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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.

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.

Introduction: Multiple factors contribute to the etiology of addiction, including genetics, sex, and a number of addiction-related behavioral traits. For example, individuals that are predisposed to assign incentive salience to food stimuli ("sign-trackers", ST), are not only more impulsive compared to those that do not ("goal-trackers", GT), but are also more sensitive to drugs and drug stimuli as well. 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. 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. 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: 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. In the female STs, attention, as measured by omissions in the reaction time test revealed notable microbiome correlations. In both males and females, many measures were correlated with bacterial family Ruminocococcaceae and Lachnospiraceae. Conclusions: These data demonstrate correlations between several addiction-related behaviors and the microbiome specific to sex. Funding Statement: Funding sources: P50DA037844, 12/RC/2273. AB was supported by a fellowship from the Wellcome Trust (105941/Z/14/Z). Declaration of Interests: JFC & TGD are in receipt of research funding from 4D‐Pharma, Mead Johnson, Suntory Wellness, Nutricia, and Cremo. Timothy Dinan has been an invited speaker at meetings organized by Servier, Lundbeck, Janssen, and AstraZeneca. John Cryan has been an invited speaker at meetings organized by Mead Johnsen, Alkermes, and Janssen. Ethics Approval Statement: Animals were treated in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the experiments were conducted in accordance with a protocol approved by the Institutional Animal Care and Use Committee (IACUC) at the University at Buffalo, The State University of New York.

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 observing response procedures, participants respond to produce a stimulus (CS+) that is correlated with the occurrence of reinforcement even though there is no contingency between the observing response and reinforcement. The rate of responding to produce the CS+ is considered a measure of the conditioned reinforcement and considerable individual differences have been observed on this measure. The goal of this study was to examine individual differences in conditioned reinforcement among 36 undergraduates selected for self-reported levels of behavioral approach (BAS). The procedure involved tones as conditioned stimuli, one of which was correlated with receiving money (CS+), the other was uncorrelated with reward (CS0). Extending prior work, participants acquired differential observing for CS+ vs. CS0, and there were marked individual differences in observing behavior. Contrary to our prediction that high BAS participants would demonstrate greater conditioned reinforcement, group differences were not reliable overall. There was some evidence of more rapid acquisition of conditioned responding among high- compared to low-BAS participants. Possible reasons for the relatively modest association are discussed. The present data call attention to potential ties between the largely separate literatures of observing responses as measures of conditioned reinforcement and reinforcement-based models of personality.

Impulsivity as a behavioral construct encompasses a wide range of what are often considered maladaptive behaviors. Impulsivity has been assessed using a variety of measures, including both self-report personality questionnaires and behavioral tasks, and each of these measures has been further subdivided into separate components which are thought to represent different underlying processes. However, few studies have employed both personality measures and behavioral tasks, and so the relations among these measures are not well understood. In one analysis we examined correlations between three widely used personality measures (i.e., BIS-11, I7, and MPQ) and four laboratory-task measures of impulsive behavior (behavioral inhibition (2), delay discounting, and risk taking) in 70 healthy adult volunteers. The correlations among the various self-report measures were high, but self-reports were not correlated with behavioral-task measures. In a second analysis we performed a principal-components analysis using data from the four behavioral tasks for 99 participants. Two components emerged, labeled “impulsive disinhibition” (Stop Task and Go/No-Go task) and “impulsive decision-making” (Delay-Discounting task and Balloon Analog Risk Task). Taken collectively, these analyses support other recent findings indicating that self-report and behavioral tasks probably measure different constructs, and suggest that even among the behavioral measures, different tasks measure different, perhaps unrelated, components of impulsive 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.

Rationale Drug-induced stimulus control has proven to be a powerful tool for the assessment of a wide range of psychoactive drugs. Although a variety of species has been employed, the majority of studies have been in the rat. However, with the development of techniques which permit the genetic modification of mice, the latter species has taken on new importance. Lysergic acid diethylamide [LSD], the prototypic indoleamine hallucinogen, has not previously been trained as a discriminative stimulus in mice. Objective To demonstrate the feasibility of LSD-induced stimulus control in the mouse and to provide a preliminary characterization of the stimulus properties of LSD in that species. Methods Male C57BL/6 mice were trained using a left or right nose-poke operant on a fixed ratio 10, water reinforced task following the injection of lysergic acid diethylamide [LSD, 0.17 or 0.30 mg/kg, SC; 15 min pretreatment] or vehicle. Results Stimulus control was established in 6 of 16 mice at a dose of LSD of 0.17 mg/kg after 39 sessions. An increase in dose to 0.30 mg/kg for the remaining mice resulted in stimulus control in an additional 5 subjects. In the low dose group, subsequent experiments demonstrated an orderly dose–effect relationship for LSD and a rapid offset of drug action with an absence of LSD effects 60 min after injection. When LSD [0.17 mg/kg] was administered in combination with the selective 5-HT2A antagonist, M100907, LSD-appropriate responding was significantly but incompletely reduced to approximately 50%; concurrently, response rates declined significantly. In mice trained with a dose of LSD of 0.30 mg/kg, full generalization to the phenethylamine hallucinogen, [−]-2,5-dimethoxy-4-methylamphetamine [DOM] was observed. Conclusions The present data demonstrate the feasibility of LSD-induced stimulus control in the mouse. The general features of stimulus control by LSD in the mouse closely resemble those observed in the rat but the present data suggest that there may be significant differences as well.

This study examined the effects of low, therapeutic doses of diazepam on several measures of impulsive behavior in healthy volunteers. Volunteers (N=35) participated in a three-session double-blind randomized design in which they received diazepam (5 or 10 mg) or placebo. The volunteers were classified as high and low impulsive based on the Barratt Impulsiveness Scale-11 (BIS-11). One hour after ingesting the capsule on each session, participants completed mood questionnaires and five impulsivity tasks: go/no-go task, delay discounting task, time estimation task, stop task, and the balloon analogue risk task (BART). Diazepam (5 and 10 mg) produced its prototypic sedative-like mood effects. However, the drug did not affect performance on any of the measures of impulsive behavior in either the high or low BIS participants. These results suggest that low doses of diazepam, including doses that are used therapeutically, do not increase impulsive behavior. Whether higher doses would increase impulsivity remains to be determined.

This study examined relations between different patterns of adolescent cigarette smoking and discounting of monetary rewards due to delay (delay discounting) and probabilistic uncertainty (probability discounting). The study also examined the relation between smoking and the number of peer friends who smoke and level of parent education. Participants were 55 adolescents (28 females) between 14 and 16 years of age who were categorized according to the following patterns of smoking behavior: "never smokers" (n=19; 10 females) who had not tried even one cigarette; "triers" (n=17; 9 females) who had recently tried cigarettes for the first time; and "current smokers" (n=19; 9 females) who smoked a minimum of one cigarette every week for at least 6 months prior to data collection. It was hypothesized that current smokers would discount more than those who had never smoked. No specific hypotheses were made for participants only trying cigarettes. Unexpectedly, results indicated no differences in discounting between the current smokers and never smokers. However, the trier group discounted probabilistic rewards significantly more than the never- and current-smoker groups. Also, triers and current smokers both reported having more friends who smoked than never smokers, and fathers of never smokers had significantly more education than fathers of either triers or current smokers. These results suggest that impulsive discounting may be more related to adolescents trying cigarettes than to their becoming regular smokers, whereas number of peer friends who smoke and parent level of education seem to differentiate between those who have smoked to some extent (triers and current smokers) and those who have not even tried cigarettes (never smokers).

Delay discounting (DD) and delay of gratification (DG) are two measures of impulsive behavior often viewed as reflecting the same or equivalent processes. However, there are some key differences in the contingencies of reinforcement between the procedures that may have implications for understanding impulsivity. This study used DD and DG procedures to determine if differences in contingencies of reinforcement specified by DD and DG alters how much organisms discount the value of delayed reinforcers. Twenty-four water-deprived rats performed one of two Adjusting Amount procedures, which consisted of repeated choices between a fixed amount of water (250mgr;l) delivered after a delay (0, 4, 8, 16, or 32 s) and an adjusting, usually lesser amount delivered immediately. Half of the rats (n=12) performed a DD procedure designed to assess preference for immediate over delayed reinforcers in which they had discrete choices between the immediate and delayed amounts of water. A DG procedure was used for the other half of the rats (n=12). In the DG procedure rats also selected between immediate and delayed alternatives, but if they chose the delayed alternative they could switch to and receive the immediate alternative at any time during the delay to the larger reward. In the DD procedure switching responses were not reinforced but were still recorded and used for analyses. The DD functions of the two groups did not differ significantly. However, at the longer delays, the DG group made significantly fewer switching responses than the DD group. A possible role of response inhibition in the DG procedure is discussed.

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.

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.

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.

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.

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.