Preclinical behavior models used for screening pharmacological treatments for mental disorders have generally used only male research subjects, and for studies that have included female subjects, few have utilized sex as a study variable. In fact, many mental disorders vary by prevalence and symptomatology between sexes, creating a need to evaluate established subject models for sex differences. Compulsive behavior is a feature shared across many mental disorders and effective treatments have been examined pre-clinically using the schedule-induced polydipsia procedure in rats. Drugs effective for reducing polydipsia include psychostimulants, such as d -amphetamine. Virtually no studies have examined sex differences using this procedure. For the present study, male and female rats were examined in the schedule-induced polydipsia paradigm. Rats were food-restricted and trained on a fixed-interval food reinforcement schedule and given free access to water during experimental sessions. Estrous stages were assessed during training and test sessions. The psychostimulant d -amphetamine was also tested once stable water consumption occurred. Excessive water intake developed over the course of training. Females required significantly more sessions to reach a stable level of drinking. Treatment with d -amphetamine (1.0 mg/kg, but not 0.25 or 0.5 mg/kg) significantly reduced drinking in both male and female rats. No sex differences were observed across other study variables including comparisons between diestrus and proestrus stages. Overall, these findings suggest that schedule-induced polydipsia procedures that employ similar methods can produce results generalizable across male and female subjects.

[Figure: see text].

Male Wistar strain rats subcutaneously administered haloperidol at the dose of 0.035 mg/kg at 3-4 days interval, 10 times, in the avoidance situation. Enhancement of the prolactin-secreting effect of haloperidol was observed when it was given in the home cages at the 10th day after termination of the repeated administration. In these animals, 3H-spiperone binding sites in the pituitary significantly increased, while the DOPAC/DA ratio in the hypothalamus significantly decreased. The enhancement phenomenon may be produced by a decrease in the activity of dopamine neurons in the hypothalamus.

Temporal changes in the avoidance responses and serum prolactin levels were investigated for a 360 min period after s.c. administration of antipsychotic drugs such as chlorpromazine (2 mg/kg), prochlorperazine (2 mg/kg), haloperidol (0.035 mg/kg), droperidol (0.03 mg/kg), YM-09151-2 (0.005 mg/kg) and sulpiride (80 mg/kg) in rats. Male adult rats of the Wistar strain were trained under a continuous lever-press avoidance schedule (Sidman type) to observe avoidance-suppressing effects of the drugs. The avoidance response was suppressed after administration of chlorpromazine, prochlorperazine, haloperidol, droperidol and YM-09151-2, showing significant decrease in response rate and significant increase in shock rate when compared with those after saline administration, while it was scarcely suppressed within 150 min after sulpiride. On the other hand, serum prolactin levels were increased after administration of all the drugs used. Furthermore, parallelism between temporal changes in the avoidance responses and those in serum prolactin levels was observed after administration of the antipsychotic drugs, except for sulpiride. These results suggest that the prolactin-increasing effects of antipsychotic drugs are applicable for predicting antipsychotic efficacies in humans, excluding sulpiride therapy.

5-Methoxy-N,N-dimethyltryptamine (5-MeODMT), a potent serotonin (5-HT) receptor agonist, exerts a biphasic effect on rat prolactin (PRL) secretion. 5-MeODMT (2.5-10 mg/kg) produces a marked, dose-related but short-lasting (less than 30 min) rise in serum PRL levels. At intervals longer than 30 min, 5-MeODMT (1-15 mg/kg) inhibits the stimulation of PRL secretion by another 5-HT agonist, 5-methoxytryptamine (5-MeOT, 10 mg/kg), by alpha-methylparatyrosine (50 mg/kg) or by haloperidol (0.15 mg/kg). 5-MeODMT did not significantly alter the PRL-releasing effect of gamma-butyrolactone (500 mg/kg) or a higher dose of haloperidol (1 mg/kg). The biphasic effect of 5-MeODMT on rat PRL secretion is shared by the centrally-acting 5-HT agonist quipazine, but not by 5-MeOT, an indole derivative excluded by the blood-brain barrier. The initial stimulation of PRL secretion by 5-MeODMT is probably due to its ability to activate postsynaptic 5-HT receptors. The subsequent inhibitory effect of 5-MeODMT appears to be due to increased functional activity of tuberoinfundibular dopamine neurons. The possible mechanisms underlying the inhibitory effect of 5-MeODMT on PRL release are discussed.

Administration of single doses of d-amphetamine (0.5-4.0 mg/kg i.p.) to adult, male rats produced the expected dose-related increases in spontaneous motor activity. This effect was reduced by pretreatment with alpha-methylparatyrosine (alpha MT) and virtually unaffected by pretreatment with pargyline or parachlorophenylalanine (PCPA). Single doses of l-amphetamine (0.25-8.0 mg/kg) evoked an initial decrease in activity followed by increased activity of smaller magnitude than that caused by the d-isomer. The depressant effects of the l-isomer were prolonged by pretreatment with alpha MT, and abolished by pretreatment with pargyline or PCPA.

Primiparous rats received 0.05, 0.25, 0.50, or 1.50 mg d-amphetamine/kg body weight, injected IP, when offspring reached 3-4 and 10-11 days of age. A multidimensional analysis of their maternal behavior revealed that at doses as low as 0.25 mg/kg, amphetamine had a disruptive effect on mother-pup intercontact interval, retrieval latency, inter-retrieval interval, number of pup retrieved and number of corners to which they were retrieved, time nest building, number of paper strips used, nursing time, time in motion, and number of squares entered. Disruption was dose-dependent for all the preceding except number of corners and time nest building. Amphetamine had no effect on the rate of maternal locomotion. The impact of amphetamine on nursing was significantly greater at pup ages of 3-4 days than at 10-11 days. Drug-induced augmentation of arousal exceeding optimal levels for adequate care-giving and locomotor stimulation incompatible with elements of maternal behavior may account for dose-dependent impairment in the range of 0.25 to 1.50 mg/kg d-amphetamine.

p-Chloroamphetamine hydrochloride (0.5-10 mg/kg, i.p.) caused a rapid (within 30 minutes), dose-related increase in serum prolactin concentration in male rats. The effect was antagonized by pretreatment with p-chlorophenylalanine, an inhibitor of serotonin synethesis, or by metergoline, a serotonin receptor antagonist. The acute elevation of serum prolactin may have been mediated by the release of serotonin by p-chloroamphetamine.