Autoshaping Learning Test

Auto-shaping learning tests consist of a Pavlovian instrumental test, which requires striatal (stimulus-response habit formation) participation (Meneses 2002a), and prefrontal interaction, particularly of the orbitofrontal cortex (Chudasama and Robbins 2003). The auto-shaping learning test is conducted in an operant chamber in which ten trials are given in a first test and 20 trials are given in a second test to food-deprived animals. A trial consists of the presentation of an illuminated retractable lever for 8 s (conditioned stimulus) followed by delivery of a food pellet (unconditioned stimulus) with a 60-s intertrial interval. When the animals press the lever the trial is shortened, the lever retracted, the light turned off, and the food pellet is immediately delivered. The response during the lever presentation is regarded as a conditioned response. The increase or decrease of conditioned responses is considered as enhancement or impairment of learning, respectively. The first session (training) occurs 24 h before the retention test and the treatments are administered immediately after the first session of training (Meneses 2002b). In rats, 5-HT depletions produce an increase in the speed and number of responses in this task (Winstanley et al. 2004a), whereas the administration of serotonin uptake inhibitors such as fluoxetine (10 mg/kg IP) increases the proportion of conditioned responses, when tested shortly (1.5 h) after drug administration or longer (24 h) (Meneses 2007a).

Meneses and Hong (1997) tested the effects of several 5HT receptor antagonists as well as an uptake inhibitor and 5-HT depleters on the auto-shaping task. The results showed that both postsynaptic stimulation of 5-HT2A/2C/1B (through mCPP administration, 5 and 10 mg/kg IP) and postsynaptic blockade of 5-HT2B/2C receptors through [1-(naphthyl)piperazine, 1-NP; 0.5-1.0 mg/kg IP] impaired the memory. Moreover, an improvement of this cognitive function occurred after presynaptic activation of 5-HT2C receptors by administration of (±)-2,5-dimethoxy-4-iodoamphet-amine (DOI), a 5-HT2A/2C receptor agonist (0.01 and 0.1 mg/kg IP), or presynaptic blockade of 5-HT2C receptors through 6-(2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (ketanserin), a 5-HT2A/2C receptor antagonist (0.001, 0.01, and 0.1 mg/kg IP) and ritanserin (0.5 mg/kg), result in improvement in the retention test 24 h later. In addition, the injection of 5 and 10 mg/kg of 1-(3-trifluoromethyl)phenyl)piperazine (TFMPP), a 5-HT2A/2B/2C agonist, or mesulergine (0.4 mg/kg) decreased the rate of conditioned responses, indicating impairment of memory (Meneses and Hong 1997). In a later work, Meneses (Meneses 2002b) analyzed the participation of 5-HT2 receptors in the auto-shaping learning task and observed that the posttraining administration of N-(1-methyl-indolyl)-N'-(3-pyridyl)urea (SB 200646; 2-20 mg/kg IP), a selective 5-HT2B/2C receptor antagonist, had no effect on consolidation; however, it was able to antagonize the memory impairment induced by mCPP, 1-NP, and mesulergine and to attenuate the impairment produced by TFMPP administration even though SB 200646 was unable to block the memory enhancement caused by DOI and ketanserin. Recently, Meneses evaluated the effect of different agonists and antagonists of 5-HT receptors in short-term memory (STM), tested 1.5 h after the training session, and long-term memory (LTM), testing 24 h after the training session in the auto-shaping test (Meneses 2007a). Both STM and LTM were impaired by mCPP and mesulergine, a 5-HT2C antagonist (although it displays affinity for 5-HT2C/2A/7 receptors), at doses of 1.0, 5.0, and 10.0 mg/kg IP, while DOI also impaired STM(0.1, 0.5, and 1.0 mg/kg) and LTM (1.0 mg/kg). In other work, it was found that the administration of SB 200646 (2 mg/ kg IP) significantly increased the number of conditioned responses in rats in the LTM test but not in the STM test (Meneses 2007b).

Studies aimed to evaluate auto-shaping learning after the administration of highly specific 5-HT2C agonists or antagonist compounds have not been carried out. However, the results summarized here serve to highlight the fact that the nonselec-tive agonists mCPP and TFMPP impair animal performance, whereas the agonist DOI leads to either impairment or improvement, depending on the dose. The detrimental effect of mCPP and TFMPP could be mediated through 5-HTB receptors because, as Meneses (Meneses 2007a) showed, 7-trifluoromethyl-4(4-met-hyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline maleate (CGS-12066A), a 5-HT1B agonist, causes impairment in this task when administered at doses of 10 mg/kg. Accordingly, Meneses (2003) reported that deficits in learning have been observed after the presynaptic overstimulation of 5-HT1B receptors by drugs displaying high affinity for 5-HT1B receptors, including mCPP and TFMPP. Moreover, antagonism of 5-HT1B/1D receptors through 2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)-biphenyl]-amide (GR 127935) increases the consolidation (Meneses et al. 1997).

In line with this interpretation, 1-NP has been reported to act as a 5-HT1B agonist (Hoyer 1988).

The 5-HT2A/2B/2C receptor agonist TFMPP causes impairment in consolidation that could be related to the agonism on 5-HT2B receptors. In fact, DOI, an agonist of 5-HT2A/2C receptors, improves the consolidation through 5-HT2A receptors, as can be inferred from the effects of the antagonist of 5-HT2A (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), which abolishes the improving effect induced by DOI, that is not affected by SB 200646 (Meneses et al. 1997). The 5-HT2B/2C receptor antagonist SB 200646 has no effect when administered alone (2 mg/kg IP) but is able to prevent the impairment in memory consolidation caused by mCPP and TFMPP. This may support an effect of SB 200646 through 5-HTB receptor blockade since, as mentioned previously, TFMPP also has affinity for 5-HT1B receptors. However, recently, Meneses (2007a, b) also reported that SB 200646 was able to increase the proportion of conditioned responses in LTM but not in STM. The possible influence of extra training provided by the STM session in which the antagonists had no effect and the proposed better efficacy of SB 200646 as a 5-HT2B antagonist (Hannon and Hoyer 2008) in these effects deserves further research.

In this sense, some apparently contradictory results show that DOI, acting as agonist, as well as ketanserin and ritanserin, acting as antagonists of 5-HT2A/2C receptors, improved the consolidation, while mesulergine caused impairment in memory consolidation by acting through 5-HT2A/2C/7 receptor antagonism. Since it has been proposed that the DOI effect was mediated by 5-HT2A receptors and that 5-HT2A and 5-HT7 antagonists were inactive in this task (Meneses 2007a; Meneses et al. 1997), it seems possible that both impairment and improvement would be observed after 5-HT2C activation. However, experimental data concerning the effects of highly specific 5-HT2C agonists and antagonists have still to be obtained in order to gain information to clarify these apparently conflicting findings.

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