8‐Hydroxy‐2‐(di‐n‐propylamino)tetralin impairs spatial learning in a water maze: role of postsynaptic 5‐HT_1A receptors

Abstract

1 The effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, on place navigation was studied by use of two spatial tasks in a water maze. 2 In the first experiment, rats treated subcutaneously with 100 and 300 (but not 30) p1gkg-1 8-OH-DPAT were impaired in their ability to locate a hidden platform. The probe test confirmed the impairment of spatial navigation but the effect (time spent in the training quadrant) was quantitatively different, depending on whether 8-OH-DPAT was administered only before each training session, only before the probe test or in both conditions. 3 In the second experiment, rats received 150pg 5,7-dihydroxytryptamine (5,7-DHT) intracerebroventricularly to destroy 5-hydroxytryptamine (5-HT-containing neurones and 24 days later were examined for choice accuracy in a two-platform spatial discrimination task.4 At 100 (but not 30)pgkg-1 8-OH-DPAT impaired rats' accuracy with no effect on latency and no errors of omission. In 5,7-DHT-treated rats, this dose had a greater effect, including errors of omission. Sham-operated rats injected with 300pugkg'-8-OH-DPAT were markedly impaired in accuracy but they had longer latencies and made more errors than controls. All the effects were increased in 5,7-DHT treated rats. 5 The results suggest that, at doses causing no apparent changes in motor behaviour or motivation, 8-OH-DPAT impairs spatial navigation by stimulating postsynaptic 5-HTlA receptors in the rat brain.

Analysis of the Role of the 5-HT1B Receptor in Spatial and Aversive Learning in the Rat

“…The serotonin syndrome has been shown to result from postsynaptic 5-HT 1A receptor activation (Tricklebank et al, 1984). Moreover, stimulation of (postsynaptic) 5-HT 1A receptors has consistently been shown to impair learning and memory in the WM and PA tasks (Carli and Samanin, 1992;Carli et al, 1993;Misane et al, 1998;Ö gren, 1985), which could contribute to the cognitive deficits caused by anpirtoline. However, pretreatment with NAS-181 (10 mg/kg) completely blocked both the impairment of WM acquisition/retention and PA retention caused by anpirtoline.…”

“…Moreover, the facilitatory effects of NAS-181 on PA retention are difficult to reconcile with an increase in 5-HT release and subsequent stimulation of 5-HT 1A receptors. Both systemic and intrahippocampal (CA1 region) administration of a 5-HT 1A receptor agonist (8-OH-DPAT) consistently impair acquisition of spatial memory and PA retention (Carli and Samanin, 1992;Carli et al, 1993;Misane et al, 1998), deficits attributable to the activation of postsynaptic 5-HT 1A receptors.…”

“…The physiological effects of 5-HT in brain areas of innervation are mediated by seven families of 5-HT receptors, comprising at least 14 different subtypes (Hoyer and Martin, 1997). Among these, the 5-HT 1A receptor has so far received most attention in cognitive research (Buhot et al, 2000;Carli and Samanin, 1992;Misane et al, 1998;Schechter et al, 2002;Ö gren, 1986). The 5-HT 1A receptor is localized both at the midbrain raphe nuclei cell bodies (autoreceptor), where it can regulate the firing rate of the 5-HT neurons, as well as at postsynaptic localizations (heteroreceptor) in brain regions that regulate cognitive processes including the cortex, the hippocampal formation, and the basal forebrain (Chalmers and Watson, 1991;Pompeiano et al, 1992;Schmitz et al, 1995;Sprouse and Aghajanian, 1987).…”

Involvement of the 5-HT1AReceptors in Classical Fear Conditioning in C57BL/6J Mice

“…In addition, presynaptic 5-HT 1A receptors (somatodendritic autoreceptors) are abundant in the midbrain raphe nuclei (Laporte et al, 1994;Gozlan et al, 1995;Khawaja, 1995). The representation of the 5-HT 1A receptors in the limbic forebrain probably explains the marked effects of the 5-HT 1A agonists such as 8-hydroxy-2-(di-n-propyloamino)tetralin hydrobromide (8-OH-DPAT) in various learning and memory tasks in rats and mice ranging from aversive conditioning (Carli et al, 1993;Misane et al, 1998;Misane and Ö gren, 2000) to spatial learning (Carli and Samanin, 1992;Bertrand et al, 2000) (for review, see Meneses, 1999). Although the exact mechanisms underlying these effects are not well defined, they might be related to the inhibitory effects of the 5-HT 1A agonists on limbic (Sprouse and Aghajanian, 1988;Grunschlag et al, 1997;Tada et al, 1999) and neocortical (Hajos et al, 1999) neuronal activity.…”

Attenuation of Scopolamine-Induced and Age-Associated Memory Impairments by the Sigma and 5-Hydroxytryptamine1A Receptor Agonist OPC-14523 (1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethanesulfonate)

“…Stimulation of presynaptic 5-HT 1A receptors can reverse memory impairments induced by scopolamine (Carli et al, 1998(Carli et al, , 1999. In contrast, however, Carli and Samanin (1992) showed that the full 5-HT 1A receptor agonist, 8-OH-DPAT, impairs performance in a dose-dependent manner in two different versions of the Morris water maze test. They also showed that intraventricular 5-hydroxytryptamine depletion induced by 5,7-dihydroxytryptamine increases the amnesic effects of 8-OH-DPAT in the Morris water maze test, indicating that full agonism of postsynaptic 5-HT 1A receptors can impair spatial navigation.…”