene amplicon sequencing. Behavior and microbiome were characterized and correlated with behavioral phenotypes. Robust sex differences were observed in both behavior and microbiome; further analyses were conducted within sex using the pre-established goal/sign-tracking (GT/ST) phenotype and partial least squares differential analysis (PLS-DA) clustered behavioral phenotype. Results Overall microbiome composition was not associated to the GT/ST phenotype. However, microbial alpha diversity was significantly decreased in female STs. On the other hand, a measure of impulsivity had many significant correlations to microbiome in both males and females. Several measures of impulsivity were correlated with the genus Barnesiella in females. Female STs had notable correlations between microbiome and attentional deficient. In both males and females, many measures were correlated with the bacterial families Ruminocococcaceae and Lachnospiraceae. Conclusions These data demonstrate correlations between several addiction-related behaviors and the microbiome specific to sex.

The neuropeptide, arginine vasopressin (AVP), is thought to contribute to sex differences in normative and pathological social development by regulating social motivation. Recent studies using Brattleboro rats that have a mutation in the Avp gene, however, have suggested that AVP impacts adolescent social behaviors of males and females in a similar manner through actions on behavioral state (i.e., arousal). In the present study, we made use of a recently developed operant conditioning paradigm to test whether the chronic, lifelong AVP deficiency caused by the Brattleboro mutation impacts the reinforcement value of social stimuli during adolescence. Operant responding for access to a familiar conspecific was assessed in male and female adolescent wild type (WT; normal AVP), heterozygous Brattleboro (HET), and homozygous Brattleboro (HOM) rats. Following the social reinforcement test, rats were tested in the same operant paradigm except that the social reinforcer was replaced with a light reinforcer to determine whether effects of the Brattleboro mutation were specific to social stimuli or a general characteristic of operant conditioning. WT males directed a greater proportion of their responding toward the social and light stimuli than WT females; only males exhibited a preference for these reinforcers over unreinforced ports. The sex difference in social reinforcement was absent in HOM rats, whereas the sex difference in light reinforcement was present in all genotypes. These data indicate that adolescent males are more sensitive to the reinforcing properties of social and light stimuli, and that the sex difference in social, but not light, reinforcement depends upon normal levels of AVP. These findings support the hypothesis that AVP plays a critical role in sex differences in social development by acting on factors that influence social motivation.

Stimulant drugs such as nicotine (NIC) and methylphenidate (MPH) are hypothesized to increase the reinforcing value of sensory stimuli, thus increasing the effectiveness of such reinforcers as alternatives to sucrose reinforcers. Inbred Fischer-344 rats (n = 30) were assigned to three groups: saline (SAL; n = 10), nicotine (NIC; n = 10), or methylphenidate (MPH; n = 10). Testing was done in three phases: sucrose only, (SUC), sucrose and drug (SUC/DRUG), and sucrose, drug, and social reinforcement (SUC/DRUG/SOC). During the SUC phase, rats were trained on a progressive ratio 5 (PR5) reinforcement schedule for sucrose (20% solution). In the SUC/DRUG phase, animals were treated with SAL, NIC (0.4 mg/kg, n = 10 SC), or MPH (2.0 mg/kg, n = 10 IP) 30 min prior to testing. In the SUC/DRUG/SOC phase, animals continued receiving drug treatment, and social reinforcement was introduced concurrently with the sucrose reinforcer. The progressive ratio for each reinforcer ran independently of the others. Reinforcing value was measured as break point (BP), the highest number of responses resulting in a reinforcer. SAL-treated animals showed no significant change in sucrose BP. MPH-treated animals showed decreased sucrose BP in the SUC/DRUG phase, with a further reduction in the SUC/DRUG/SOC phase. NIC-treated animals decreased sucrose BP only when a social alternative was offered. Both NIC and MPH reduce the sucrose BP in the presence of a social alternative. The decrease in sucrose responding, coupled with increased social responding, suggests that the social alternative acted as an effective alternative reinforcer to sucrose. From a translational perspective, these results suggest that stimulant drugs such as NIC and MPH may increase the effectiveness of treatments that use alternative social reinforcers to decrease eating.

Indifferent sensory stimuli, such as light-onset, can be reinforcers (for reviews, see Berlyne, 1969; Eisenberger, 1972; Glanzer, 1958; Kish, 1966; Lockard, 1963; Tapp, 1969). In comparison to important biological reinforcers such as food and water, the reinforcing effectiveness of sensory reinforcers is weak and transient. Responding for sensory reinforcers has often been characterized as investigatory behavior. Experiments with light reinforcement were first reported by Girdner (1953), who considered the operant responding for novel light-onset analogous to investigatory loco-motor responses that expose organisms to novel environmental change (as described by Kish, 1966, p. 111). For example, exploratory activity is high when a rat is first placed into a novel locomotor chamber and then decreases within the same session. Similarly, operant responding for novel light-onset is initially high at the start of a test session and then shows a within-session decline (Gancarz, Ashrafioun, et al., 2012; Gancarz, Robble, Kausch, Lloyd, & Richards, 2012). Within-session declines in locomotor activity and responding for novel light-onset are often characterized as indicators of habituation involving memory processes. A rat, when placed in the novel chamber, forms an internal representation (memory) of the chamber and the objects within and around it (Antunes & Biala, 2012; Leussis & Bolivar, 2006). Locomotor activity decreases as a consistent internal representation of the test chamber is formed and perceived stimuli are recognized. This interpretation is consistent with memory-based explanations of habituation (Konorski, 1963; Sokolov, 1963; Wagner, 1979). According to memory-based explanations of habituation, perceived stimuli are compared with existing memory. If the perceived sensory stimuli do not match memory, they are novel and cause dishabituation. On the other hand, if the perceived stimuli match memory, then they are not novel or surprising and do not cause dishabituation. McSweeney and Murphy (2009) have argued that within-session declines in operant responding are a function of habituation to the sensory properties of repeatedly presented reinforcers. In agreement with their work, we have provided evidence that within-session declines in the effectiveness of sensory reinforcers is attributable to habituation (Lloyd, Gancarz, Ashrafioun, Kausch, & Richards, 2012). Within-session decreases in light-reinforced responding can be reasonably attributed to habituation of reinforcer effectiveness because there is a programmed contingency between responding and light-onset. In contrast, locomotor activity in a novel locomotor chamber is more likely to be described as elicited or evoked by exposure to novel environmental stimuli, suggesting that locomotor activity in a novel environment is a Pavlovian process. However, as has been previously pointed out (Berlyne, 1960), exploratory behavior can be characterized as a mixture of Pavlovian and operant processes. Novel sensory stimuli such as light-onset activate orienting or targeting reflexes that bring sensory receptors into contact with the sensory stimulus (Sokolov, 1963). Some of the sensory stimuli (e.g., localized changes in relative illumination) evoke targeting reflexes and are also reinforcers that increase the probability of the responses that produced them. It is likely that naturally occurring contingencies between responding and sensory stimulation that occur while an animal is exploring a novel environment may similarly increase locomotor activity in a novel environment. Thus, even though there are no programmed operant contingencies in a novel locomotor chamber, the habituation of the reinforcing effectiveness of inherent operant contingencies may contribute to declines in exploratory activity. This is supported by evidence from McSweeney and Swindell (1999) who showed that decreases in exploratory activity follow the same mathematical relationship as habituation in other paradigms. As was originally suggested by Girdner (1953), operant responding to produce light-onset may be an effective way to precisely measure exploratory behavior. Habituation to the reinforcing effectiveness of sensory stimuli may be mediated by decreases in dopamine (DA) neurotransmission evoked by novel or surprising sensory stimuli. Novel sensory stimuli increase phasic firing of DA neurons. This effect rapidly habituates when sensory stimuli are repeatedly presented (Ljungberg, Apicella, & Schultz, 1992). Redgrave and Gurney (2006) have hypothesized that phasic firing of DA neurons elicited by novel sensory stimuli activate the animal to repeat responses that produced the novel sensory stimulation. According to Redgrave and Gurney, this DA-mediated mechanism allows organisms to “discover” contingencies between investigatory behaviors and novel sensory events. Following initial “discovery,” phasic firing of DA neurons is cancelled by timed inhibitory input to DA as the sensory stimulus becomes predictable (familiar) through repetition. Redgrave and Gurney (2006) have described the phasic firing of DA neurons evoked by novel sensory stimulation as a sensory prediction error signal. The concept of phasic firing of DA neurons as a function of the difference between perceived and remembered stimuli fits well with memory-based explanations of habituation, where comparison of perceived and remembered stimuli leads to the identification of novel stimuli that produce dishabituation (arousal). However, instead of arousal, Redgrave and Gurney emphasize that an increase in DA neurotransmission evoked by novel stimuli determines the reinforcing effectiveness (or effects) of indifferent sensory stimuli. More specifically, they hypothesize that novelty-induced increases in DA cause the animal to repeat actions that precede novel stimuli, leading to the discovery of the action that produced it. The hypothesis that the reinforcing effects of sensory stimuli rapidly habituate, in combination with the concept of phasic DA as a sensory prediction error signal that mediates the behavioral expression of habituation, makes predictions that can be tested with both behavioral and drug manipulations. To test these predictions we have developed a method for quantitatively characterizing the rate of habituation for operant responding that takes into account relative differences in response rate so that the habituation rate (HR) measure is independent of absolute response rate measures. In Phase 1 of the current experiment, we use this method to measure the HR of the operant level of snout poking in a novel environment. Memory-based theories of habituation predict that the rate of habituation will increase with repeated exposure to the novel environment as sensory consequences of investigatory behaviors become familiar. The DA as a sensory error signal hypothesis predicts that phasic firing of DA neurons will decrease with repeated exposure, resulting in decreased activation. Both theories therefore predict that repeated exposure will lead to a decrease in measured operant level responding (snout-poking). In Phase 2, the effects of the stimulant drugs nicotine (NIC) and methamphetamine (METH) on HR are measured. The DA as a sensory error signal hypothesis predicts that stimulant drugs such as NIC and METH which artificially increase DA neurotransmission will disrupt (decrease) expression of normally occurring habituation. In Phase 3, the effects on HR of making a novel sensory stimulus contingent upon snout poking are tested. Memory-based theories of habituation predict that introduction of a novel response-contingent sensory stimulus will decrease the rate of habituation. In addition, the DA as a sensory error signal hypothesis predicts that introduction of a novel stimulus will increase DA neurotransmission and increase activation. The apparatus and procedures used in this experiment have previously been found to reliably produce light reinforced responding (Gancarz, Ashrafioun, et al., 2012; Gancarz, Robble, Kausch, Lloyd, & Richards, 2012, 2013; Lloyd, Gancarz, et al., 2012; Lloyd, Kausch, Gancarz, Beyley, & Richards, 2012). We selected 0.75 mg/kg METH for this experiment because it was within the range of known effective doses (Gancarz, Ashrafioun, et al., 2012), and we selected the NIC dose of 0.4 mg/kg because this dose was found to effectively increase light reinforced responding (Palmatier et al., 2007).

© 2016, Springer-Verlag Berlin Heidelberg. Rationale: Disorders of behavioral regulation, including attention deficit hyperactivity disorder (ADHD) and drug addiction, are in part due to poor inhibitory control, attentional deficits, and hyper-responsivity to reward-associated cues. Objectives: To determine whether these traits are related, we tested genetically variable male and female heterogeneous stock rats in the choice reaction time (CRT) task and Pavlovian conditioned approach (PavCA). Sex differences in the response to methylphenidate during the CRT were also assessed. Methods: In the CRT task, rats were required to withhold responding until one of two lights indicated whether responses into a left or right port would be reinforced with water. Reaction time on correct trials and premature responses were the operational definitions of attention and response inhibition, respectively. Rats were also pretreated with oral methylphenidate (0, 2, 4 mg/kg) during the CRT task to determine whether this drug would improve performance. Subsequently, during PavCA, presentation of an illuminated lever predicted the delivery of a food pellet into a food-cup. Lever-directed approach (sign-tracking) and food-cup approach (goal-tracking) were the primary measures, and rats were categorized as “sign-trackers” and “goal-trackers” using an index based on these measures. Results: Sign-trackers made more premature responses than goal-trackers but showed no differences in reaction time. There were sex differences in both tasks, with females having higher sign-tracking, completing more CRT trials, and making more premature responses after methylphenidate administration. Conclusions: These results indicate that response inhibition is related to reward-cue responsivity, suggesting that these traits are influenced by common genetic factors.

Rationale Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT2A receptors, with serotonergic receptors of the 5-HT1A and 5-HT2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT2A receptor density is decreased and, at a functional level, the head-twitch response following the administration of DOI, an index of activation of 5-HT2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter. Objective Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice. Methods SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle. Results The visual stimulus exerted control in both genotypes. LSD-induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital-induced stimulus control in 80% of WT mice and 54% of knockout mice. Conclusions Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT1A and/or 5-HT2A receptors underlies the absence of stimulus control by LSD.

In humans, prepulse inhibition (PPI) of startle is greater during attended prestimuli than it is during ignored prestimuli, whereas in rats, most work has focused on passive PPI, which does not require attention. In the work described in this article, researchers developed a paradigm to assess attentional modification of PPI in rats using motivationally salient prepulses. Water-deprived rats were either conditioned to attend to a conditioned stimulus (CS; 1-s, 7-dB increase in white noise) paired with water (CS(+) group), or they received uncorrelated presentations of white noise and water (CS0 group). After 10 conditioning sessions, startle probes (50 ms, 115 dB) were introduced, with the CS serving as a continuous prepulse. Three experiments examined PPI across a range of prepulse intensities (4-10 dB) and stimulus onset asynchronies (SOAs; 30-960 ms). PPI was consistently reduced in the CS(+) group, particularly with a 10-dB prepulse and a 60-ms SOA. Thus, PPI in rats differed between attended and ignored prestimuli, but the effect was reversed in the results of research with humans. A fourth study eliminated the group difference by reversing the CS-water contingency. Methodological and motivational hypotheses regarding the current findings are discussed.

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.

Behavioral and neuronal abnormalities observed in mice exhibiting a reduced expression of the dopamine transporter model important aspects of schizophrenia, addiction, and attentional disorders. As the consequences of a chronic hyperdopaminergic tone for striatal output regulation have remained poorly understood, the present experiments were designed to determine the status of striatal interneuronal cholinergic neurotransmission in dopamine transporter knockdown animals. The high-affinity choline transporter represents the rate-limiting step of acetylcholine synthesis and release. Compared with wild type mice, striatal high-affinity choline transporter expression in dopamine transporter knockdown mice was significantly decreased. As in vivo basal striatal acetylcholine release did not differ between the strains, reduced high-affinity choline transporter expression in dopamine transporter knockdown mice was not due to reduced basal cholinergic activity. Furthermore, the proportion of high-affinity choline transporters expressed in plasma membrane-enriched versus vesicular membrane-enriched fractions did not differ from wild type animals, suggesting that changes in intracellular high-affinity choline transporter trafficking were not associated with lower overall levels of striatal high-affinity choline transporters. Synaptosomal choline uptake assays indicated a reduced capacity of striatal high-affinity choline transporters in dopamine transporter knockdown mice, and thus the functional significance of the reduced level of high-affinity choline transporter expression. Likewise, in vivo measures of the capacity of striatal high-affinity choline transporters to clear increases in extracellular choline concentrations, using choline-sensitive microelectrodes, revealed a 37-41% reduction in hemicholinium-sensitive clearance of exogenous choline in dopamine transporter knockdown mice. Furthermore, clearance of potassium-evoked choline signals was reduced in dopamine transporter knockdown mice (1.63+/-0.15 microM/s) compared with wild type animals (2.29+/-0.21 microM/s). Dysregulated striatal cholinergic neurotransmission is hypothesized to disrupt the integration of thalamic and cortical information at spiny projection neurons and thus to contribute to abnormal striatal information processing in dopamine transporter knockdown mice.

Children with fetal alcohol spectrum disorder (FASD) are often diagnosed with attention-deficit/ hyperactivity disorder (ADHD). These children show increases in reaction time (RT) variability and false alarms on choice reaction time (CRT) tasks. In this study, adult rats prenatally exposed to ethanol were trained to perform a CRT task. An analysis of the distribution of RTs obtained from the CRT task found that rats with a history of prenatal ethanol exposure had more variable RT distributions, possibly because of lapses of attention. In addition, it was found that, similar to children with FASD, the ethanol-exposed rats had more false alarms. Thus, rats with prenatal ethanol exposure show attention deficits that are similar to those of children with FASD and ADHD.

It has been reported that human opiate addicts discount delayed rewards more than non-addicts, indicating that they are more impulsive. However, it is not clear whether this difference reflects pre-existing traits, or the effects of exposure to the opiates. This study was designed to investigate the effects of an opioid agonist and antagonist on delay discounting in rats. The study had three objectives: to determine (1) the acute effects of the opioid agonist morphine (MOR) on delay discounting, (2) the acute effects of the opioid antagonist naltrexone (NAL) on delay discounting, and (3) whether NAL reverses the effects of MOR on delay discounting. An adjusting amount procedure (AdjAmt) was used to determine how much animals discounted the value of delayed rewards. Acute doses of MOR (0.3, 1.0, and 1.8 mg/kg SC), NAL (0.01, 0.1, 1.0, and 10 mg/kg SC) and NAL (0.1 mg/kg SC) prior to MOR (1.8 mg/kg SC) were tested in 15 rats. MOR dose dependently increased the rate of delay discounting (i.e., made the animals more impulsive). NAL alone had no effect on the value of delayed rewards, but NAL blocked the effects of MOR. These results suggested that the direct effects of MOR may contribute to the high level of impulsive behavior seen among opiate users.

Rationale: Moderate doses of d-amphetamine (given both acutely and chronically) have been shown to decrease impulsivity in children with attention deficit hyperactivity disorder (ADHD) and to improve attention and learning in normal adults. In contrast, chronic doses of methamphetamine (METH) in drug abusers have been associated with increased impulsivity, and impairments in learning and attention. Objectives: We report the effects of METH on an animal model of impulsive behavior. Methods: Rats were tested using the adjusting amount (AdjAmt) procedure in which the animals choose between a delayed fixed (large) amount of water and an immediate adjusting (small) amount of water. In the acute METH study, rats were given a single dose of 0.5, 1.0, 2.0, and 4.0 mg/kg METH or saline 30 min before testing. In the chronic METH study, we determined the effects of the 4.0 mg/kg dose of METH injected chronically 1 h after behavioral testing for 14 days. Thus the rats were tested using the AdjAmt procedure 22 h after injections of METH or saline. Results: After 0.5, 1.0 and 2.0 mg/kg METH, the rats valued the delayed large rewards more than after saline, indicating that the METH decreased impulsiveness. At the 4.0 mg/kg dose, the rats failed to respond. Rats treated repeatedly with the post-session large behaviorally disruptive dose of METH valued the delayed large rewards less than the saline-treated rats, indicating that this dosing regimen of METH increased impulsiveness. Conclusions: In these experiments, the rats became less impulsive after acute non-disruptive doses of pre-session METH, whereas they became more impulsive after receiving repeated post-session injections of a dose that was behaviorally disruptive when administered acutely.

Background: The functioning of the brain serotonin system has been implicated in the action of antidepressant drugs. The behavior of rats performing the Differential Reinforcement of Low Rate–72 sec (DRL 72s) has been used as a screen for drugs with antidepressant activity. Many antidepressant drugs alter serotonergic function. Hence, experiments were designed to investigate the role of the brain serotonin system in the performance of DRL 72s behavior. Methods: Rats were trained to perform a DRL 72s, and then depleted (LESION) of brain serotonin (5-HT) using intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT). Control rats (SHAM) were injected with the 5,7-DHT vehicle. Results: The 5,7-DHT-treated rats showed a higher response rate, a decrease in the number of reinforcements, and a shift in the interresponse time (IRT) distribution toward shorter IRTs when compared to SHAM and prelesion performance. The behavioral deficit in the 5,7-DHT rats persisted for 17 weeks. Postmortem assays indicated extensive depletion of 5-HT in all the assayed brain regions of the LESION rats. The effects of the serotonergic agonists 8-hydroxy-2-di-N-propylaminotetralin (8-OH-DPAT), 5-methoxy-dimethyltryptamine (5-MeODMT), buspirone, and 5-hydroxytryptophan (5-HTP) were assessed. 5-MeODMT and 8-OH-DPAT resulted in greater improvement of DRL 72s performance in the LESION rats than in the SHAM rats. Buspirone failed to ameliorate the behavioral deficit in the LESION rats and produced a behavioral deficit in the SHAM rats. 5-HTP improved performance in the SHAM rats and in the LESION rats. Conclusions: These results support the contention that the brain 5-HT system is involved in the mediation of antidepressant drug effects.

BIMT 17, the only compound reported to be a full 5-HT1A agonist and a 5-HT2A antagonist at the frontal cortex, was assessed in three animal paradigms sensitive to antidepressants in rats: olfactory bulbectomy (OB), differential-reinforcement-of-low rate 72-s (DRL 72-s) and learned helplessness (LH). In the OB rats, BIMT 17, given once daily for 14 consecutive days at an i.p. dose of 10 mg/kg, but not of 20 mg/kg, reduced the increase in ambulation of OB rats, 24 h after the last administration. In the DRL 72-s test, BIMT 17 had a different profile than imipramine. A single i.p. injection of 5, 10, 15 or 20 mg/kg BIMT 17, in contrast to the same doses of imipramine, did not affect response and reinforcement rate in DRL 72-s 1 h after the administration. On the other hand, BIMT 17 slightly shifted the peak of the interresponse time (IRT) distribution towards shorter IRT duration, while imipramine shifted the peak of the IRT distribution towards longer IRT duration. In the LH test, acute oral doses (36, 48 or 60 mg/kg) of BIMT 17, given 30 min before testing, reduced the number of escape failures in LH without altering the intertrial crossings. This effect was also induced by a repeated, but not single, administration with 8 or 16 mg/kg imipramine. The plasma levels following i.p. 10 or oral 48 mg/kg BIMT 17 were in the same range. These results indicate that BIMT 17 does not behave like imipramine in all the tests, and suggest that BIMT 17 acts through different mechanisms of action than imipramine. Only clinical trials will tell whether these mechanisms will be relevant, but if so, BIMT 17 might induce a faster onset of therapeutic activity.

Due in part to their rich behavioral repertoire rats have been widely used in behavioral studies of drug abuse-related traits for decades. However, the mouse became the model of choice for researchers exploring the genetic underpinnings of addiction after the first mouse study was published demonstrating the capability of engineering the mouse genome through embryonic stem cell technology. The sequencing of the mouse genome and more recent re-sequencing of numerous inbred mouse strains have further cemented the status of mice as the premier mammalian organism for genetic studies. As a result, many of the behavioral paradigms initially developed and optimized for rats have been adapted to mice. However, numerous complex and interesting drug abuse-related behaviors that can be studied in rats are very difficult or impossible to adapt for use in mice, impeding the genetic dissection of those traits. Now, technological advances have removed many of the historical limitations of genetic studies in rats. For instance, the rat genome has been sequenced and many inbred rat strains are now being re-sequenced and outbred rat stocks are being used to fine-map QTLs. In addition, it is now possible to create "knockout" rats using zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs) and related techniques. Thus, rats can now be used to perform quantitative genetic studies of sophisticated behaviors that have been difficult or impossible to study in mice. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

UNLABELLEDPyruvate dehydrogenase (PDH) complex (PDC) deficiency is an inborn error of pyruvate metabolism causing a variety of neurologic manifestations. Systematic analyses of development of affected brain structures and the cellular processes responsible for their impairment have not been performed due to the lack of an animal model for PDC deficiency.METHODSIn the present study we investigated a murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene encoding the α subunit of PDH to study its role on brain development and behavioral studies.RESULTSMale embryos died prenatally but heterozygous females were born. PDC activity was reduced in the brain and other tissues in female progeny compared to age-matched control females. Immunohistochemical analysis of several brain regions showed that approximately 40% of cells were PDH(-). The oxidation of glucose to CO2 and incorporation of glucose-carbon into fatty acids were reduced in brain slices from 15 day-old PDC-deficient females. Histological analyses showed alterations in several structures in white and gray matters in 35 day-old PDC-deficient females. Reduction in total cell number and reduced dendritic arbors in Purkinje neurons were observed in PDC-deficient females. Furthermore, cell proliferation, migration and differentiation into neurons by newly generated cells were reduced in the affected females during pre- and postnatal periods. PDC-deficient mice had normal locomotor activity in a novel environment but displayed decreased startle responses to loud noises and there was evidence of abnormal pre-pulse inhibition of the startle reflex.CONCLUSIONSThe results show that a reduction in glucose metabolism resulting in deficit in energy production and fatty acid biosynthesis impairs cellular differentiation and brain development in PDC-deficient mice.

The ability of locomotor activity in a novel environment (Loco) and visual stimulus reinforcement (VSR) to predict acquisition of responding for cocaine and water reinforcers in the absence of explicit audiovisual signals was evaluated.In Experiment 1 (Exp 1), rats (n = 60) were tested for VSR, followed by Loco, and finally acquisition of responding for cocaine (0.3 mg/kg/inf). In Experiment 2 (Exp 2), rats (n = 32) were tested for VSR, followed by Loco, and finally acquisition of responding for water (0.01 mL/reinforcer).There were three main findings. First, Loco and VSR were significantly associated (Exp 1: r = 0.49, p 0.00; Exp 2: r = 0.35, p 0.05). Second, neither Loco (r = .00, p = 0.998) nor VSR (r = -0.12, p = 0.352) predicted acquisition of cocaine SA. Third, in the subgroup of animals that acquired cocaine SA, VSR (r = 0.41, p 0.01) but not Loco (r = 0.28, p = 0.10) was positively associated with operant responding for cocaine. Both Loco and VSR (Loco: r = 0.37, p 0.04; VSR: r = 0.51, p 0.00) were positively associated with operant responding for water reinforcers.The results indicate that VSR is at least as good a predictor of cocaine reinforced responding as Loco. VSR was predictive of operant responding for both drug and water reinforcers, while Loco was found to be predictive of responding only for water reinforcers. In studies that present visual stimuli in association with drug delivery, Loco may be predicting acquisition of responding for VSR rather than drug.

Background Light onset can be both a sensory reinforcer (SR) with intrinsic reinforcing properties, and a conditioned reinforcer (CR) which predicts a biologically important reinforcer. Stimulant drugs, such as methamphetamine (METH), may increase the reinforcing effectiveness of CRs by enhancing the predictive properties of the CR. In contrast, METH-induced increases in the reinforcing effectiveness of SRs, are mediated by the immediate sensory consequences of the light. Methods The effects of novelty (on SRs) and METH (on both CRs and SRs) were tested. Experiment 1: rats were pre-exposed to 5 s light and water pairings presented according to a variable-time (VT) 2 min schedule or unpaired water and light presented according to independent, concurrent VT 2 min schedules. Experiment 2: rats were pre-exposed to 5 s light presented according to a VT 2 min schedule, or no stimuli. In both experiments, the pre-exposure phase was followed by a test phase in which 5 s light onset was made response-contingent on a variable-interval (VI) 2 min schedule and the effects of METH (0.5 mg/kg) were determined. Results Novel light onset was a more effective reinforcer than familiar light onset. METH increased the absolute rate of responding without increasing the relative frequency of responding for both CRs and SRs. Conclusion Novelty plays a role in determining the reinforcing effectiveness of SRs. The results are consistent with the interpretation that METH-induced increases in reinforcer effectiveness of CRs and SRs may be mediated by immediate sensory consequences, rather than prediction.

The term “sensory reinforcer” has been used to refer to sensory stimuli (e.g. light onset) that are primary reinforcers in order to differentiate them from other more biologically important primary reinforcers (e.g. food and water). Acquisition of snout poke responding for a visual stimulus (5 s light onset) with fixed ratio 1 (FR 1), variable-interval 1 min (VI 1 min), or variable-interval 6 min (VI 6 min) schedules of reinforcement was tested in three groups of rats ( n = 8/group). The VI 6 min schedule of reinforcement produced a higher response rate than the FR 1 or VI 1 min schedules of visual stimulus reinforcement. One explanation for greater responding on the VI 6 min schedule relative to the FR 1 and VI 1 min schedules is that the reinforcing effectiveness of light onset habituated more rapidly in the FR 1 and VI 1 min groups as compared to the VI 6 min group. The inverse relationship between response rate and the rate of visual stimulus reinforcement is opposite to results from studies with biologically important reinforcers which indicate a positive relationship between response and reinforcement rate. Rapid habituation of reinforcing effectiveness may be a fundamental characteristic of sensory reinforcers that differentiates them from biologically important reinforcers, which are required to maintain homeostatic balance.

The human personality trait of sensation seeking (SS) indicates an attraction to novel sensations and experiences, and is associated with greater likelihood of drug abuse. In rodents, locomotor activity in a novel environment (Loco) has been found to predict drug self-administration (SA), and has been hypothesized to be a translational model of human SS. Previously, we reported (Gancarz et al., 2011) that high responder (HR) animals responded more than low responder (LR) animals to produce a response contingent light onset. The primary goal of this paper was a detailed analysis of the association between Loco and light contingent responding in a large sample of rats (n = 93).Male rats were pre-exposed to dark operant test chambers for ten 30 min sessions and baseline levels of responding (snout poking) were determined. The pre-exposure phase was followed by 6 sessions during which active responding produced a visual sensory reinforcer (VSR; 5 s light onset) according to a variable interval 1 min schedule of reinforcement. After completion of the VSR phase, Loco was tested.The activating effects (total responding) of light were associated with Loco, but the response guiding effects (proportion of active responding) of the light were not. In addition, HR rats habituated more slowly in both the VSR and Loco tests than LR rats.These data indicate that VSR measures aspects of the rodent’s response to novel sensations and experiences that are not detected by Loco. These data provide some evidence for the use of light reinforcement as an animal model of SS.

The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5-HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT1A compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT1A compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT1A receptor.

A between-session progressive ratio (BtwPR) procedure was tested in rats responding for cocaine and water reinforcers.Experiment 1 evaluated the sensitivity of the BtwPR procedure to the magnitude of cocaine and water reinforcers. Experiment 2 compared BtwPR performance to within-session progressive ratio (WinPR) performance.In experiment 1, rats were tested on a BtwPR procedure with three doses of cocaine (0.1, 0.3, and 1.0 mg/kg/inf) or volumes of water (0.01, 0.03, and 0.1 mL/reinforcer). BtwPR test sessions began with a seeking phase, during which the animal is required to complete a fixed ratio in order to initiate a 2-h consumption phase, where the reinforcer was available according to a fixed ratio 1 (FR1) schedule. Failure to complete the seeking ratio, which was increased after each test session, determined the breakpoint (BP). In experiment 2, the same BtwPR procedure was used except that the consumption phase was a WinPR schedule of reinforcement for cocaine (1.0 mg/kg/inf) or water (0.1 mL) reinforcers.BtwPR BPs increased as a function of the magnitude of both cocaine and water reinforcers. The BtwPR produced smaller BPs than the WinPR for cocaine reinforcers. In contrast, the BtwPR produced larger BPs than the WinPR for water reinforcers. One possible explanation is that priming and response activating effects of the cocaine reinforcer increased the WinPR BP. BtwPR and WinPR procedures may measure different aspects of drug-seeking.

Rats were treated with a high-dose methamphetamine (METH) regimen (50 mg/kg 3 times at 8-h intervals). Three weeks after treatment, they were trained on a reaction-time task. METH-treated rats failed to improve over a 3-month test period, while controls demonstrated a gradual increase in reaction-time speed over the same test period. METH treatment resulted in a significant dopamine depletions in the caudate/putamen and nucleus accumbens/olfactory tubercle; significant serotonin depletions in caudate/putamen, nucleus accumbens/olfactory tubercle, somatosensory cortex, amygdala and hippocampus. In contrast to the decreases observed in other brain regions, serotonin levels were significantly greater than controls in the hypothalamus. It is suggested that the behavioral impairment in the METH-treated animals is due to (a) serotonin and/or dopamine depletions or (b) abnormal or hyper-innervation of serotonin to the hypothalamus.

The beta adrenergic (beta) agonist salbutamol increased reinforcement rates and decreased response rates on a differential-reinforcement-of-low-rate (DRL) 72-S schedule. These changes in DRL 72-S schedule performance are also produced by most clinically used antidepressants. The effects of salbutamol on a DRL 72-S schedule were dose-dependently antagonized by the beta antagonist metoprolol, but not changed by the 5HT antagonist methysergide. Additionally, neither salbutamol nor the antagonism of salbutamol by metoprolol caused disruption of DRL 72-S schedule performance. These results indicate that stimulation of beta receptors, and not of 5HT receptors, mediates salbutamol antidepressant-like effects on a DRL 72-S schedule.

Rats with hippocampal dialysis probes were treated with DL-fenfluramine (FEN), fluoxetine, or FEN with fluoxetine pre-treatment. FEN (12.5 mg/kg) increased extracellular serotonin (5-HT) from 0.4 +/- 0.04 to 25.2 +/- 4.16 pg/10 microliters. Fluoxetine (10.0 mg/kg) increased extracellular 5-HT levels from 0.4 +/- 0.05 to 2.4 +/- 0.33 pg/10 microliters. FEN-induced increases in extracellular 5-HT were attenuated by 66% with fluoxetine pre-treatment. This result supports the view that the 5-HT releasing properties of FEN are mediated by the 5-HT uptake transporter.

Rats were administered 8 injections of 12.5 mg/kg fenfluramine over a 4-day period. Extracellular hippocampal serotonin levels were monitored in vivo during the 4-day treatment period. Predrug baseline serotonin levels were 0.6 +/- 0.17 pg/5 microliters; 60 min after the first fenfluramine injection extracellular serotonin levels were increased to 28.06 +/- 5.2 pg/5 microliters. Fenfluramine-induced increases in serotonin were substantially reduced on the 2nd through 4th days of the regimen. Baseline serotonin levels were increased on days 2 through 4 of the treatment regimen. In a separate group of animals post-mortem tissue concentrations of serotonin were measured 2 weeks after 1,2,4, or 8 injections of 12.5 mg/kg fenfluramine. There were decreases in serotonin tissue concentrations which were related to the number of fenfluramine injections administered. The in vivo dialysis and post-mortem tissue assay results are consistent with the view that fenfluramine is neurotoxic.

We describe an interresponse-time analysis of performance on a differential-reinforcement-of-low-rate 72-s schedule. This analysis compares the obtained interresponse-time distribution of individual rats to a corresponding random interresponse-time distribution. The random interresponse-time distribution is a negative exponential probability function; it predicts the relative distribution of interresponse times if the rat emitted the same number of responses randomly (i.e., with a constant probability) with respect to time. The analysis provides quantitative measures of peak location and dispersion of the interresponse times toward random performance. In Experiment 1, an unexpected outcome of this analysis was that the rats would have obtained more reinforcers had they responded at the same rate but randomly. Based on the interresponse-time analysis in Experiment 1, it was shown that rats trained on the differential-reinforcement-of-low-rate 72-s schedule could increase the number of reinforcers obtained in two ways: first, by a coherent shift of the interresponse-time distribution toward longer durations and, second, by dispersal of the interresponse times toward a random interresponse-time distribution. Experiment 2 applied the analysis described in Experiment 1 to the effects of desipramine and gepirone. Both drugs decreased response rate and increased reinforcement rate, but their effects on the distribution of interresponse times were different. The increase in reinforcement rate observed with desipramine was accompanied by a coherent shift of the reinforcement rate observed with gepirone was accompanied by dispersal of the interresponse-time distribution toward the random negative exponential prediction.

Rats trained to turn in circles have been used by a number of investigators to study brain dopamine metabolism. We report the results of a behavioral analysis of conditioned rotation and describe the apparatus used in our laboratory to train rats and monitor their performance. A novel discrimination procedure was used which required each rat to turn left in one training chamber with one set of stimulus conditions and right in a different chamber. Water-deprived animals were trained to circle for a water reward. Initial acquisition of this task required 11 days of training. At the end of acquisition, a discrimination test indicated that turning in the left and right directions was under stimulus control of the chamber environment. We found that trained turning had a highly stereotyped temporal organization with a rapid movement component during which the rat executed the turn, and a longer pause time component during which the rat consumed the water reinforcer.

Rats were trained to rotate for a water reward using a procedure which required each rat to turn in both the left and right directions. The rats were then lesioned with unilateral injections of 6-hydroxydopamine in the nigrostriatal bundle to produce unilateral dopamine depletion. Rats which had greater than 95% depletion had significant deficits in turning both ipsilateral and contralateral to the depleted side. Circling contralateral to the lesion was more impaired than circling ipsilateral to the lesion. All animals showed deficits in both the initiation of movement and in speed of turning. In addition, the rats displayed a chronic turning bias in the ipsilateral direction 16 weeks postlesion. These results indicate that unilateral dopamine depletion causes a variety of impairments in trained circling behavior. Although contralateral circling is most impaired, there is a significant decrease in ipsilateral performance. We conclude that normal conditioned circling behavior requires bilateral dopamine innervation.

In vivo dialysis was used to measure extracellular fluid concentrations of dopamine and dihydroxyphenylacetic acid (DOPAC) in rats which were trained to run on a circular disk treadmill for water reinforcement. Turning resulted in bilateral increases in DOPAC in lateral striatum as well as nucleus accumbens/medial striatum. Dopamine release showed small but not significant increases at both sides. Changes in DOPAC release were not lateralized. Free drinking without circling also resulted in significant increases in DOPAC in these two brain areas. During free drinking, dopamine release was significantly increased in lateral striatum but not in nucleus accumbens/medial striatum. These experiments indicate that dopamine metabolism is increased in rat striatum and nucleus accumbens in animals running on circular treadmills as well as by free drinking.

Both humans and non-humans discount the value of rewards that are delayed or uncertain, and individuals that discount delayed rewards at a relatively high rate are considered impulsive. To investigate the neural mechanisms that mediate delay discounting, the present study examined the effects of excitotoxic lesions of the nucleus accumbens (NAC) on discounting of reward value by delay and probability. Rats were trained on delay ( n = 24) or probability discounting ( n = 24) tasks. Following training, excitotoxic lesions of the NAC were made by intracranial injections of 0.5 μl 0.15 M quinolinic acid ( n = 12) or vehicle ( n = 12) aimed at the NAC (AP +1.6, ML ±1.5, DV −7.1). NAC lesions did not alter performance in animals tested with a constant delay (4 s) or probability (0.4) of reinforcement. However, when tested with between session changes in the delay (0, 1, 2, 4, and 8 s) of reinforcement, the lesioned rats had flatter discount curves than the sham group, indicating that they were less sensitive to frequent changes in the delay to reward. In contrast, the NAC lesions did not affect discounting of probabilistic rewards. NAC lesions impaired the ability to adapt to frequent between session changes in the delay to reward but did not increase or decrease discounting when the delay was held constant across sessions. NAC lesions may disrupt the ability of the animals to predict the timing of delayed rewards when the delay to reward is changed frequently.

Experiment I investigated the effects of reinforcer magnitude on differential-reinforcement-of-low-rate (DRL) schedule performance in three phases. In Phase 1, two groups of rats (n = 6 and 5) responded under a DRI. 72-s schedule with reinforcer magnitudes of either 30 or 300 microl of water. After acquisition, the water amounts were reversed for each rat. In Phase 2, the effects of the same reinforcer magnitudes on DRL 18-s schedule performance were examined across conditions. In Phase 3, each rat responded unider a DR1. 18-s schedule in which the water amotnts alternated between 30 and 300 microl daily. Throughout each phase of Experiment 1, the larger reinforcer magnitude resulted in higher response rates and lower reinforcement rates. The peak of the interresponse-time distributions was at a lower value tinder the larger reinforcer magnitude. In Experiment 2, 3 pigeons responded under a DRL 20-s schedule in which reinforcer magnitude (1-s or 6-s access to grain) varied iron session to session. Higher response rates and lower reinforcement rates occurred tinder the longer hopper duration. These results demonstrate that larger reinforcer magnitudes engender less efficient DRL schedule performance in both rats and pigeons, and when reinforcer magnitude was held constant between sessions or was varied daily. The present results are consistent with previous research demonstrating a decrease in efficiency as a function of increased reinforcer magnituide tinder procedures that require a period of time without a specified response. These findings also support the claim that DRI. schedule performance is not governed solely by a timing process.

This study was designed to develop a version of the stop task, a putative measure of behavioral inhibition, for use in rats and to assess the effects of d-amphetamine (AMP) and alcohol (ALC). The stop task provides a quantitative index of the ability to inhibit a response that has been initiated. Rats (N = 11) were tested after intraperitoneal injections of AMP (0.125, 0.25, 0.5, 1.0 mg/kg) and ALC (250, 500, 750 mg/kg). AMP improved the ability to inhibit responses only in rats with relatively poor inhibitory performance at baseline. ALC impaired inhibition at doses that did not affect simple reaction time. The results support the sensitivity, reliability, and validity of the procedure as a measure of behavioral inhibition in rats and are highly concordant with a parallel study conducted with humans.

Rationale: Impulsive individuals exhibit an exaggerated preference for immediate rewards over delayed but larger rewards, perhaps because they value the delayed rewards less. Dopamine (DA) has been postulated to mediate the incentive value of rewards, thus it may also mediate the exaggerated preference for immediate rewards in impulsive individuals. In this paper, we investigate the effects of DA agonists and antagonists on the value of delayed versus immediate rewards. Objectives: The study had three main objectives: (1) to determine the effects of D1 and D2 type DA antagonists on the value of delayed rewards, (2) to determine the effect of the indirect DA agonist d-amphetamine on the value of delayed rewards, (3) to determine the sensitivity of the adjusting amount (AdjAmt) procedure to acute one-day changes in delay to reward, amount of reward, deprivation level and starting amount. Methods: In the AdjAmt procedure, rats choose between an adjusting amount of water given immediately (adjusting alternative) and a constant 150 µl water delayed by 4 s (standard alternative). The immediate amount of water is adjusted across trials until the rat chooses both alternatives with equal frequency (indifference point). The final adjusted amount is an indicator of the subjective value of the standard alternative. Results: The D1/D2 antagonist flupenthixol (25, 50, and 100 μg/kg) and the D2 antagonist raclopride (40, 80, and 120 μg/kg), decreased the indifference points, whereas the D1 antagonist SCH 23390 (5, 10, and 20 μg/kg) did not affect the indifference point. All three DA antagonists slowed responding. The indirect DA agonist amphetamine (0.5, and 1.0 mg/kg) had effects opposite to those of the DA antagonists, it decreased choice latency, increased the number of trials completed and increased the indifference point. Decreasing the water deprivation level (6, 24, and 48 h) had no effect on the indifference points but slowed responding. Increasing the delay to reward (2, 4, and 8 s) and decreasing the amount of water available for choosing the standard alternative (300, 150, 75 µl) decreased the indifference point. Conclusions: The results indicate that amphetamine increased the value of delayed rewards (decreased impulsivity) and that D2 but not D1 receptor antagonists decreased the value of delayed rewards (increased impulsivity). The procedure was sensitive to acute 1-day changes in delay and magnitude of reward.

An adjusting-amount procedure was used to measure discounting of reinforcer value by delay. Eight rats chose between a varying amount of immediate water and a fixed amount of water given after a delay. The amount of immediate water was systematically adjusted as a function of the rats' previous choices. This procedure was used to determine the indifference point at which each rat chose the immediate amount and the delayed amount with equal frequency. The amount of immediate water at this indifference point was used to estimate the value of the delayed amount of water. In Experiment 1, the effects of daily changes in the delay to the fixed reinforcer (100 microliters of water delivered after 0, 2, 4, 8, or 16 s) were tested. Under these conditions, the rats reached indifference points within the first 30 trials of each 60-trial session. In Experiment 2, the effects of water deprivation level on discounting of value by delay were assessed. Altering water deprivation level affected the speed of responding but did not affect delay discounting. In Experiment 3, the effects of varying the magnitude of the delayed water (100, 150, and 200 microliters) were tested. There was some tendency for the discounting function to be steeper for larger than for smaller reinforcers, although this difference did not reach statistical significance. In all three experiments, the obtained discount functions were well described by a hyperbolic function. These experiments demonstrate that the adjusting-amount procedure provides a useful tool for measuring the discounting of reinforcer value by delay.

Amphetamine and related compounds have previously been shown to differentially release dopamine (DA) and serotonin (5HT) in vivo and in vitro. The purpose of this report is directly to compare five amphetamine analogs on differential reinforcement of low rate 36-s (DRL 36-s) schedule performance, and to determine whether the reported increases in dopamine and/or serotonin release induced by these drugs can be related to observed behavioral differences. Amphetamine (AMPH) and methamphetamine (METH) induced large increases in response rate, methylene-dioxymethamphetamine (MDMA) and para-chloroamphetamine (PCA) caused small increases in response rate, while fenfluramine (FEN) had no effect on response rate. AMPH, METH, PCA and MDMA caused a dose-dependent decrease in reinforcement rate, and FEN had no effect on reinforcement rate. AMPH, METH, and PCA but not FEN, shifted the peak of the inter-response time (IRT) distribution toward shorter intervals, MDMA decreased peak location only at the highest dose. All five drugs caused a dose-dependent decrease in peak area, indicating a loss of schedule control on the DRL 36-s schedule. Consistent with in vitro and in vivo release studies, the differential results of these five drugs on DRL 36-s schedule performance suggest a predominant dopamine role for AMPH and METH, a predominant serotonin role for FEN, and different degrees of combined dopaminergic and serotonergic roles for MDMA and PCA in the mediation of the task.

Peak deviation analysis is a quantitative technique for characterizing interresponse-time distributions that result from training on differential-reinforcement-of-low-rate schedules of reinforcement. It compares each rat's obtained interresponse-time distribution to the corresponding negative exponential distribution that would have occurred if the rat had emitted the same number of responses randomly in time, at the same rate. The comparison of the obtained distributions with corresponding negative exponential distributions provides the basis for computing three standardized metrics (burst ratio, peak location, and peak area) that quantitatively characterize the profile of the obtained interresponse-time distributions. In Experiment 1 peak deviation analysis quantitatively described the difference between the interresponse-time distributions of rats trained on variable-interval 300-s and differential-reinforcement-of-low-rate 72-s schedules of reinforcement. In Experiment 2 peak deviation analysis differentiated between the effects of the psychomotor stimulant d-amphetamine, the anxiolytic compound chlordiazepoxide, and the antidepressant desipramine. The results suggest that peak deviation analysis of interresponse-time distributions may provide a useful behavioral assay system for characterizing the effects of drugs.

Caffeine and PD 116,600 were found to decrease the reinforcement rate and increase the response rate in rats performing under a differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule of reinforcement. In contrast, antidepressant drugs previously have been found to increase the reinforcement and decrease the response rate. Caffeine has been found to test similar to antidepressant drugs on at least one other behavioral screen, but caffeine does not possess clinical antidepressant properties. These results provide further support for the DRL 72-s schedule as a behavioral screen for antidepressant drugs.

Rats were trained to turn for water reinforcement and then were given unilateral 6- hydroxydopamine lesions. After lesion, rats showed deficits in trained turning both contraand ipsilateral to the side of the lesion, with contralateral turning more severely impaired. The lesioned rats were then transplanted with fetal mesencephalic dopamine tissue into striatum. A control group of lesioned rats were sham transplanted. Four weeks after transplant, 1.5 mg/kg D-amphetamine challenge injections were used to test the functioning of the transplants. In the control rats, D-amphetamine induced ipsilateral turning; in transplanted rats, D-amphetamine slowed the rate of ipsilateral turning or reversed the direction of amphetamine-induced rotation. Only rats which reversed their, amphetamine-induced turn direction after transplant were used for the rest of the experiment. Trained turning was assessed at 4, 8, 12 and 16 weeks post transplant. Transplants did not improve learned performance at any time post transplant. When D-amphetamine was administered in conjunction with the trained turning sessions, a low dose (0.12 mg/kg) enhanced contralateral trained turn rates, without affecting ipsilateral turn rates. Higher doses of amphetamine reduced ipsilateral turn rate in the transplanted animals. The results of this study suggest that transplants alone do not reinstate performance of conditioned rotation.

The non-competitiveN-methyl- d -aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain. dl -Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.

Advances in technology and decreasing costs are enabling microcomputers to displace more traditional devices in the scientific laboratory. The availability of various approaches to software-system development for the use of microcomputers in the on-line control of experiments has contributed to the trend. This report describes a software system developed to control conditioned behavior during schedules of reinforcement while simultaneously accumulating behavioral data and physiological (analog) data using a hardware system base on the Radio Shack TRS-80 Model I microcomputer. The software utilizes a high-level interpretive language (Microsoft BASIC), assembly language and compiled BASIC to attain an acceptable execution speed and ease of programming.