E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat.

RATIONALE AND OBJECTIVES: In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT(6) receptor agonists and antagonists on a rodent model of recognition memory. METHODS: Selective 5-HT(6) receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats. RESULTS: After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT(6) receptor agonists, E-6801 (1.25-10 mg/kg i.p.) and EMD-386088 (5-10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04-6790 (5 and 10 mg/kg), along with donepezil (0.1-3 mg/kg) and memantine (5-20 mg/kg) all produced significant and mostly dose-dependent increases in novel object exploration, indicative of memory enhancement. Furthermore, sub-effective doses of E-6801 (1 mg/kg) when co-administered with either SB-271046 (3 mg/kg), donepezil (0.1 mg/kg) or memantine (5 mg/kg), and EMD-386088 (2 mg/kg) co-administered with SB-271046 (3 mg/kg) also significantly enhanced object-recognition memory. Additionally, using a 1-min inter-trial delay, E-6801 (2.5 and 5 mg/kg) was as effective as donepezil (0.3 and 1 mg/kg) in reversing a scopolamine-induced (0.5 mg/kg) impairment in object recognition. CONCLUSIONS: This is the first study to demonstrate that E-6801, a potent 5-HT(6) receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission.

Long-lasting changes in behavioural and neuroendocrine indices in the rat following neonatal maternal separation: gender-dependent effects.

Neonatal maternal separation (MS) has been used to model long-term changes in neurochemistry and behaviour associated with exposure to early-life stress. This study characterises changes in behavioural and neuroendocrine parameters following MS. On postnatal days (PND) 3-15, male and female Long-Evans rats underwent 3 h daily MS. Non-handled (NH) control offspring remained with the dams. Starting at PND 90, behaviour was assessed at weekly intervals in the elevated plus-maze, elevated T-maze, and locomotor activity boxes, and body weight monitored throughout. At the end of the study, adrenals were weighed and blood collected for analysis of plasma corticosterone and adrenocorticotropic hormone (ACTH) under basal conditions and following restraint stress. As adults, MS weighed more than NH animals. Activity on the open arms of the plus-maze was similar between MS and NH animals. In the T-maze, MS males had shorter emergence latencies than their NH counterparts. Spontaneous ambulation in a novel environment was significantly higher in MS than in NH animals, and males exhibited overall lower activity than females. Basal plasma corticosterone was lower in MS than in NH females, but no rearing condition difference was observed following restraint stress. Females had higher corticosterone and ACTH levels than males, whereas adrenal glands of MS animals weighed less than those of NH controls. The MS paradigm caused long-term gender dependent effects on behaviour and HPA axis status. The consistent gender differences confirm and expand existing results showing altered anxiety and stress reactivity in male and female rats.

Photic and nonphotic effects on the circadian activity rhythm in the diurnal rodent Arvicanthis ansorgei.

The main purpose of the study was to compare behavioural properties of entrainment to photic (30 min; 200lx) and nonphotic (melatonin: 1 h; 100 microg) stimuli in the diurnal rodent Arvicanthis ansorgei. Male animals (n=38) were used, and running wheel activity was recorded. Following entrainment to 12:12 h LD the animals were transferred to DD (dim red light) to freerun before treatment started. A phase response curve (PRC) to light was determined showing a phase delay region in the early subjective night (CT 8-16) and a phase advance region in the late subjective night (CT 18-4). Activity onset defined CT=0. Entrainment to daily phase advance and phase delay light pulses occurred at circadian phases corresponding to the respective phase shift regions of the PRC. Similarly, also entrainment to daily melatonin pulses occurred in two narrow time windows located near the beginning (CT 0) and the end of the subjective day (CT 10), but where light had a phase advance effect melatonin had a phase delay effect and vice versa. These results are consistent with the neurobiological model of Hastings et al. (Chronobiol Int 1998;15:425-445) on the differential effects of photic and nonphotic resetting cues on the circadian pacemaker.

Daily infusion of melatonin entrains circadian activity rhythms in the diurnal rodent Arvicanthis ansorgei.

The effect of exogenous melatonin (MEL) on the circadian system in nocturnal species has been extensively studied, but little is known about its chronobiotic effect in diurnal mammals. The present study investigated the effect of exogenous MEL on the circadian locomotor activity rhythm in the diurnal rodent Arvicanthis ansorgei. Male animals (n=34) were fitted with a subcutaneous catheter for daily infusion of MEL (1 h; 100 microg) and their running wheel activity was recorded. The results showed that administration of MEL to animals free-running in DD entrained their activity rhythm by phase advances at circadian time (CT) 10.62, and by phase delays at CT -0.40 (CT 0, activity onset). The range of entrainment was 17 and 11.5 min for advance and delay stimuli, respectively. Interestingly, in the nocturnal rat and the A. ansorgei, entrainment of the activity rhythm to exogenous MEL by phase advances occurs at exactly the same phase of the circadian cycle. In both nocturnal and diurnal species, the sensitivity window for exogenous MEL is located near the activity/rest transition points. It is concluded that the functional properties of entrainment to exogenous MEL are similar to those of other nonphotic stimuli. Furthermore, A. ansorgei might be an interesting animal model for studies on the chronobiotic effects of exogenous MEL in diurnal mammals including humans.

Entrainment of circadian activity rhythms in rats to melatonin administered at T cycles different from 24 hours.

Entrainment of running wheel activity in DD was studied in adult male Long Evans rats exposed to cycles of a constant dose of melatonin (MEL; 100 microg/h) infused subcutaneously. The period (T) of the MEL cycle was initially kept at 24 h until stable entrainment was established; T was then changed in a stepwise manner, and each new T value was maintained for at least 20 cycles. Entrainment by phase advance occurred near circadian time 12 (activity onset), and the range of entrainment was between 30 and 35 min. The negative phase angle difference between activity onset and MEL onset increased as T values approached the entrainment limit, whereas no change in the duration of daily activity periods was found. No difference was observed between pre- and posttreatment values of the endogenous circadian period; hence, no aftereffects were found for any T value. These results indicate that the functional properties of entrainment to MEL are similar to those of entrainment to light, suggesting that both zeitgebers share a common timing mechanism.