The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: A possible role for 5-HT1A receptors in memory

doi:10.1016/0091-3057(87)90184-5

Pharmacology Biochemistry and Behavior

Volume 27, Issue 4, August 1987, Pages 625-628

https://doi.org/10.1016/0091-3057(87)90184-5 Get rights and content

Abstract

A group of ten rats was trained to obtain food pellets in an 8-arm radial maze. The effects of pretreatment with (+)-Lysergic acid diethylamide (+)-tartrate (LSD), m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-N,N-dimethyltryptamine oxalate (5-MeO-DMT), racemic 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-IH-DPAT), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) were then evaluated. All drugs were administered IP 15 min before testing. With the exception of an increased rate of responding at a dose of 0.1 mg/kg of 8-OH-DPAT, all drugs produced a dose-related decline in response rate. In addition, LSD, RU 24969, and 8-OH-DPAT caused a statistically significant decrease in efficiency of responding. Of the three, 8-OH-DPAT was clearly the most active. Doses of 0.3, 1.0, and 3.0 mg/kg resulted in efficiencies of 61%, 53%, and 44%, respectively. The present results taken in light of 8-OH-DPAT's preferential binding to 5-HT_1A receptors, the high density of these receptors in hippocampus, and the observation that the number of 5-HT_1A receptors is decreased in Alzheimer's disease, suggest a possible role for this serotonergic receptor subtype in memory.

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The partial ergoline structure is a mixture of 8-OH-DPAT and 5HT structures [71–74]. The SAR at C-6 is similar to the SAR at C-8 of the 2-Aminotetralins [75]. So here the main aim was to create ligands with more selectivity and high affinity.
Serotonin (5-hydroxytryptamine) is a small molecule that acts both in the central and peripheral nervous system as a neurotransmitter and a hormone, respectively. Serotonin is synthesized via a multi-stage pathway beginning with l-tryptophan, which is converted by an enzyme called tryptophan hydroxylase into L-5-Hydroxytryptophan. It is well-known for its significance in the control of mood, anxiety, depression, and insomnia as well as in normal human functions such as sleep, sexual activity, and appetite. Thus, for medical chemists and pharmaceutical firms, serotonin is one of the most desirable targets. Among the seven different classes of serotonin receptors, the 5-HT_1A was one of the first discovered serotonin receptors, and the 5-HT₇ was the last addition to the serotonin receptor family. Both the classes were thoroughly examined. 5-HT_1A neurotransmission-related dysfunctions are linked to many psychological conditions such as anxiety, depression, and movement disorders.
5-HT₇ is a member of the cell surface receptor GPCR superfamily and is regulated by the serotonin neurotransmitter. It has been the focus of intensive research efforts since its discovery, which was prompted by its presence in functionally important regions of the brain. The thalamus and hypothalamus have the highest 5-HT₇ receptor densities. They are also found in the hippocampus and cortex at higher densities. Thermoregulation, circadian rhythm, learning and memory, and sleep are all associated with the 5-HT₇ receptor. It is also suspected that this receptor may be involved in the control of mood, indicating that it may be a beneficial target for depression treatment. Several differently structured molecules such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines, and aryloxyalkyl-amines are known to bind to 5-HT_1A and 5-HT₇ receptor sites. In brain serotonin receptors 5-HT_1A and 5-HT₇ are strongly co-expressed in regions involved in depression. However, their functional interaction has not been identified. An overview of the 5-HT_1A and 5-HT₇ receptor ligands belonging to different chemical groups is mentioned in this review.
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Serotonergic cell bodies are located in the raphe nuclei and innervate practically all brain regions. It is known that the activation of 5-HT1A receptors result in a deterioration of the acquisition and memory processes, as evaluated through different spatial and cognitive tasks (Winter and Petti, 1987). As animals that have been injected solely with Hc-TeTx into the MS could have major levels of 5-HT, this modification of 5-HT neurotransmission could affect the rats’ cognitive process in the radial maze.
The recombinant C-terminal domain of tetanus toxin (Hc-TeTx) is a new non-toxic peptide of the tetanus toxin that exerts a protective action against glutamate excitotoxicity in motoneurons. Moreover, its efficacy as a neuroprotective agent has been demonstrated in several animal models of neurodegeneration. The eleven amino acids in the β amyloid peptide (Aβ_25–35) mimic the toxic effects of the full β amyloid peptide (Aβ₁_–₄₂), causing the impairment of the cholinergic system in the medial septum (MS) which, in turn, alters the septo-hippocampal pathway and leads to learning and memory impairments. The aim of this study was to examine the neuroprotective effects of the Hc-TeTx fragment against cholinotoxicity. The Hc-TeTx fragment (100 ng) was injected into the rats intercranially, with the Aβ₍₂₅_–₃₅₎ (2 μg) then injected into their MS. The animals were tested for spatial learning and memory in the eight-arm radial maze. The brains were removed to assess cholinergic markers, such as choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), and to explore neurodegeneration in the MS and hippocampus, using amino-cupric silver and H&E staining. Finally, capase-3, a marker of apoptosis, was examined in the MS. Our results clearly demonstrate that the application of Hc-TeTx prevents the loss of cholinergic markers (ChAT and AChE), the activation of capase-3, and neurodegeneration in the MS and the CA1 and CA3 subfields of the hippocampus. All these improvements were reflected in spatial learning and memory performance, and were significantly higher compared with animals treated with Aβ₍₂₅_–₃₅₎. Interestingly, the single administration of Hc-TeTx into the MS modified the ChAT and AChE expression that affect cognitive processes, without inducing neurodegeneration or an increase in capase-3 expression in the MS and hippocampus. In summary, our findings suggest that the recombinant Hc-TeTx fragment offers effective protection for the septo-hippocampal pathway, given that it reduces the neurodegeneration caused by Aβ₍₂₅_–₃₅₎ and improves learning and memory processes.
The role of 5-HT<inf>1A</inf> receptors in learning and memory
2008, Behavioural Brain Research
The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT_1A subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT_1A receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors).
This review assesses the pharmacological and genetic evidence that implicates the 5-HT_1A receptor in learning and memory. The 5-HT_1A receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT_1A receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT_1A receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT_1A receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT_1A receptor in memory consolidation. Available results also implicate the 5-HT_1A receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT_1A receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT_1A receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT_1A receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.
The stimulus effects of 8-OH-DPAT: Evidence for a 5-HT<inf>2A</inf> receptor-mediated component
2008, Pharmacology Biochemistry and Behavior
A previous investigation in our laboratory found that the stimulus effects of the 5-HT_2A agonist, LSD, are potentiated by 5-HT_1A receptor agonists including the prototypic agonist, 8-OH-DPAT. Also suggestive of behaviorally relevant interactions between 5-HT_1A and 5-HT_2A receptors are behavioral analyses of locomotor activity, head-twitch response, forepaw treading and production of the serotonin syndrome; in some instances effects are augmented, in other, diminished. These observations led us in the present investigation to test the hypothesis that stimulus control by 8-OH-DPAT [0.2 mg/kg; 15 min pretreatment time] is modulated by 5-HT_2A ligands. Stimulus control was established with 8-OH-DPAT in a group of 10 rats. A two-lever, fixed ratio 10, positively reinforced task with saline controls was employed. As shown previously, stimulus control by 8-OH-DPAT and the generalization of 8-OH-DPAT to the 5-HT_1A partial agonist, buspirone, was completely blocked by the selective 5-HT_1A antagonist, WAY-100635. In contrast, antagonism by the selective 5-HT_2A antagonist, M100907 [0.1 mg/kg; 30 min pretreatment time], of 8-OH-DPAT and of the generalization of 8-OH-DPAT to buspirone was statistically significant but less than complete. In light of our previous conclusions regarding the interactions of 5-HT_1A agonists with LSD-induced stimulus control, the present data suggest that the interaction between 5-HT_1A and 5-HT_2A receptors is bidirectional in drug discrimination studies.
5-HT<inf>1A</inf> receptors and memory
2007, Neuroscience and Biobehavioral Reviews
The study of 5-hydroxytryptamine (5-HT) systems has benefited from the identification, classification and cloning of multiple 5-HT receptors (5-HT₁–5-HT₇). Increasing evidence suggests that 5-HT pathways, reuptake site/transporter complex and 5-HT receptors represent a strategic distribution for learning and memory. A key question still remaining is whether 5-HT markers (e.g., receptors) are directly or indirectly contributing to the physiological and pharmacological basis of memory and its pathogenesis or, rather, if they represent protective or adaptable mechanisms (at least in initial stages). In the current paper, the major aim is to revise recent advances regarding mammalian 5-HT_1A receptors in light of their physiological, pathophysiological and therapeutic implications in memory. An attempt is made to identify and discuss sources of discrepancies by employing an analytic approach to examine the nature and degree of difficulty of behavioral tasks used, as well as implicating other factors (for example, brain areas, training time or duration, and drug administration) which might offer new insights into the understanding and interpretation of these data. In this context, 8-OH-DPAT deserves special attention since for many years it has been the more selective 5-HT drug and, hence, more frequently used. As 5-HT_1A receptors are key components of serotonergic signaling, investigation of their memory mechanisms and action sites and the conditions under which they might operate, could yield valuable insights. Moreover, selective drugs with agonists, neutral antagonists or inverse agonist properties for 5-HT_1A (and 5-HT₇) receptors may constitute a new therapeutic opportunity for learning and memory disorders.
Investigation of mechanisms mediating 8-OH-DPAT-induced impairment of spatial memory: Involvement of 5-HT<inf>1A</inf> receptors in the dorsal hippocampus in rats
2006, Brain Research
Citation Excerpt :
For example, systemic administration of the 5-HT1A/5-HT7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (Hoyer et al., 1994) impairs the performance of (i) delayed match and non-match to position task (Cole et al., 1994; Ruotsalainen et al., 1998; Warburton et al., 1997), (ii) the passive avoidance task (Carli et al., 1992a,b; Moyano et al., 2004), and (iii) the water maze task (Carli et al., 1995; Carli and Samanin, 1992). 8-OH-DPAT has also been reported to impair spatial memory in the radial maze (Winter and Petti, 1987). In addition, a selective 5-HT1A receptor antagonist WAY-100635 attenuated the 8-OH-DPAT-induced impairment of spatial memory (Helsley et al., 1998), suggesting that the action of 8-OH-DPAT was 5-HT1A-receptor-mediated.
The purpose of this study was to identify mechanisms that mediate the impairment of spatial memory induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT_1A/5-HT₇ receptor agonist, in the eight-arm radial maze in rats. WAY-100635 and NAN-190, 5-HT_1A receptor antagonists, reversed the impairment of spatial memory induced by systemic injection of 8-OH-DPAT (1 mg/kg, i.p.). On the other hand, the α₁-adrenoceptor antagonist prazosin and a selective 5-HT₇ receptor antagonist SB269970 had no effect on 8-OH-DPAT-induced impairment of spatial memory. Bilateral microinjection of 8-OH-DPAT (4 μg/side) impaired spatial memory when injected into the dorsal hippocampus (DH). Contrastingly, spatial memory was unaffected by microinjections of 8-OH-DPAT into the other six areas examined: ventral hippocampus (VH), central amygdaloid nucleus (ACE), lateral hypothalamus (LH), nucleus accumbens (NAc), and dorsal (DR) and median (MR) raphe nucleus. Furthermore, NAN-190 significantly reversed the impairment of spatial memory induced by intra-DH injection of 8-OH-DPAT. These findings suggest that 5-HT_1A receptors in the DH play an important role in the mechanisms underlying the 8-OH-DPAT-induced impairment of spatial memory in rats.

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Pharmacology Biochemistry and Behavior

Abstract

References (27)

Spatial working memory in rats: Effects of monoaminergic antagonists

Pharmacol Biochem Behav

Biochemical assessment of the central 5-HT agonist activity of RU 24969 (a piperidinyl indole)

Eur J Pharmacol

Effect of 1-(m-trifluoromethylphenyl) piperazine on ³H-serotonin binding to membranes from rat brain in vitro and on serotonin turnover in rat brain in vivo

Eur J Pharmacol

The behavioral effects of RU 24969, a suggested 5-HT₁ agonist in rodents and the effect on the behaviors of various antidepressant treatments

Neuropharmacology

Biochemical evidence for the serotonergic agonist properties of 8-OH-DPAT in the rat brain

Eur J Pharmacol

Species variation in RU 24969 interactions with non-5-HT_1A binding sites

Eur J Pharmacol

Molecular pharmacology of 5-HT₁ and 5-HT₂ recognition sites in rat and pig membranes: Radioligand binding studies with [³H]5-HT, [³H]8-OH-DPAT, (−) [¹²⁵I]iodocyanopindolol, [³H]mesulergine and [³H]ketanserin

Eur J Pharmacol

The distribution of serotonin binding sites in the hippocampal region of the rat brain. An autoradiographic study

Neuroscience

Autoradiographic evidence for the heterogeneity of 5-HT₁ sites in the rat brain

Brain Res

Effects of phencyclidine, N-allyl-N-mormetazocine (SKF-10,047) and verapamil on performance in a radial maze

Pharmacol Biochem Behav

TFMPP may produce its stimulus effects via a 5-HT_1B mechanism

Pharmacol Biochem Behav

8-OH-DPAT discriminates between subtypes of the 5-HT₁ recognition site

Eur J Pharmacol

Hippocampal connections and spatial discrimination

Brain Res

Cited by (85)

Development and challenges in the discovery of 5-HT<inf>1A</inf> and 5-HT<inf>7</inf> receptor ligands

The recombinant C-terminal fragment of tetanus toxin protects against cholinotoxicity by intraseptal injection of β-amyloid peptide (25-35) in rats

The role of 5-HT<inf>1A</inf> receptors in learning and memory

The stimulus effects of 8-OH-DPAT: Evidence for a 5-HT<inf>2A</inf> receptor-mediated component

5-HT<inf>1A</inf> receptors and memory

Investigation of mechanisms mediating 8-OH-DPAT-induced impairment of spatial memory: Involvement of 5-HT<inf>1A</inf> receptors in the dorsal hippocampus in rats