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A reduction in 5-HT1A receptor response enhances learning and memory performance in rats. Pre- and postnatal treatment with 5-methoxytryptamine (5MT), a non-selective serotonergic agonist, and early handling, reduce the number of 5-HT1A receptors in neonatal and pre-pubertal rat progeny. The aim of this study was to investigate in adolescent male rats the consequences of pre- and postnatal treatment with 5MT and its interaction with early handling on an object-place association learning task, the "Can test", a motivated, non-aversive, spatial/object discrimination task. Results show that a single daily injection of 5MT from gestational days 12 to 21 (1 mg/kg s.c.) and from postnatal days 2 to 18 to pups (0.5 mg/kg s.c.), increases the level of activity and the number of correct responses, and decreases the number of reference memory errors in the progeny as adolescent, compared to vehicle-treated rats. Similar effects are observed following a daily, brief, maternal separation of the pups from postnatal days 2 until 21. Furthermore, when 5MT-treated rats underwent to early handling procedure, the effects induced by 5MT increased handling-induced facilitation of the object-place association. These results suggest that pre- and postnatal treatment with 5MT enhances learning in the "Can test", probably due to a reduction in 5-HT1A receptors in the hippocampus. Whether the potentiation exerted by pre- and postnatal 5MT on early handling effects may be related to a further damping of 5-HT1A receptor response is not yet assessed; however, our data demonstrate that this association is able to induce long-term facilitative effects on spatial learning performance in a non-aversive spatial/object discrimination task in the adolescent rat offspring.

Central GABAergic and serotoninergic systems interact with one another and are implicated in controlling different behaviours. A gentle early long-lasting handling can prevent the deficits in locomotion and exploration in open field (O.F.) in 3-month-old male rats prenatally exposed to diazepam (DZ). Purpose of this study was to extend the research to older handled rats prenatally exposed to DZ and to assess the activity of 5-HT1A receptors (Rs), evaluating the performance in O.F. at 3 and 18 months of age following 8-OH-DPAT administration. A single daily s.c. injection of DZ (1.5 mg/kg) from gestation day 14 to gestation day 20 induced in aged, but not in young rats, a decrease in total distance travelled (TDT) and in rearing frequency (RF) and an increase of transitions from the periphery to the centre of the arena (CNT) and in the time spent in the centre of the arena (CAT), compared to controls. 8-OH-DPAT (0.150 mg/kg s.c.), given 1 h before testing, increased TDT and decreased RF, CNT and CAT in both vehicle- and DZ-exposed young rats. In aged rats prenatally exposed to DZ, 8-OH-DPAT induced an increase in TDT and a slight decrease in RF, CNT and CAT. These findings indicate that the effects of handling and of 8-OH-DPAT in prenatally DZ-exposed rats are age-dependent and suggest that O.F. test can represent a valid tool to identify the changes in 5-HT1A Rs activity following drug treatment.

Locomotor activity and antidepressant-like effect in the forced swim test (FST) of 5-HT(1A) agonist LY 228729 were investigated in adult rats prenatally exposed at doses of diazepam (DZ) and alprazolam (ALP) which induce persistent downregulation of GABA/ benzodiazepine (BZ) receptors. Prenatal exposure to ALP and DZ did not modify the efficacy of subchronic LY 228729 to decrease immobility time in the FST. Prenatal DZ and ALP potentiated the facilitatory effect of subchronic LY 228729 on locomotor activity; prenatal DZ was more effective than prenatal ALP. Moreover, prenatal DZ increased stereotypic movements induced by LY 228729. These data suggest that the persistent downregulation of GABA/BZ receptors, induced by prenatal BZs, does not play a role in the anti-immobility effect in the FST of 5-HT(1A) agonist LY 228729 while it can increase locomotor activity and stereotypic movements. Moreover, this study indicates that increases in locomotor activity do not seem to influence the anti-immobility effect in the FST of LY 228729 in rats.

The behavioural responsiveness to picrotoxin and desipramine was investigated in adult rats prenatally exposed to different benzodiazepine receptor agonists such as diazepam, alprazolam and zolpidem. Prenatal exposure to diazepam and alprazolam similarly potentiated the anti-immobility effect on the forced swimming test and the inhibitory effect on spontaneous motor activity of picrotoxin and desipramine and increased the seizure sensitivity to picrotoxin. Prenatal zolpidem seems to be ineffective. These data suggest that, despite the differences in their pharmacodynamic profile, prenatal exposure to diazepam and alprazolam, but not zolpidem, may have similar permanent consequences on the behavioural effects of drugs acting on the GABAA receptors.

We studied the effects of desipramine, alprazolam, muscimol and dizocilpine (MK-801) (alone or associated with desipramine) in the forced swimming test in rats after long-lasting termination of chronic exposure to vehicle and pentylenetetrazol. Sensitisation with pentylenetetrazol was ineffective in changing immobility time in the forced swimming test compared to vehicle treatment; pentylenetetrazol enhanced the anti-immobility effect of desipramine, abolished the anti-immobility effect of alprazolam and did not affect the anti-immobility effect of muscimol. MK-801 at the dose that did not modify immobility time in vehicle-treated rats and in pentylenetetrazol-treated animals strongly potentiated the anti-immobility effect of desipramine in pentylenetetrazol-treated rats. MK-801 in association with desipramine induced a marked hyperlocomotion and hyperexcitability, with swaying movements and oral stereotypies in pentylenetetrazol-sensitised rats. Results are considered the experimental representation of a 'gating mechanism' toward psychotic-like symptoms.

Rats were treated for 5 weeks with three subconvulsant doses of picrotoxin (PTX) and pentylenetetrazol (PTZ) per week to induce a persistent reduction of the GABAA receptor function which results in chemical kindling. Fifteen days after termination of this treatment schedule, the effect of desipramine (DMI) and alprazolam (ALP) on immobility time in the forced swim test (FST) was evaluated. Chronic PTX and PTZ did not alter the immobility time. Acute PTX and PTZ reduced the immobility of rats chronically treated with vehicle but not of those exposed chronically to PTX and PTZ. Chronic PTX did not influence the anti-immobility effect of DMI, but blocked that of ALP. Chronic PTZ markedly potentiated the anti-immobility effect of DMI but blocked that of ALP. Concomitant administration of chlordiazepoxide prevented the effects of chronic PTX and PTZ. These findings suggest that a long-lasting reduction in GABAA receptor function, unlike acute reduction, does not play an important role in the mobility of rats in the FST and in the anti-immobility effect of DMI while it blocks that of ALP.