Sex differences in sucrose reinforcement in Long-Evans rats

Background There are sex differences in addiction behaviors. To develop a pre-clinical animal model to investigate this, the present study examined sex differences in sucrose taking and seeking using Long-Evans rats. Methods Five experiments were conducted using separate groups of subjects. The first two examined sucrose or saccharin preference in two-bottle home cage choice tests. Experiment three assessed sucrose intake in a binge model with sucrose available in home cage bottles. Experiments four and five utilized operant-based procedures. In experiment four rats responded for sucrose on fixed and progressive ratio (FR, PR) schedules of reinforcement over a range of concentrations of sucrose. A final component of experiment four was measuring seeking in the absence of sucrose challenged with the dopamine D1 receptor antagonist SCH23390. Experiment five assessed responding for water on FR and PR schedules of reinforcement. Results When accounting for body weight, female rats consumed more sucrose than water; but there was no sex difference in saccharin preference over a range of saccharin concentrations. When accounting for body weight, females consumed more sucrose than males in the binge model, and only females increased binge intake over 14 days of the study. Females responded at higher rates for sucrose under both FR and PR schedules of reinforcement. Females responded at higher rates in extinction (seeking); SCH23390 reduced sucrose seeking of both females and males. Females responded at higher rates for water on FR and PR schedules than males, although rates of responding were low and decreased over sessions. Conclusions Across bottle-choice, binge intake, and operant procedures, female Long-Evans rats consumed more sucrose and responded at higher rates for sucrose. Although females also responded more for water, the vigor of responding did not explain the consistent sex difference in sucrose taking and seeking. The sex difference in sucrose taking was also not explained by sweet preference, as there was no sex difference in saccharin preference. These data provide a pre-clinical model to further evaluate sex differences in addiction behaviors and manipulations designed to reduce them.

Assessment of the Reinforcing Properties of Orally Administered MDMA ('Ecstasy') in Rats

<p>The so-called “party drug” 3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) may share many of the addictive properties common to other CNS stimulants. In humans MDMA is primarily consumed orally in one more pills per session. However, animal research has mostly focused on examining the effects of MDMA as a function of other routes of administration. Route of administration can have profound effects on the subjective and reinforcing properties of drugs of abuse. This thesis assessed the locomotor-activating and reinforcing properties of MDMA when delivered orally. MDMA-induced hyperlocomotion was used to examine magnitude of response and onset of action as a function of ip, sc and oral administration. Significant route-dependant effects were found with ip producing higher locomotor activity than sc and oral respectively. Onset of action was slower for subcutaneous administration compared with both ip and oral administration. The reinforcing properties of MDMA were examined by use of the self-administration procedure. Oral MDMA self-administration was firstly examined using simple schedules of reinforcement as a function of two different vehicle substrates, water (under water deprivation) and saccharin. Oral MDMA maintained responding and reliable dose-response curves were obtained under both water and saccharin vehicle conditions. However, both saccharin and water vehicle conditions also acted as strong reinforcers in these studies. Further studies utilising a behavioural economic approach were conducted in order to delineate the reinforcing effects of MDMA from that of its parent vehicle. In addition, demand-curve analysis using both the Linear-Elasticity model (Hursh et al., 1988, 1989) and the Exponential Model of Demand (Hursh & Silberberg, 2008) were compared in order to evaluate each model and assess the relative reinforcing efficacy of oral MDMA. Demand curves for the oral self-administration of MDMA revealed that responding for MDMA was more elastic (lower Pmax) than responding for saccharin-alone indicating that saccharin functioned as stronger reinforcer than did MDMA+saccharin. The results of these studies provide evidence for the positive-reinforcing effects of MDMA when it is delivered via the oral route of administration, however, the relative reinforcing efficacy of orally delivered MDMA appears to be low.</p>

Assessment of the Reinforcing Properties of Orally Administered MDMA ('Ecstasy') in Rats

<p>The so-called “party drug” 3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) may share many of the addictive properties common to other CNS stimulants. In humans MDMA is primarily consumed orally in one more pills per session. However, animal research has mostly focused on examining the effects of MDMA as a function of other routes of administration. Route of administration can have profound effects on the subjective and reinforcing properties of drugs of abuse. This thesis assessed the locomotor-activating and reinforcing properties of MDMA when delivered orally. MDMA-induced hyperlocomotion was used to examine magnitude of response and onset of action as a function of ip, sc and oral administration. Significant route-dependant effects were found with ip producing higher locomotor activity than sc and oral respectively. Onset of action was slower for subcutaneous administration compared with both ip and oral administration. The reinforcing properties of MDMA were examined by use of the self-administration procedure. Oral MDMA self-administration was firstly examined using simple schedules of reinforcement as a function of two different vehicle substrates, water (under water deprivation) and saccharin. Oral MDMA maintained responding and reliable dose-response curves were obtained under both water and saccharin vehicle conditions. However, both saccharin and water vehicle conditions also acted as strong reinforcers in these studies. Further studies utilising a behavioural economic approach were conducted in order to delineate the reinforcing effects of MDMA from that of its parent vehicle. In addition, demand-curve analysis using both the Linear-Elasticity model (Hursh et al., 1988, 1989) and the Exponential Model of Demand (Hursh & Silberberg, 2008) were compared in order to evaluate each model and assess the relative reinforcing efficacy of oral MDMA. Demand curves for the oral self-administration of MDMA revealed that responding for MDMA was more elastic (lower Pmax) than responding for saccharin-alone indicating that saccharin functioned as stronger reinforcer than did MDMA+saccharin. The results of these studies provide evidence for the positive-reinforcing effects of MDMA when it is delivered via the oral route of administration, however, the relative reinforcing efficacy of orally delivered MDMA appears to be low.</p>

The Novel Positive Allosteric Modulator of the GABAB Receptor, KK-92A, Suppresses Alcohol Self-Administration and Cue-Induced Reinstatement of Alcohol Seeking in Rats

Positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs) are of interest in the addiction field due to their ability to suppress several behaviors motivated by drugs of abuse. KK-92A is a novel GABAB PAM found to attenuate intravenous self-administration of nicotine and reinstatement of nicotine seeking in rats. This present study was aimed at extending to alcohol the anti-addictive properties of KK-92A. To this end, Sardinian alcohol-preferring rats were trained to lever-respond for oral alcohol (15% v/v) or sucrose (0.7% w/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding behavior had stabilized, rats were exposed to tests with acutely administered KK-92A under FR5 and progressive ratio schedules of reinforcement and cue-induced reinstatement of previously extinguished alcohol seeking. KK-92A effect on spontaneous locomotor activity was also evaluated. Treatment with 10 and 20 mg/kg KK-92A suppressed lever-responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol. Treatment with 20 mg/kg KK-92A reduced sucrose self-administration. Combination of per se ineffective doses of KK-92A (2.5 mg/kg) and the GABAB receptor agonist, baclofen (1 mg/kg), reduced alcohol self-administration. Treatment with 5, 10, and 20 mg/kg KK-92A suppressed reinstatement of alcohol seeking. Only treatment with 80 mg/kg KK-92A affected spontaneous locomotor activity. These results demonstrate the ability of KK-92A to inhibit alcohol-motivated behaviors in rodents and confirm that these effects are common to the entire class of GABAB PAMs. The remarkable efficacy of KK-92A is discussed in terms of its ago-allosteric properties.

Submitted as a Research Report to Biology of Sex Differences

Background: There are sex differences in addiction behaviors. To develop a pre-clinical animal model to investigate this, the present study examined sex differences in sucrose taking and seeking using LongEvans rats. Methods: Five experiments were conducted using separate groups of subjects. The first two examined sucrose or saccharin preference in two-bottle home cage choice tests. Experiment three assessed sucrose intake in a binge model with sucrose available in home cage bottles. Experiments four and five utilized operant-based procedures. In Experiment four rats responded for sucrose on fixed and progressive ratio (FR, PR) schedules of reinforcement over a range of concentrations of sucrose. A final component of experiment four was measuring seeking in the absence of sucrose challenged with the dopamine D1 receptor antagonist SCH23390. Experiment five assessed responding for water on FR and PR schedules of reinforcement. Results: When accounting for body weight, female rats consumed more sucrose than water; but there was no sex difference in saccharin preference over a range of saccharin concentrations. When accounting for body weight, females consumed more sucrose than males in the binge model, and only females increased binge intake over the 14 days of the study. Females responded at higher rates for sucrose under both FR and PR schedules of reinforcement. Females responded at higher rates in extinction (seeking); SCH23390 reduced sucrose seeking of both females and males. Females responded at higher rates for water on FR and PR schedules than males, although rates of responding were low and decreased over sessions. Conclusions: Across bottle-choice, binge intake, and operant procedures, female Long-Evans rats consumed more sucrose and responded at higher rates for sucrose. Although females also responded more for water, the vigor of responding did not explain the consistent sex difference in sucrose taking and seeking. The sex difference in sucrose taking was also not explained by sweet preference, as there was no sex difference in saccharin preference. These data corroborate with findings of sex differences in addiction behaviors in humans, providing a pre-clinical model to further evaluate sex differences in these behaviors and manipulations designed to reduce them.

Effects of β-Phenylethylamine on Psychomotor, Rewarding, and Reinforcing Behaviors and Affective State: The Role of Dopamine D1 Receptors

Beta-phenylethylamine (β-PEA) is a well-known and widespread endogenous neuroactive trace amine found throughout the central nervous system in humans. In this study, we demonstrated the effects of β-PEA on psychomotor, rewarding, and reinforcing behaviors and affective state using the open-field test, conditioned place preference (CPP), self-administration, and ultrasonic vocalizations (USVs) paradigms. We also investigated the role of the dopamine (DA) D1 receptor in the behavioral effects of β-PEA in rodents. Using enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we also determined the DA concentration and the DA-related protein levels in the dorsal striatum of mice administered with acute β-PEA. The results showed that acute β-PEA increased stereotypic behaviors such as circling and head-twitching responses in mice. In the CPP experiment, β-PEA increased place preference in mice. In the self-administration test, β-PEA significantly enhanced self-administration during a 2 h session under fixed ratio (FR) schedules (FR1 and FR3) and produced a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement in rats. In addition, acute β-PEA increased 50-kHz USV calls in rats. Furthermore, acute β-PEA administration increased DA concentration and p-DAT and TH expression in the dorsal striatum of mice. Finally, pretreatment with SCH23390, a DA D1 receptor antagonist, attenuated β-PEA-induced circling behavior and β-PEA-taking behavior in rodents. Taken together, these findings suggest that β-PEA has rewarding and reinforcing effects and psychoactive properties, which induce psychomotor behaviors and a positive affective state by activating the DA D1 receptor in the dorsal striatum.

Post-weaning social isolation modulates reward-seeking behavior in a sex-specific manner in mice

Social isolation is a growing concern in public health. Although isolation at any age is harmful, previous studies have shown that isolation during adolescence, correlating with critical periods of brain development, can impair cognitive function and increase the risk for psychiatric illness later in life. In this study, we utilized a mouse model of adolescent social isolation (SI) and compared performance of isolated and group-housed mice on a touchscreen-based continuous performance test (CPT) and fixed ratio/progressive ratio (FR/PR) tasks in adulthood. SI increased sensitivity in the CPT in male mice and had no effect in female mice. The increase in sensitivity was consistent across time bins within the 45-minute testing session and there were no SI effects on reaction times or reward retrieval latencies. A possible confound for performance in the CPT would be SI-induced changes in reward-seeking or motivation for the strawberry milk reward. We next compared the SI mice to their group-housed littermate controls on both FR and PR schedules of reinforcement and found that male SI mice earned significantly more reinforcers on FR schedules of reinforcement and had higher breakpoints on PR schedules compared to their group-housed littermates. These data indicate that SI during adolescence has striking, sex-specific effects on reward-seeking behavior in adult mice and may provide a useful behavioral model for studying the link between SI and risk for neuropsychiatric disorders.

Beyond single discrete responses: An integrative and multidimensional analysis of behavioral dynamics assisted by Machine Learning

Behavioral systems, understanding it as an emergent system comprising the environment and organism subsystems, includes the spatial dynamics as a basic dimension in natural settings. Nevertheless, under the standard approaches in the experimental analysis of behavior that are based on the single response paradigm and the temporal distribution of these discrete responses, the continuous analysis of spatial behavioral-dynamics has been a scarcely studied field. The technological advancements in computer vision have opened new methodological perspectives for the continuous sensing of spatial behavior. Derived from them, recent studies suggest that there are multiple features embedded in the spatial dynamics of behavior, such as entropy, and that they are affected by programmed stimuli (e.g., schedules of reinforcement), at least, as much as features related to discrete responses. Despite the progress, the characterization of behavioral systems is still segmented, and integrated data analysis and representations between discrete responses and continuous spatial behavior, are exiguous. Machine Learning advancements, such as t-SNE, variable ranking, among others, provide invaluable tools to crystallize an integrated approach for the analysis and representation of multidimensional behavioral-data. Under this rational, the present work: 1) proposes a multidisciplinary approach for the integrative and multilevel analysis of behavioral systems; 2) shows behavioral aspects usually ignored under the standard approaches in the experimental analysis of behavior; and 3) provides sensitive behavioral measures, based on spatial dynamics, and useful data representations for the study of behavioral systems. In order to exemplify and evaluate our approach, the spatial-dynamics of behavior embedded in phenomena relevant to the behavioral science, namely water-seeking behavior and motivational operations, is examined, showing aspects of behavioral systems hidden until now.