Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

Rationale  

5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia.     

5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine

5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating which is often affected in schizophrenic patients, we tested whether Ro 4368554, a 5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro 4368554 altered fear conditioning using fear potentiated startle, a model for emotional learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg) when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine (0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or Ro 4368554 were administered before two daily fear conditioning sessions; rats were tested on the following day. Rats that received scopolamine displayed no fear potentiated startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped Fos induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased Fos expression in the central nucleus of the amygdala and this was attenuated by Ro 4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related disorders.     

5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice

Rationale

Blockade of 5-HT6 receptors (5-HT6R) is known to improve cognitive performances in the rodent. This improvement has been hypothesized to be the result, at least in part, of a modulation of the cholinergic neurotransmission.

Objective

We assessed the effects of 5-HT6R blockade on selected types of memory relevant to functional deficits of ageing and neurodegenerative diseases, in mice that present a scopolamine-induced cholinergic disruption of memory.

Method

Following the selection of an adequate dose of scopolamine to induce cognitive deficits, we have studied the effects of the selective 5-HT6R antagonist SB-271046, alone or in combination with scopolamine, on working memory (spontaneous alternation task in the T-maze), recognition memory (place recognition) and aversive learning (passive avoidance).

Results

SB-271046 alone failed to affect working memory, recognition memory and aversive learning performances. In contrast, SB-271046 was able to reverse the scopolamine-induced deficits in working memory (only at 30?mg?kg^?1) and those of acquisition and retrieval of aversive learning (dose-dependent effect); scopolamine-induced deficits in episodic-like memory (acquisition and retrieval) were partially counteracted by 5-HT6R blockade.

Conclusion

The modulation between 5-HT6R and the cholinergic system appears to be predominant for working memory and aversive learning, but not for other types of memory (i.e. episodic-like memory). Interactions between 5-HT6R and alternative neurotransmission systems (i.e. glutamatergic system) should be further studied. The respective involvement of these interactions in the memory disorders related to ageing and neurodegenerative diseases is of pivotal importance regarding the possible use of 5-HT6R antagonists in the treatment of memory disorders in humans.     

Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats.

Serotonin (5-hydroxytryptamine, or 5-HT) is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. However, there is little information on the contribution of different 5-HT receptors in reversal learning. Thus, we investigated the effects of systemic administration of the 5-HT(2A) antagonist M100907 (0, 0.01, 0.03, and 0.1 mg/kg, i.p.) and the 5-HT(2C) antagonist SB 242084 (0, 0.1, 0.3, and 1.0 mg/kg, i.p.) on the performance of an instrumental two-lever spatial discrimination and serial spatial reversal learning task, where both levers were presented and only one was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of within-session reversals was presented. Neither M100907 nor SB 242084 altered performance during spatial discrimination and retention of the previously reinforced contingencies. M100907 significantly impaired reversal learning by increasing both trials to criterion (only at the highest dose) and incorrect responses to criterion in Reversal 1, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, SB 242084 improved reversal learning by decreasing trials and incorrect responses to criterion in Reversal 1, with significantly fewer perseverative responses. These data support the view that 5-HT(2A) and 5-HT(2C) receptors have distinct roles in cognitive flexibility and response inhibition. The improved performance in reversal learning observed following 5-HT(2C) receptor antagonism suggests these receptors may offer the potential for therapeutic advances in a number of neuropsychiatric disorders where cognitive deficits are a feature, including obsessive-compulsive disorder.     

Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: A potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT_1A receptor agonist and 5-HT₃ receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT₃ receptor antagonist) or flesinoxan (5-HT_1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1 mg/kg (∼80% 5-HT₃ receptor occupancy; OR) and ≤3.0 mg/kg (5-HT_1A, 5-HT_1B, 5-HT₃ receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0 μg/kg (∼25% 5-HT₃ receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0 mg/kg (∼25% 5-HT_1A receptor occupancy; SA); only 1.0 mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT₃, 5-HT_1B, and 5-HT_1A receptors, respectively. Vortioxetine′s effects on SA performance may involve 5-HT_1A receptor agonism, but not 5-HT₃ receptor antagonism, whereas the effects on OR performance may involve 5-HT₃ receptor antagonism and 5-HT_1A receptor agonism.     

Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task

In this work we aimed to re-examine the 5-HT6 receptor role, by testing the selective antagonists SB-357134 (1-30 mg/kg p.o.) and SB-399885 (1-30 mg/kg p.o.) during memory consolidation of conditioned responses (CR%), in an autoshaping Pavlovian/instrumental learning task. Bioavailability, half-life and minimum effective dose to induce inappetence for SB-357134 were 65%, 3.4 h, and 30 mg/kg p.o., and for SB-399885 were 52%, 2.2 h, and 50 mg/kg p.o., respectively. Oral acute and chronic administration of either SB-357134 or SB-399885 improved memory consolidation compared to control groups. Acute administration of SB-357134, at 1, 3, 10 and 30 mg/kg, produced a CR% inverted-U curve, eliciting the latter dose a 7-fold increase relative to saline group. Acute injection of SB-399885 produced significant CR% increments, being 1 mg/kg the most effective dose. Repeated administration (7 days) of either SB-357134 (10 mg/kg) or SB-399885 (1 mg/kg) elicited the most significant CR% increments. Moreover, modeling the potential therapeutic benefits of 5-HT6 receptor blockade, acute or repeated administration of SB-399885, at 10 mg/kg reversed memory deficits produced by scopolamine or dizocilpine, and SB-357134 (3 and 10 mg/kg) prevented amnesia and even improved performance. These data support the notion that endogenously 5-HT acting, via 5-HT6 receptor, improves memory consolidation.     

D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D₁-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P < 0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D₁-like receptor antagonist (P < 0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P < 0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P < 0.05). These results suggest a role for D₁-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.     

Involvement of 5-HT receptors in learning and memory

Cumulative evidence indicates that the serotonin (5-HT) system plays a modulatory role in cognitive processes, particularly in learning and memory. The present review focuses on the effects of agonists and antagonists on different 5-HT receptors, administered during pre-learning, post-learning or pre-retention, in different behavioral tasks. The effects of these pharmacological compounds were either facilitative or disruptive, or allowed for recovery from impaired cognitive performance following the activation or blockade of 5-HT(1), 5-HT(2), 5-HT(3) and 5-HT(4) receptors. Since little or no data on learning and memory are currently available for the 5-ht(5), 5-ht(6) and 5-HT(7) receptors, this article presents an overview of their brain locations and possible involvement in these highly cognitive processes.     

5-HT(6) receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

BACKGROUND AND PURPOSE

5-HT₆ receptors are abundant in the hippocampus, nucleus accumbens and striatum, supporting their role in learning and memory. Selective 5-HT₆ receptor antagonists produce pro-cognitive effects in several learning and memory paradigms while 5-HT₆ receptor agonists have been found to enhance and impair memory.

EXPERIMENTAL APPROACH

The conditioned emotion response (CER) paradigm was validated in rats. Then we examined the effect of the 5-HT₆ receptor antagonist, EMD 386088 (10 mg·kg⁻¹, i.p.), and agonists, E-6801 (2.5 mg·kg⁻¹, i.p.) and EMD 386088 (5 mg·kg⁻¹, i.p.) on CER-induced behaviour either alone or after induction of memory impairment by the muscarinic receptor antagonist, scopolamine (0.3 mg·kg⁻¹, i.p) or the NMDA receptor antagonist, MK-801 (0.1 mg·kg⁻¹, i.p).

KEY RESULTS

Pairing unavoidable foot shocks with a light and tone cue during CER training induced a robust freezing response, providing a quantitative index of contextual memory when the rat was returned to the shock chamber 24 h later. Pretreatment (−20 min pre-training) with scopolamine or MK-801 reduced contextual freezing 24 h after CER training, showing production of memory impairment. Immediate post-training administration of 5-HT₆ receptor antagonist, SB-270146, and agonists, EMD 386088 and E-6801, had little effect on CER freezing when given alone, but all significantly reversed scopolamine- and MK-801-induced reduction in freezing.

CONCLUSION AND IMPLICATIONS

Both the 5-HT₆ receptor agonists and antagonist reversed cholinergic- and glutamatergic-induced deficits in associative learning. These findings support the therapeutic potential of 5-HT₆ receptor compounds in the treatment of cognitive dysfunction, such as seen in Alzheimer''s disease and schizophrenia.     

Chronic tryptophan deprivation attenuates gating deficits induced by 5-HT1A,but not 5-HT2 receptor activation

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a multifaceted function in the modulation of information processing, through the activation of multiple receptor families. In particular, stimulation of 5-HT_1A and 5-HT_2A receptors leads to sensorimotor gating impairments and perceptual perturbations. Previous evidence has shown that chronic deprivation of l-tryptophan (TRP), the precursor of 5-HT, results in marked reductions of 5-HT brain levels, as well as neuroplastic alterations in 5-HT_1A and 5-HT_2A expression and/or signaling. Building on these premises, in the present study we tested whether a prolonged TRP deprivation may differentially impact the roles of these receptors in the regulation of the prepulse inhibition (PPI) of the acoustic startle reflex, a dependable index of gating. Male Sprague-Dawley rats were fed for 14 days with either a regimen with negligible TRP content (TR?) or the same diet supplemented of TRP (TR+). At the end of this schedule, rats were treated with the prototypical 5-HT_1A receptor agonist 8-OH-DPAT (62.5–250 μg/kg, subcutaneous, s.c.) or the 5-HT₂ receptor agonist DOI (0.25–1 mg/kg, s.c.). Notably, the PPI deficits induced by 8-OH-DPAT in TR? rats were significantly milder than those observed in their TR+ counterparts; these effects were fully prevented by the 5-HT_1A antagonist WAY-100135 (10 mg/kg, intraperitoneal). Conversely, TRP deprivation did not affect the PPI-disrupting properties of DOI. These findings suggest that prolonged 5-HT depletion attenuates the influence of 5-HT_1A, but not 5-HT₂ receptors on sensorimotor gating, confirming the distinct mechanisms of these two targets in PPI regulation.     

维生素E对阿尔茨海默病模型学习记忆能力损伤的改善作用

目的：观察维生素E对阿尔茨海默病（AD）模型小鼠学习记忆能力的改善作用及其机制。方法：采用D-gal与NaNO2联合腹腔注射方法建立AD模型小鼠,在造模同时及模型建立后两个时间点灌胃给予维生素E（28,280IU／kg）观察疗效,实验结束后水迷宫检测各组小鼠的逃避潜伏期的变化,化学比色法检测脑组织AChE、SOD活性、MDA含量;免疫组织化学方法检测大脑皮层Aβ、NF-B表达的变化。结果：造模同时给予维生素E可使D-gal与NaNO2联合诱导的AD模型鼠的逃避潜伏期缩短[第1天F（3,56）=6．959;第2天F（3,56）=6．689;第3天F（3,56）=17．379;第4天F（3,56）：13．391;P〈0．05],AChE活性降低[F（3,28）=29．431,P〈0．05],SOD活性提高[F（3,28）=7．372,P〈0．05],MDA含量降低[F（3,28）=11．235,P〈0．05];同时可明显降低AD模型鼠脑组织中Aβ、NF-κB的表达（P〈0．05）。模型建立后给予维生素E未发现上述变化。结论：维生素E可预防化学诱导的AD模型小鼠学习记忆能力损伤,可能机制与提高SOD活性、降低MDA含量、降低AChE活性、降低脑组织中Aβ、NF-κB的表达等相关。     

The 5-HT1A receptor full agonist, 8-OH-DPAT inhibits ACTH-induced 5-HT2A receptor hyperfunction in rats: involvement of 5-HT1A receptors in the DOI-induced wet-dog shakes in ACTH-treated rats

We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats.     

5-HT(1A) receptor activation improves anti-cataleptic effects of levodopa in 6-hydroxydopamine-lesioned rats

Background and the purpose of the study

In Parkinson›s disease (PD) prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID). In this investigation the effect of 8-OHDAPT, as a 5-HT_1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA) lesioned male Wistar rats was investigated.

Methods

Catalepsy was induced by unilateral injection of 6-OHDA (8 µg/2µl/rat) into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p.) L-DOPA (15 mg/kg) twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20.

Results and major conclusion

The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p.) and L-DOPA (15 mg/kg, ip). 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OHDAPT) improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was abolished by 1-(2-methyoxyphenyl)-4-[4-(2-phthalamido) butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p.) as a 5-HT_1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT_1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT_1A and dopaminergic neurons.     

Involvement of 5-HT6 receptors in nigro-striatal function in rodents

1. 4-Amino-N-(2,4 bis-methylamino-pyrimidin-4-yl) benzene sulphonamide (Ro 04-6790) is a potent, selective and competitive antagonist for the 5-HT₆ receptor which can be detected in the cerebro-spinal fluid (CSF) of rats following intraperitoneal administration. Since 5-HT₆ receptor mRNA and 5-HT₆ receptor-like immunoreactivity have been shown to be present in the striatum, the purpose of the present study was to evaluate the effect of 5-HT₆ receptor antagonism on haloperidol- and SCH 23390-induced catalepsy in mice and on the turning behaviour of rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle.
2. Ro 04-6790 (3, 10 and 30 mg kg⁻¹ i.p.) did not induce catalepsy and had no effect on catalepsy induced by either haloperidol or SCH 23390.
3. Ro 04-6790 (3, 10 and 30 mg kg⁻¹ i.p.) did not itself induce rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle nor did it affect the rotational behaviour induced by either L-Dopa or amphetamine.
4. 5-HT₆ receptor antagonism inhibited the rotational behaviour of 6-OHDA lesioned rats induced by treatment with the muscarinic antagonists scopolamine and atropine.
5. The data support earlier conclusions from experiments with antisense oligonucleotides that the 5-HT₆ receptor is involved in the control of acetylcholine neurotransmission in the rat brain.

     

Serotonin-glutamate interaction in rat cerebellum: involvement of 5-HT1 and 5-HT2 receptors

The effects of serotonin (5-HT) on the release of endogenous glutamate (GLU) in rat cerebellum were investigated in slices depolarized with 35 mM K+. The Ca2+-dependent release of GLU was potently inhibited by 5-HT in a concentration-dependent way. Release was also inhibited by the 5-HT1 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and by the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The inhibition by 10 nM 5-HT was partly (35-40%) counteracted by the 5-HT2 receptor antagonist ketanserin but was fully blocked by the mixed 5-HT1/5-HT2 receptor antagonist methiothepin. The effect of 8-OH-DPAT was not affected by ketanserin but was totally antagonized by methiothepin, while the effect of DOI was entirely suppressed by ketanserin. Ketanserin or methiothepin themselves increased (by 23 and 55%, respectively, at 10 nM) the K+-evoked release of GLU. In conclusion the release of endogenous GLU in rat cerebellum can be inhibited by 5-HT through receptors of the 5-HT1 and 5-HT2 type. The enhancement of GLU release by ketanserin or methiothepin could suggest a tonic inhibition. The possible localization of the 5-HT receptors involved in the interaction with the GLU systems is discussed.     

The His452Tyr variant of the gene encoding the 5-HT2A receptor is specifically associated with consolidation of episodic memory in humans

Basic research has shown that serotonin plays an important role in memory formation. Accordingly, genetic variation of serotonin receptors can be expected to affect memory and to underlie, in part, the heritability of memory capacity. A study by de Quervain and colleagues found a highly significant association of the functional 5-HT2A receptor variant His452Tyr (rs6314) with long-term memory. We replicated this finding in a cohort of 133 adults (mean age 43.5 yr). Carriers of the Tyr allele showed poorer verbal delayed recall and recognition, while immediate recall and additional measures of attentional and executive function were not affected by the His452Tyr genotype. Results suggest a possible role of 5-HT2A receptors in memory consolidation. Serotonergic drugs may have the potential to improve memory.     

Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats

Rationale

Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits.

Objective

We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test.

Results

MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25–1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit.

Conclusion

The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs.     

Effect of serotonin depletion on 5-HT2A-mediated learning in the rabbit: evidence for constitutive activity of the 5-HT2A receptor in vivo

Rationale Associative learning during Pavlovian eyeblink conditioning has been shown to be regulated by 5-HT_2A receptors. The existence of inverse agonists that retard learning through an action at the 5-HT_2A receptor suggests the existence of constitutive activity at that receptor and that depletion of serotonin should have minimal effects on learning. Objectives We examined whether depletion of serotonin would impair trace eyeblink conditioning or the enhancement of conditioning produced by the agonist lysergic acid diethylamide (LSD) and the retardation of conditioning produced by the inverse agonist MDL11,939. Methods Animals received bilateral intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) at doses of 760 or 1,140 μg/side (1.88 or 2.82 μmol/side) and were later exposed to eight daily conditioning sessions. Results Serotonin depletion produced by the lower dose of 5,7-DHT was 71 and 72% in cortex and hippocampus, respectively, with no change in 5-HT_2A receptor density, no effect on learning, and no effect on the ability of LSD to enhance and MDL11,939 to retard learning. The higher dose of 5,7-DHT produced serotonin decreases of 85 and 90% in cortex and hippocampus, respectively, accompanied by a 96% decrease in the density of the serotonin transporter, but no significant effect on learning. Conclusions Pavlovian trace eyeblink conditioning is regulated predominantly by the constitutive activity of the 5-HT_2A receptor rather than by serotonin release onto the receptor during learning. It was suggested that the 5-HT_2A receptor regulates learning by modulating the release of dopamine, acetylcholine, and glutamate, transmitters known to affect eyeblink conditioning.     

Role of 5-HT6 receptors in memory formation

Mice lacking the 5-HT(6) receptor presented neither gross anatomical or behavioral abnormalities nor obvious changes in microscopic brain morphology, and their performance in rotarod, open field and novel object testing paradigms revealed no differences compared with wild-type animals. Nevertheless, an association between the 5-HT(6) receptor polymorphism C267T and Alzheimer's disease has been reported. Interestingly, the 5-HT(6) antisense oligonucleotide decreased 5-HT(6) gene expression and enhanced spatial learning acquisition in the water maze. Similarly, injection of the 5-HT(6) receptor antagonist Ro-04-6790 improved learning consolidation in an autoshaping task, while mCPP, scopolamine and dizocilpine decreased performance. The effect induced by scopolamine or dizocilpine, but not that induced by mCPP, was completely or partially reversed by Ro-04-6790. Ro-04-6790 did not modify the 8-OH-DPAT facilitatory effects on learning consolidation. Since Ro-04-6790 facilitatory effect was unaffected by 5-HT(1A), 5-HT(2A/2B/2C), 5-HT(3), 5-HT(4) or 5-HT(7) receptor blockade, the facilitatory effect induced by Ro-04-6790 involved specifically 5-HT6 receptors. Similarly, the 5-HT(6) receptor antagonist SB-271046 improved retention in the water maze and produced a significant performance improvement in aged rats in an operant-delayed alternation task. A series of Ro-04-6790 analogues that penetrate the brain and specifically bind to 5-HT(6) receptors reversed scopolamine-induced retention deficit in a passive avoidance learning test. Collectively, these data provide further support to the notion that 5-HT systems, via 5-HT(6) receptors, also play a significant role in memory formation under normal and dysfunctional memory conditions.