Passive Avoidance

There is evidence that the dorsal striatum is involved in aversive conditioning. Lesions of this cerebral structure produce deficits in active avoidance (Winocur 1974) and passive avoidance learning (Winocur 1974; Prado-Alcala et al. 1975). Passive avoidance learning is based on the innate preference of rodents for darkness. An inescapable shock is given to the animals when they enter the dark compartment of an apparatus containing a dark and an illuminated compartment. The suppression of the innate preference as consequence of the shock serves as a measure of learning (retention of this memory is tested 24 h later). The serotoninergic modulation of this passive avoidance has been observed in studies in which modulation of 24-h posttraining retention occurs after application of serotonin agents. Specifically, the posttraining application of the 5-HT1A receptor agonist 8-hydroxy-2-(di-«-propylamino) tetralin (8-OH-DPAT) (0.1-0.3 mg/kg subcutaneously [SC]) produced a dose-dependent deficit in the 24-h retention test (Misane and Ogren 2000).

Misane and Ogren (2000) evaluated the involvement of multiple serotonin receptors in passive avoidance using different compounds including the serotonin-releasing compound p-chloroamphetamine (PCA) (0.3, 1.0, and 3.0 mg/kg intraperitoneal IP]) in rats, showing PCA impairment in this task, which has been related to the PCA-induced release of serotonin, when evaluated 24 h after training. This impairment was antagonized by the selective 5-HT-reuptake inhibitor zimelidine, whereas no effect was observed after desipramine administration (inhibitor of the noradrenaline reuptake), showing the involvement of serotonin on the detrimental effect of PCA (Ogren 1985, 1986). Similarly, Santucci et al. (1996) showed that increased serotoninergic activity after p-chlorophenylalanine (PCPA) administration in rats induces deficits in passive avoidance, related to the acute increase of serotonin but not to the subsequent serotonin depletion.

In accordance with this finding, the intrastriatal infusion of serotonin produces retention deficits in inhibitory avoidance tests (Prado-Alcala et al. 2003a).

Concerning the specific role of 5-HT2C receptors, Martin et al. (1998) administered the 5-HT2C agonist (S)-2-(4,4,7-trimethyl-1,4,-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine (Ro 60-0332) (5 mg/kg SC) and observed an amelioration of the passive avoidance deficits caused by bulbectomy in the rat. Bulbectomy is used as a model for depression in the rat because it produces disturbed emotive behavior and impaired passive avoidance acquisition that is ameliorated by antidepressant treatment (Broekkamp et al. 1980). Misane and Ogren (2000) also administered m-chlorophenylpiperazine (mCPP) (3.0 and 5.0 mg/kg IP), a 5-HT2A/2C/1B receptor agonist, before the passive avoidance test and observed that mCPP produced a dose-related impairment of memory in the 24-h retention test. Apparently, the effect was mediated through 5-HT1A receptor activation because the impairment was reversed by the application of 5-HT1A receptor antagonists, whereas the authors did not observe any effect mediated by 5-HT2C receptors. However, the simultaneous application of the 5-HT2C receptor antagonist N-(2-naphthyl)-N'-(3-pyridyl)-urea (Ro 60-0491) (3.0 mg/kg IP) with mCPP, was able to block the inhibitory effect of mCPP, suggesting an indirect modulatory role for 5-HT2C receptors. Recently, Marquis (Marquis et al. 2007) tested the 5-HT2C receptor agonist (7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b](Aouizerate et al. 2005; Roth 1994)diaxepino[6,7,1hi]indole (WAY 163909) and observed a dose-dependent reduction in the avoidance response (0.3-3 mg/kg IP) at doses that had little or no effect on the number of failures to escape. The effect was blocked by the application of the 5-HT2B/2C receptor antagonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (SB 206553) (10.0 mg/kg p.o.).

From previous findings, we can summarize that agonists of 5-HT2C (mCPP and WAY 163909) administered systemically produced impairment of passive avoidance tasks that were reversed by the administration of specific 5-HT2C receptor antagonists (Ro 60-0491 and SB 206553), supporting an inhibitory role for 5-HT2C receptor activation on memory in retention tests. Di Giovanni et al. (2000) have reported that mCPP IP administration decreased in a dose-dependent manner the firing rate of ventral tegmental area dopaminergic neurons and the basal firing rate of dopaminergic neurons from the substantia nigra pars compacta. These changes were associated with a decrease in dopamine release in the nucleus accumbens. All effects were blocked by the application of the 5-HT2C receptor antagonist 6-chloro-5-methyl-N-[6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl]indoline-1-carboxamide (SB 242084). Thus, the inhibitory effect of 5-HT2C receptors on mesolimbic and nigrostriatal dopaminergic function could underlie the effects of 5-HT2C activation or inactivation in passive avoidance tests. The 5-HT2C receptor antagonist SB 206553, dose-dependently increases dopamine levels in the prefrontal cortex, accumbens, and striatum (Gobert et al. 2000) similarly to SB 242084, whereas the 5-HT2C receptor agonist (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine (Ro 60-0175) reduced dopamine levels in the same areas. Thus, the increase and decrease of dopamine function could be related to the deficit of retention produced by 5-HT2C agonists in passive avoidance tests.

Blocking of 5-HT2 receptors, through the bilateral intrastriatal infusion of ketan-serin (5-HT2A/2C receptor antagonist; 0.5, 1.0, 2.0, and 4.0 ng) immediately after inhibitory avoidance training, induced a dose-dependent retention deficit when tested 24 h later (Prado-Alcala et al. 2003b). Lucas and Spampinato (2000) reported that the intrastriatal infusion of SB 206553 reduced the dopamine efflux in freely moving rats, whereas the 5-HT2A receptor antagonist 1(Z)-[2-(dimethylamino) ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene (SR 46349B) had no effect on dopamine efflux. Thus, the impairment in passive avoidance observed by these authors could be related to a decrease in dopamine efflux in the striatum caused by ketanserin acting through 5-HT2C antagonism. However, this interpretation could be an over simplification of striatal neurotransmitter interactions. For example, the role of striatal acetylcholine on consolidation processes in passive avoidance has been extensively demonstrated. The posttraining intrastriatal infusion of atropine (acetylcholine antagonist) and scopolamine (cholinergic mus-carinic antagonist) impairs passive avoidance in a dose-dependent manner (Prado-Alcala et al. 1984, 1985; Quirarte et al. 1993). Moreover, experiments evaluating passive avoidance under dopaminergic manipulation showed a detrimental effect mediated through the activation of D2 receptors (Ichihara et al. 1992). So, it is clear that studies that specifically evaluate 5-HT2C receptor activity in specific cerebral areas are required to gain a more complete understanding of their role in learning processes, including the 5-HT2C modulation (and modulation of all other receptors) of dopamine and acetylcholine, acting either locally in the striatum or on dopamin-ergic systems to influence the organization of passive avoidance learning.

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