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Sex differences in tolerance to the locomotor depressant effects of lobeline in periadolescent rats.

ABSTRACT: Lobeline is being tested in clinical trials as a pharmacotherapy for methamphetamine abuse and attention deficit hyperactivity disorder. Preclinical research demonstrates that lobeline produces locomotor hypoactivity apart from its therapeutic effects; however, the hypothesis that there are sex differences in hypoactivity or in the development of tolerance to its locomotor depressant effects has not been investigated. Periadolescent rats were injected with saline to determine baseline locomotor activity. Animals received saline or lobeline (1.0-10mg/kg) daily for 7 consecutive days (post natal days 29-35), and were challenged with saline 24h later to assess baseline activity. Lobeline produced hypoactivity in total horizontal activity and center distance travelled. Tolerance developed to the lobeline-induced hypoactivity and sex differences in lobeline tolerance were observed on both measures. Females acquired tolerance to lobeline 5.6 mg/kg at a slower rate than males. Saline challenge revealed a linear dose-dependent trend of hyperactivity on both measures, which indicates that rats exhibited altered locomotor behavior 24h after the final lobeline treatment. These findings demonstrate sex differences in the hypoactive response to lobeline prior to puberty and suggest that females may experience more locomotor depressant effects than males. Chronic lobeline may induce hyperactivity following cessation of treatment.

SUBMITTER: Harrod SB

PROVIDER: S-EPMC2766100 | biostudies-other | 2009 Dec

REPOSITORIES: biostudies-other

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Sex differences in tolerance to the locomotor depressant effects of lobeline in periadolescent rats.

Harrod Steven B SB Van Horn M Lee ML

Pharmacology, biochemistry, and behavior 20090917 2

Lobeline is being tested in clinical trials as a pharmacotherapy for methamphetamine abuse and attention deficit hyperactivity disorder. Preclinical research demonstrates that lobeline produces locomotor hypoactivity apart from its therapeutic effects; however, the hypothesis that there are sex differences in hypoactivity or in the development of tolerance to its locomotor depressant effects has not been investigated. Periadolescent rats were injected with saline to determine baseline locomotor ...[more]

PMID: 19766134

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Project description:BackgroundThere 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.MethodsFive 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.ResultsWhen 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.ConclusionsAcross 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.

Dataset Information

Sex differences in tolerance to the locomotor depressant effects of lobeline in periadolescent rats.

Publications

Sex differences in tolerance to the locomotor depressant effects of lobeline in periadolescent rats.

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