5-HT1AReceptors Modulate the Consolidation of Learning in Normal and Cognitively Impaired Rats

5-HT1A Receptors Modulate the Consolidation ofLearning in Normal and Cognitively Impaired Rats

Alfredo Meneses and Enrique Hong

Terapeutica Experimental, Departamento de Farmacologıa y Toxicologıa, CINVESTAV-IPN,Apartado Postal 22026, Mexico, D.F., 14000, Mexico

Attempts were made to further analyze the role of 5-HT1A receptors in consolidationof learning by evaluating the role of these receptors in cognitively normal and impairedanimals. The effects of post-training administration of 8-OH-DPAT and 5-HT1A recep-tor antagonists, WAY 100135, WAY 100635, and S-UH-301, plus the cholinergic andglutamatergic antagonists, scopolamine and dizolcipine, respectively, were determinedusing an autoshaping learning task. The results showed that 8-OH-DPAT increased thenumber of conditioned responses, whereas WAY100135, WAY100635, and S-UH-301,and the 5-HT depleter, p-chloroamphetamine (PCA), had no effect. PCA did not changethe silent properties of the 5-HT1A receptor antagonists. PCA, WAY100635, and S-UH-301, but not GR127935 (a 5-HT1B/1D-receptor antagonist) or MDL100907 (a 5-HT2A

receptor antagonist), reversed the effect to 8-OH-DPAT. Ketanserin (a 5-HT2A/2C re-ceptor antagonist) and ondansetron (a 5-HT3 receptor antagonist), at a dose thatincreased the conditioned responses by itself, reversed the effect of 8-OH-DPAT. More-over, 8-OH-DPAT or S-UH-301 reversed the learning deficit induced by scopolamineand dizocilpine whereas WAY100635 reversed the effect of scopolamine only. Thesedata confirm a role for presynaptic 5-HT1A receptors during the consolidation of learn-ing and support the hypothesis that serotonergic, cholinergic, and glutamatergic sys-tems interact in cognitively impaired animals. © 1999 Academic Press

Key Words: learning; autoshaping; serotonin; receptors; 5-HT1A; rats.

INTRODUCTION

It is well established that serotonergic pathways project (Jacobs & Azmitia,1992; Zifa & Fillion, 1992; Wright, Seroogy, Lundgren, Davis, & Jennes, 1995)to brain areas involved in learning and memory (Meneses & Hong, 1997a,1997b; Zola-Morgan & Squire, 1993), and that 5-hydroxytryptamine (5-HT)receptor agonists and antagonists modify these processes (Altman & Normile,1988; Meneses & Hong, 1997a). Evidence suggesting a pathophysiologicaland/or therapeutic role of the serotonergic system in learning and memory hasbeen provided (Altman & Normile, 1988; Azmitia Whitaker, 1995; Bartolomeo,Morris, Moyer, & Boast, 1996; Cassel & Jeltsch, 1995; Cliffe, Fletcher, &Dourish, 1993; Cole, Jones, & Turner, 1994; Fletcher, Forster, Bill, Brown,

The authors thank the pharmaceutical companies for their generous gifts (see the Drugssection). This work was written while A.M. was a Pan American–CONACYT Fellow at theGerontology Research Center, National Institute on Aging, in Baltimore, MD. The authors thankEdward L. Spangler for critically reading the manuscript.

Correspondence and reprint requests should be addressed to Alfredo Meneses, TerapeuticaExperimental, Departomento de Farmacologıa y Toxicologıa, CINVESTAV-IPN, Apartado Postal22026, Mexico, D.F., 14000, Mexico.

207

Neurobiology of Learning and Memory 71, 207–218 (1999)Article ID nlme.1998.3866, available online at http://www.idealibrary.com on

1074-7427/99 $30.00Copyright © 1999 by Academic Press

All rights of reproduction in any form reserved.

Cliffe, Hartley, Jones, McLenachan, Stanhope, Critchley, Childs, Middlefell,Lanfumey, Corradetti, Laporte, Gozlan, Hamon, & Dourish, 1996; Francis,Pangalos, Pearson, Midlemiss, Stratmann, & Bowen, 1992; Harder, Maclean,Alder, Francis, & Ridley, 1996; Herremans, Hijzen, Olivier, & Slangen, 1995;Hodges, Sowinkski, Turner, & Fletcher, 1996; Meneses & Hong, 1994a, 1994b;Whitaker-Azmitia & Azmitia, 1994; Zhang, Zeise, & Wang, 1994). Among themultiple classes (5-HT1-7) and subtypes (5-HT1A/1B/1D/1E/1F, 5-HT2A/2B/2C,5-HT3(a)/3(b), 5-HT4(a)/4(b), 5-HT5A/5B, and 5-HT7(a)/7(b)) of the 5-HT receptorscharacterized so far in mammalian species (Glennon & Dukat, 1995; Hoyer,Hartig, & Humphrey, 1994; Hoyer & Martin, 1997), the 5-HT1A subtype is themost extensively studied (see Meneses & Hong, 1997b, for review). Despite thisextensive investigation, the role of the 5-HT1A receptor in learning and mem-ory remains unclear. For instance, (6)-8-hydroxy-2-(di-n-propilamino) tetralinHCl (8-OH-DPAT) administration enhanced, impaired, or had no effect onlearning (Meneses & Hong, 1997b), which could be attributed, at least in part,to different times of drug administration used. From a methodological point ofview it is necessary to note that investigators have administered 5-HT1A drugseither before or after the learning task and/or the preretention phase; pre-training administration is the most frequently used (Meneses and Hong,1997b). Each of these protocols of drug administration allows the study ofdifferent stages of learning, e.g. acquisition, consolidation, and/or retrieval(McGaugh, 1989; Meneses & Hong, 1997a, 1997b). The effects induced bypretraining injections seem to reflect nonspecific changes, whereas those pro-duced by post-training injection may be attributed to learning changes (Mc-Gaugh, 1989).

Pre-training administration of 8-OH-DPAT decreases learning, at 0.09–0.25mg/kg, in passive and active avoidance and, at 1.0 mg/kg, in delayed-matching-to-position tasks. 8-OH-DPAT, at 0.003–0.3 mg/kg, enhances learning or hasno effect on delayed-matching-to-position, repeated-acquisition procedure, de-layed conditional discrimination, extinction, and autoshaping (see Meneses &Hong, 1997b, for specific references). In the water and radial mazes 8-OH-DPAT, at 0.1–0.25 mg/kg, produces mixed effects. Pre-training administrationof the partial 5-HT1A receptor agonists buspirone, ipsapirone, gepirone, tan-dospirone, flesinoxan, BMY 7378, and NAN-190 also produces mixed effects. Itmust be highlighted that WAY 100665 alone has no effect of learning (Meneses& Hong, 1997b) but is able to eliminate the nonspecific effects induced by thepre-training injection of 8-OH-DPAT on motor/motivational aspects (Fletcheret al., 1996). Post-training or pre-retention administration of 8-OH-DPAT, at0.09–0.5 mg/kg, impairs or has no effect in the passive and active avoidancelearning tasks, whereas at 0.015–0.62 mg/kg it improves learning in theautoshaping, water maze, and extinction tasks (Meneses & Hong, 1997b).Interestingly, the stimulation of 5-HT1A receptors has no effect once consoli-dation of learning is attained (Meneses & Hong, 1994a, 1994b).

The above-mentioned contrasting findings notwithstanding, it has beenproposed that 5-HT1A receptor agonists (Stanhope, McLenachan, & Dourish,1995) or antagonists (Cliffe et al., 1993; Fletcher et al., 1996) could be useful inthe treatment of learning and memory dysfunctions (Azmitia & Whitaker,1995; Bartolomeo et al., 1996; Cliffe et al., 1993; Cole et al., 1994; Darman &Reeves, 1996; Fletcher et al., 1993, 1996; Francis et al., 1992; Herder et al.,1996; Meneses & Hong, 1994a, 1994b). To further test this hypothesis, we

208 MENESES AND HONG

designed a group of experiments to investigate the effects of 5-HT1A receptoragonist and antagonists on cognitively normal and impaired animals.

METHODS

Animals

Male Wistar rats (12 weeks old) were collectively housed in a temperatureand light-controlled room under a 12:12 h light:dark cycle (light on at 7:00A.M.). Water and food were provided ad libitum for a week. After that period,their body weights were reduced to 85% by gradually reducing the food intakeover seven days.

Apparatus

Operant chambers with standard sound attenuation were used. Chamberswere 25 cm wide, 29 cm long, and 25 cm high. A 3.5-cm-wide retractable leverwas mounted 4 cm above the floor and 10 cm from both the right and left walls.The lever required a load of 10 g for operation. A food magazine for rat pellets(Bio Serv, Frenchtown, NJ) was located 5 cm to the right of the lever and 3 cmabove the floor. A household light was located in the right top corner. Solid-state programming equipment was used for control and recording (CoulbournInstruments, Lehigh Valley, PA).

Training

Each rat was placed into an experimental chamber and allowed to habituateto the experimental environment. The animals were left in the chambers untilthey were able to find and eat 45 food pellets (45-mg pellets) that were madeavailable simultaneously. Immediately afterward, the trial began and therewas an intertrial interval of 60 s. A trial consisted of the presentation of anilluminated retractable lever for 8 s (the conditioned stimulus, CS) followedimmediately by delivery of a food pellet (unconditioned stimulus, US). Eachtime that the animal pressed the retractable lever (CS), considered to be theconditioned response (CR), the trial period was shortened, the lever wasretracted, the light was turned off, and the food (US) was immediately deliv-ered. An increase or decrease in the percentage of CR was considered to be anenhancement or impairment in the consolidation of learning. The first sessionconsisted of 10 trials; the later session consisted of 20 trials.

Autoshaping training. Each rat was placed into an experimental chamberand allowed to habituate to the experimental environment until the animalfound and ate all the food pellets. Immediately thereafter, the autoshapingprogram began. There were two autoshaping sessions (i.e., training and testsessions). The results discussed correspond to the second autoshaping session.

Drug Treatment

The drugs used were p-chloroamphetamine (PCA), 8-OH-DPAT, ketanserintartrate, dizocilpine maleate (MK-801), and scopolamine HBr (Research Bio-chemical Inc., Wayland, MA); ondansetron and [1,1-biphenyl]-4-carboxamid-edehydrochloride monohydrate (GR127935) (Glaxo–Wellcome, Hertfordshire,UK); n-t-butyl, 3-[1-4(2-methoxy) phenyl] piperazinyl]-1-phenyl propionamide

2095-HT1A RECEPTORS ON LEARNING AND MEMORY

(WAY100135), and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyr-idinyl) cyclohexanene carboxamide 6trihydrochloride (WAY100635) (WythResearch, UK); (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin HCl (2)-S-UH-301 (AstraArcus, Sweden); and 4-piperidinemethanol alpha-(2,3-dime-thoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-(1)-R-(MDL100,907) (Merrel Dow,Cincinnati, OH). All drugs were injected intraperitoneally (ip) in a volume of 1ml/kg. The doses mentioned in the text refer to the salts of drugs and thesewere dissolved in physiological saline or methylcellulose. Several groups ofrats were injected with WAY100635 or S-UH-301 immediately after the firstautoshaping session and 10-min later received 8-OH-DPAT. Independent an-imals were pretreated with PCA (10 mg/kg) on consecutive days 8 and 7 beforethe autoshaping training session and compared with control groups receivingonly the vehicle (e.g., vehicle vs several dose of PCA pretreatment plus agonistor antagonists). All compounds were injected immediately after the first au-toshaping session and rats were tested 24 h later.

Measurements and Analysis

Conditioned responses (CR) were transformed into a percentage of the totaltrials of the second session. Multiple group comparisons were made usingANOVA followed by Dunnett’s t-tests. In all statistical comparisons, p , .05was used as criterion for significance. The n per group was 8 and animals wereused only once.

RESULTS

Experiment 1: Dose–Response Curve of 5-HT1A Receptor Agonist andAntagonists

The purpose of this part of the study was to determine the effect of post-training injection of 5-HT1A receptor agonists and antagonists. The resultsshow that the control group had 10 6 2% CR, whereas 8-OH-DPAT signifi-cantly [F(5, 47) 5 8.2, p , 0.05] increased the percentage of CR (Fig. 1). Afurther analysis with Dunnett’s t-test shows that 8-OH-DPAT significantlyincreased the percentage of CR at 0.031, 0.062, and 0.25 mg/kg (Fig. 1); theseincrements were 37 6 5, 25 6 4, and 19 6 2, respectively. WAY100135 (5.0–20mg/kg), WAY100635 (0.001–1.0 mg/kg), and S-UH-301 (0.3–3.0 mg/kg) had noeffect (Fig. 2).

Experiment 2: Influence of 5-HT2 and 5-HT3 Receptor Antagonists or PCA onthe Effect Induced by 8-OH-DPAT

Figure 3 shows that the increase in percentage of CR induced by 8-OH-DPATwas significantly diminished when proceeded by administration of ketanserin(11 6 1% of CR (F(5, 47) 5 9.4, p , .05)), ondansetron (12 6 2% of CR (F(5, 47)5 8.3, p , .05), and PCA (13 6 3% of CR (F(5, 47) 5 17.5, p , .05)). NeitherWAY100635 nor S-UH-301 had any effect on learning consolidation nor didPCA alter the silent characteristic of 5-HT1A antagonists in this process (Fig.2); however, they significantly (F(4, 39) 5 12.4, p , .05) reversed the effect of8-OH-DPAT (Fig. 3). Although GR127935 at 10 mg/kg significantly (F(4, 39) 53.8, p , 0.05) increased the percentage of CR and MDL109907 at 1 mg/kg had


no effect, both drugs were unable to reverse the increment induced by 8-OH-DPAT (Table 1).

Experiment 3: Influence of 5-HT1A Receptor Agonists and Antagonists on theImpaired Learning Induced by Scopolamine and Dizocilpine

The administration of scopolamine (0.17 mg/kg) or dizocilpine (0.1 mg/kg)significantly decreased the percentage of CR (Table 2). Both scopolamine (acentrally acting anticholinergic agent) and dizocilpine (a noncompetitiveNMDA receptor antagonist) were injected immediately after the first au-toshaping training session and were followed, 10 min later, by the adminis-tration of 8-OH-DPAT, WAY100635, or S-UH-30. The results show that 8-OH-DPAT [F(5, 47) 5 12.3, p , .05] or S-UH-301 [F(5, 47) 5 11.9, p , .05]significantly attenuated the decrement induced by scopolamine and dizocilpine(Table 2). In contrast, only the effect of scopolamine was significantly [F(5, 47)5 15.5, p , 0.05] decreased by the previous administration of WAY100635.

DISCUSSION

The results of the present study confirm the role of 5-HT1A receptors in theconsolidation of learning, as the 5-HT1A receptor agonist 8-OH-DPAT en-hanced the consolidation of learning whereas the 5-HT1A receptor antagonistsWAY100135, WAY100635, and S-UH-301 had no effect by themselves butsignificantly inhibited the effect of 8-OH-DPAT. Moreover, these data supportthe hypothesis that the serotonergic, glutamatergic, and cholinergic systemsinteract in cognitively impaired animals. PCA injection alone had no effect onthe consolidation of learning and did not alter the silent characteristic of5-HT1A receptor antagonists on learning consolidation, but did block the effectinduced by 8-OH-DPAT.

Taking together the evidence that parachlorophenylalanine (PCPA) alonehad no effect on learning consolidation in autoshaping (Meneses & Hong,1994b) and the present finding with PCA plus 5-HT1A drugs, it is proposed that8-OH-DPAT facilitates learning consolidation by working presynaptically (pre-sumably to inhibit 5-HT release), which may appear paradoxical consideringthat depleting 5-HT by PCPA or PCA had no effect. It should be considerednevertheless that:

FIG. 1. Effects of acute post-training administration (ip) of 8-OH-DPAT on autoshaping taskin fasted animals. Data are plotted as percentage of conditioned responses (CR%). All rats receivedan injection immediately after the first training session. Data correspond to experiments carriedout 24 h later. Values represent the mean 6 S.E.M. from eight different animals. * indicates thatsignificance was assessed by Dunnett’s t-test, p , .05, vs vehicle-injected controls.


(1) activation of presynaptic 5-HT1A receptors leads to a reduction in syn-thesis and release of serotonin, while PCA releases serotonin and causes aselective loss of fine, but not beaded, 5-HT fibers (Jacobs & Azmitia, 1992).

(2) Differential properties between pre- and postsynaptic 5-HT1A receptorsin the dorsal raphe and hippocampus have been reported (Blier, Lista, & DeMontigny, 1993). For instance, in contrast with previous (Meneses & Hong,1994b) and present findings, PCPA treatment did not alter the impairmentinduced by 8-OH-DPAT in passive avoidance (Samanin et al., 1994) andspatial discrimination; the latter effect was blocked by the 5-HT1A antagonistspiroxatrine (Carli, Luschi, Garofalo, & Samanin, 1995). These data suggestthat postsynaptic 5-HT1A receptors also may be participating during the ac-quisition of learning.

(3) Finally, PCA and PCPA produced inconsistent evidence on cognitiveprocesses (Altman & Normile, 1988; Meneses & Hong, 1997a).

It has been reported that 5-HT1A receptor blockade ameliorated the cogni-tive impairment induced by fornix transection (Harder et al., 1996) or NMDA

FIG. 2. Effects of acute post-training administration (ip) of the silent 5-HT1A receptor antag-onists S-UH-301 (upper), WAY100135 (middle), and WAY100635 (bottom) on the autoshaping taskin fasted animals. Data are plotted as a percentage of conditioned responses (CR%). All ratsreceived an injection immediately after the first training session. Data correspond to experimentscarried out 24 h later. Values represent the mean 6 S.E.M. from eight different animals.* indicates significance was assessed by the Dunnett t-test, p , .05 vs vehicle-injected controls.


antagonism with dizocilpine (Bartolomeo et al., 1996), suggesting that 5-HT1Areceptor antagonists may be useful in the treatment of disorders in cognitiveprocesses (Cliffe et al., 1993; Cole et al., 1994; Darman & Reeves, 1996;Fletcher et al., 1996; Fletcher, 1991; Francis et al., 1992; Harden et al., 1996;Samanin, Luschi, Vezzani, & Carli, 1994). On the other hand, stimulation ofpresynaptic 5-HT1A receptors induced by low, but not larger, doses of 8-OH-DPAT increased hippocampal theta, an electrophysiological pattern related toprocesses such as arousal, exploratory activity, orientation, attention, motiva-tion, learning, and memory (Marrosu, Fornal, Metzler, & Jacobs, 1996). Like-wise, cortical release of S-100b (a neurotrophic factor) possibly through thestimulation of 5-HT1A or 5-HT7 receptors on astrocytes has profound effects oncortical development and neuroplastic processes (Whitaker-Azmitia & Azmi-tia, 1994). It has been reported that excessive or insufficient S-100b activityimpairs learning consolidation (O’Dowd, Zhao, Ng, & Robinson, 1997). Alto-gether these data indicate that the activation or blockade of 5-HT1A receptorscould be useful in treating compromised learning and memory. The presentdata provide further support for these apparently contrasting results, inas-much as post-training injection of 8-OH-DPAT and S-UH-301 reversed thelearning deficit induced by dizocilpine and scopolamine, whereas WAY100635reversed only the effect of scopolamine. At the present time, we do not have anexplanation for these results; it is noteworthy, nevertheless, that electrophys-

FIG. 3. Effects of acute post-training administration (ip) of 8-OH-DPAT given alone or incombination with 5-HT receptor antagonists and PCA on autoshaping task in fasted animals. Dataare plotted as percentage of conditioned responses (CR%). All rats received an injection immedi-ately after the first training session. Data correspond to experiments carried out 24 h later. Valuesrepresent the mean 6 S.E.M. from eight different animals. * indicates significance was assessedby the Dunnett t-test, p , .05, vs vehicle-injected controls group; 1 indicates p , 0.05 vsscopolamine or dizocilpine group vs the 8-OH-DPAT alone group.


iological studies have revealed that WAY100635 inhibits cell firing in raphenuclei as an a-adrenergic antagonist whereas S-UH-301, but not WAY100635,acts as a partial 5-HT1A agonist in some brain areas (Waszczak, Martin, &Jackson, 1996). In addition, activation of 5-HT1A receptors by 8-OH-DPATappears to be involved in the increase of acetylcholine (Ach) efflux, which didnot appear to be tonically activated by 5-HT under basal conditions butoperates only when the extracellular ACh concentration is abnormally ele-vated (Fujii, Yoshiwa, Nakai, Fujimoto, Suzuki, & Kawashima, 1997).

Previous (Altman & Normile, 1988; Cassel & Jeltsch, 1995; Cole et al., 1994;Fletcher et al., 1996; Herremans et al., 1995; Hodges et al., 1996; Meneses &Hong, 1997a, 1997b; Marrosu et al., 1996; O’Dowd et al., 1997; Riekkinen,1994; Riekkinen, Tolonen, & Riekkinen, 1994; Riekkinen, Sirvio, Toiven, &

TABLE 1Effects of Various 5-HT Receptor Drugs on the Percentage of Condition

Response (CR) in the Autoshaping Learning Task

Treatment (mg/kg) CR (%)

Control 10 6 2GR127935 (10) 25 6 3a

MDL100907 (1) 10 6 18-OH-DPAT (0.062) 31 6 4a

8-OH-DPAT (0.062) 1 GR127935 (10) 29 6 5a

8-OH-DPAT (0.062) 1 MDL100907 (1) 31 6 4a

Control 11 6 3PCA (10 3 2 days) 12 6 3PCA (10 3 2 days) 1 S-UH-301 15 6 4PCA (10 3 2 days) 1 way1100635 13 6 4

a Values are significantly different from the control group (p , .05 by Dunnett’s test).

TABLE 2Effects of 5-HT1A Drugs on the Impaired Learning

Induced by Scopolamine or Dizocilpine

Treatment (mg/kg) Conditioned response (%)

Control 10 6 18-OH-DPAT (0.062) 31 6 4a

WAY100635 (0.01) 8 6 3S-UH-301 (3.0) 10 6 2Scopolamine (0.017) 3 6 1a

Dizocilpine (0.1) 2 6 1a

Control 11 6 38-OH-DPAT (0.062) 1 scopolamine (0.17) 10 6 4b

8-OH-DPAT (0.062) 1 dizocilpine (0.1) 7 6 3b

WAY100635 (0.01) 1 scopolamine (0.17) 15 6 2b

WAY100635 (0.01) 1 dizocilpine (0.1) 2 6 1a

S-UH-301 (3.0) 1 scopolamine (0.17) 6 6 1b

S-UH-301 (3.0) 1 dizocilpine (0.1) 7 6 2b

a p , .05 by Dunnett’s test vs control group.b p , .05 vs scopolamine or dizocilpine.


Riekkinen, 1995; Sirvio, Riekkinen, Jakala, & Riekkinen, 1994; Stanhope etal., 1995; Zhang et al., 1994) and the present findings indicate that diverse5-HT receptors, including 5-HT1A, could be interacting with cholinergic andglutamatergic neurotransmission systems during learning and memory pro-cesses. Interestingly, there are regional differences in the influence of 5-HTreceptors on cholinergic, GABAergic, and glutamatergic systems (Agahaja-nian, 1995; Riekkinen et al., 1994). For instance, presynaptic 5-HT1A recep-tors, acting as (auto- and/or hetero-)receptors, may modulate the cholinergic,glutamatergic, and GABAergic activity on raphe nuclei, hippocampus, andneocortex, areas implicated in cognitive processes (Zola-Morgan & Squire,1993). 5-HT1A receptors in hippocampus and cortex are co-expressed in singleneurons with 5-HT2A-2C and 5-HT4 receptors, respectively (Andrade, 1992;Wright et al., 1995), and presynaptic 5-HT autoreceptors modulate NMDA-evoked 5-HT release in the cortex (Fink, Boing, & Gothert, 1996). The possi-bility that 5-HT1A, 5-HT2A, and 5-HT2C receptor-mediated behaviors are sub-ject to functional interactions is supported by the finding that the facilitatoryeffects on the consolidation of learning induced by 8-OH-DPAT, ketanserin, orondansetron (Meneses & Hong, 1997a) are reversed by the application of anyone of the others (this work), thus indicating that those 5-HT receptors haveopposite actions during the cognitive process. Hence it is suggested that adisturbed 5-HT receptor complex balance could be responsible for alterationsin learning (Meneses & Hong, 1997a) and, possibly, in diseases such as de-pression (Berendsen, 1995). In addition, it seems that presynaptic 5-HT1Areceptors are involved in the consolidation of learning, being able to reversepoor retention, thus suggesting that the 5-HT1A receptors are mediating bothpathological and therapeutic, but not normal, mechanisms on cognitive pro-cesses.

In conclusion, although early studies showed that the pre/post-training andpreretention stimulation of 5-HT1A receptors impaired learning, recent workshave proved that: (1) Such effects regarding learning were nonspecific (e.g.,pretraining injection of 8-OH-DPAT has no effect on learning but does have aneffect on motivation and exploratory activity). (2) 5-HT1A receptors are in-volved in the acquisition and consolidation of learning; specifically, the acti-vation of presynaptic 5-HT1A receptors enhances the consolidation of learningbut it remains unclear whether it disrupts retrieval. (3) In normal animals, the5-HT1A receptor agonist, 8-OH-DPAT, has a procognitive effect (i.e., facilitat-ing the consolidation of learning), while the 5-HT1A receptor antagonistsS-UH-301 and WAY100635 are silent (i.e., have no effect alone); in contrast, incognitively impaired animals 8-OH-DPAT, S-UH-301, and WAY 100635 nor-malize cognitive functions. Admittedly, the present work raises many ques-tions and provides few answers; hence further experiments are required toclarify these apparently contradictory findings. Nevertheless, it is important tomention that five different serotonergic mechanisms of action are under in-vestigation in the treatment for Alzheimer’s disease and amnesia, including5-HT1A receptors agonists and antagonists (Meneses, 1998).

REFERENCES

Aghajanian, G. K. (1995). Electrophysiology of serotonin receptor subtypes and signal transduc-tion pathways. In E. F. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourthgeneration of progress (pp. 451–460). New York: Raven.


Altman, H. J., & Normile, H. J. (1988). What is the nature of the role of the serotonergic nervoussystem in learning and memory: Prospects for development of an effective treatment strategyfor senile dementia. Neurobiology of Aging, 9, 627–638.

Andrade, R. (1992). Electrophysiology of 5-HT1A receptors in the rat hippocampus and cortex.Drug Development Research, 26, 275–286.

Azmitia, E. C., & Whitaker-Azmitia, P. M. (1995). Anatomy, cell biology, and plasticity of seroto-nergic system. In E. F. Bloom & D. J. Kupfer (Eds.), Psychopharmacology: The fourthgeneration of progress (pp. 443–449). New York: Raven.

Bartolomeo, A. C., Morris, H., Moyer, J. A., & Boast, C. A. (1996). Attenuated MK-801-inducedimpairment of radial maze performance in rats: A possible model predicting efficacy inAlzheimer’s disease. Society of Neuroscience Abstract, 22, 143.

Berendsen, H. H. G. (1995). Interactions between 5-hydroxytryptamine receptor subtypes: Is adisturbed receptor balance contributing to the symptomatology of depression in humans?Pharmacology and Therapeutic, 66, 17–37.

Blier, P., Lista, A., & De Montigny, C. (1993). Differential properties of pre- and postsynaptic5-hydroxytryptamine1A receptors in the dorsal raphe and hippocampus. 1. Effect of spiper-one. Journal of Pharmacology Experimental Therapeutic, 265, 7–15.

Carli, M., Luschi, R., Garofalo, P., & Samanin, R. (1995). 8-OH-DPAT impairs spatial but notvisual learning in a water maze by stimulating 5-HT1A receptors in the hippocampus. Behav-ioral Brain Research, 67, 67–74.

Cassel, J. C., & Jeltsch, H. (1995). Serotonergic modulation of cholinergic function in the centralnervous system: Cognitive Implications. Neuroscience, 69, 1–41.

Cliffe, I. A., Fletcher, A., & Dourish, C. T. (1993). The evolution of selective, silent 5-HT1A receptorantagonists. Current Drugs: Serotonin, 99–124.

Cole, B. J., Jones, G. H., & Turner, J. D. (1994). 5-HT1A receptor agonists improve the performanceof normal and scopolamine-impaired rats in an operant delayed matching to position task.Psychopharmacology, 116, 135–142.

Darman, N. A., & Reeves, S. L. (1996). The mechanism by which the selective 5-HT1A receptorantagonist S-(2)UH 301 produces head-twitches in mice. Pharmacology Biochemistry Behav-ioral, 55, 1–10.

Dijk, S. N., Francis, P. T., Stratmann, G. C., & Bowen, D. M. (1995). NMDA-induced glutamateand aspartate release from rat cortical pyramidal neurones: Evidence for modulation by a5-HT1A antagonist. British Journal of Pharmacology, 115, 1169–1174.

Fink, K., Boing, C., & Gothert, M. (1996). Presynaptic 5-HT autoreceptors modulate N-methyl-D-aspartate-evoked 5-hydroxytryptamine release in the guinea-pig brain cortex. European Jour-nal of Pharmacology, 300, 79–82.

Francis, P. T., Pangalos, M. N., Pearson, R. C. A., Middlemiss, D. N., Stratmann, G. C., & Bowen,D. M. (1992). 5-Hydroxytryptamine1A but not 5-hydroxytryptamine2 receptors are enriched onneocortical pyramidal neurones destroyed by intrastriatal volkensin. Journal of Pharmacol-ogy and Experimental Therapeutic, 261, 1273–1281.

Fletcher, A., Cliffe, I. A., & Dourish, C. T. (1993). Silent 5-HT1A receptor antagonists: Utility asresearch tools and therapeutic agents. Trends in Pharmacological Sciences, 14, 441–448.

Fletcher, A., Forster, E. A., Bill, D. J., Brown, G., Cliffe, I. A., Hartley, J. E., Jones, D. E.,McLenachan, A., Stanhope, K. J., Critchley, D. J. P., Childs, K. J., Middlefell, V. C., Lanfumey,L., Corradetti, R., Laporte, A. M., Gozlan, H., Hamon, M., & Dourish, C. T. (1996). Electro-physiological, biochemical, neurohormonal and behavioral studies with WAY-100635, a po-tent, selective and silent 5-HT1A receptor antagonists. Behavioral Brain Research, 73, 337–353.

Fujii, T., Yoshizawa, M., Nakai, K., Fujimoto, K., Suzuki, T., & Kawashima, K. (1997). Demon-stration of the facilitatory role of 8-OH-DPAT on cholinergic transmission in the rat hippocam-pus using in vivo microdialysis. Brain Research, 761, 244–249.

Fletcher, P. J. (1991). Dopamine receptor blockade in nucleus accumbens or caudate nucleusdifferentially affects feeding induced by 8-OH-DPAT injected into dorsal or median raphe.Brain Research, 552, 181–189.

Glennon, R. A., & Dukat, M. (1995). Serotonin receptor subtypes. In F. E. Bloom & D. J. Kupfer


(Eds.), Psychopharmacology: The fourth generation of progress (pp. 415–429). New York:Raven.

Harder, J. A., Maclean, C. J., Alder, J. T., Francis, P. T., & Ridley, R. M. (1996). The 5-HT1A

antagonist, WAY100635, ameliorates the cognitive impairment induced by fornix transectionin the marmoset. Psychopharmacology, 127, 245–254.

Heninger, G. R. (1995). Indolamines: The role of serotonin in clinical disorders. In E. F. Bloom &D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress (pp. 471–482).New York: Raven.

Herremans, A. H. J., Hijzen, T. H., Olivier, B., & Slangen, J. L. (1995). Serotonergic drugs effectson a delayed conditional discrimination task in the rat, involvement of the 5-HT1A receptor inworking memory. Journal of Psychopharmacology, 9, 242–250.

Hodges, H., Sowinski, P., Turner, J. J., & Fletcher, A. (1996). Comparison of the effects of the5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the watermaze in rats with excitotoxic lesions of the forebrain cholinergic projection system. Psycho-pharmacology, 125, 146–161.

Hoyer, D., Hartig, P. R., & Humphrey, P. P. A. (1994). International Union of Pharmacologyclassification of receptors for 5-hydroxytryptamine (serotonin). Pharmacological Reviews, 46,157–203.

Hoyer, D., & Martin, G. (1997). 5-HT receptor classification and nomenclature: Towards a har-monization with the human genome. Neuropharmacology, 36, 419–428.

Jacobs, B. L., & Azmitia, E. C. (1992). Structure and function of the brain serotonin system.Physiological Reviews, 72, 165–229.

Marrosu, F., Fornal, C. A., Metzler, C. W., & Jacobs, B. L. (1996). 5-HT1A agonists inducedhippocampal theta activity in freely moving cats: Role of presynaptic 5-HT1A receptors. BrainResearch, 739, 192–200.

McGaugh, J. L. (1989). Dissociating learning and performance: Drug and hormone enhancementof memory storage. Brain Research Bulletin, 23, 339–345.

Meneses, A. (1998). 5-HT receptors as targets for drugs in the treatment of learning and memorydysfunctions. Current Research in Serotonin, 3, 219–228.

Meneses, A., & Hong, E. (1994a). Modification of 8-OH-DPAT effect on learning by manipulationof the assay conditions. Behavioral Neural Biology, 61, 29–35.

Meneses, A., & Hong, E. (1994b). Mechanisms of action of 8-OH-DPAT on learning and memory.Pharmacology Biochemistry Behavior, 49, 1083–1086.

Meneses, A., & Hong, E. (1997a). A pharmacological analysis of serotonergic receptors: Effects oftheir activation or blockade in learning. Progress in Neuro-Psychopharmacology and Biolog-ical Psychiatry, 21, 273–296.

Meneses, A., & Hong, E. (1997b). Role of 5-HT1A receptors in the acquisition, consolidation, andretrieval of learning. CNS Drug Review, 3, 68–82.

O’Dowd, B. S., Zhao, W. Q., Ng, K. T., & Robinson, S. R. (1997). Chicks injected with antisera toeither S-100a or S-100b protein develop amnesia for a passive avoidance task. Neurobiologyof Learning and Memory, 67, 197–206.

Riekkinen, P. (1994). 5-HT1A and muscarinic acetylcholine receptors jointly regulate passiveavoidance behavior. European Journal of Pharmacology, 262, 77–90.

Riekkinen, M., Tolonen, R., & Riekkinen, P. (1994). Interaction between 5-HT(1A) and nicotiniccholinergic receptors in the regulation of water maze navigation behavior. Brain Research,649, 174–180.

Riekkinen, M., Sirvio, J., Toiven, T., & Riekkinen, P. (1995). Combined treatment with a 5-HT1A

receptor agonist and a muscarinic acetylcholine receptor antagonist disrupts water mazenavigation behavior. Psychopharmacology, 122, 137–146.

Samanin, R., Luschi, R., Vezzani, A., & Carli, M. (1994). Impairment of spatial learning inducedby intra-hippocampal scopolamine: Its reversal by arecoline, ondansetron and intrahippocam-pal (1)-WAY 100135. Society of Neuroscience Abstracts, 20, 149.

Sirvio, J., Riekkinen, P., Jakala, P., & Riekkinen, P. J. (1994). Experimental studies on the role ofserotonin in cognition. Progress in Neurobiology, 43, 363–379.

Stanhope, K. J., McLenachan, A. P., & Dourish, C. T. (1995). Dissociation between cognitive and


motor/motivational deficits in the delayed matching to position test: Effects of scopolamine,8-OH-DPAT, and EAA antagonists. Psychopharmacology, 122, 268–280.

Waszczak, B. L., Martin, L. P., & Jackson, D. M. (1996). Inhibition of dorsal raphe cell firing byputative 5-HT1A antagonists: 5-HT1A partial agonism or a-adrenergic blockade? Society ofNeuroscience Abstracts, 22, 1322.

Whitaker-Azmitia, P. M., & Azmitia, E. C. (1994). Astroglial 5-HT1A receptors and S-100b indevelopment and plasticity. Perspectives Development Neurobiology, 2, 233–238.

Wright, D. E., Seroogy, K. B., Lundgren, K. H., Davis, B. M., & Jennes, L. (1995). Comparativelocalization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain. Journal Compar-ative Neurology, 351, 357–373.

Yu, H., Hoo, B. B., Hacksell, U., & Lewander, T. (1996). The (S)-UH-301 induced inhibition of a ratbrain serotonin and dopamine synthesis do not seem to be mediated by 5-HT1A receptors.Society of Neuroscience Abstracts, 22, 1327.

Zhang, J. Y., Zeise, M. L., & Wang, R. Y. (1994). Serotonin3 receptor agonists attenuate glutamate-induced firing in rat hippocampal CA1 pyramidal cells. Neuropharmacology, 33, 483–491.

Zifa, E., & Fillion, G. (1992). 5-Hydroxytryptamine receptors. Pharmacological Reviews, 44,401–458.

Zola-Morgan, S., & Squire, L. R. (1993). Neuroanatomy of memory. Annual Review of Neuro-science, 16, 547–563.


Documents

5-HT1AReceptors Modulate the Consolidation of Learning in Normal and Cognitively Impaired Rats