KEY WORDS : Passive avoidance; 5-HT receptors; 8-OH-DPAT; p-chloroamphetamine (PCA); m-chlorophenylpiperazine (mCPP); dopamineSerotonergic (5-HT) projections, arising from the midbrain raphe nuclei (Jacobs and Azmitia 1992; Vertes 1991) innervate limbic (amygdala and hippocampus) and cortical areas known to be involved in the cognition and processing of emotional events (Ambrogi Lorenzini et al. 1998;Gallagher and Chiba 1996;Heilman and Gilmore 1998;Lavond et al. 1993;Ledoux and Müller 1997;Pezzone et al. 1992).To investigate the role of the limbic and cortical 5-HT in behavior, different appproaches have been employed ranging from manipulations that result in multiple re- Received December 23, 1998; revised May 18, 1999; accepted July 13, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 2 Multiple 5-HT Receptors in Passive Avoidance 169 ceptor stimulation to the selective activation of 5-HT receptor subtypes. The former approach is of particular importance, because 5-HT neurotransmission seems to operate largely via non-or extrasynaptic mode of communication, also known as volume transmission (Agnati et al. 1995;Bunin and Wightman 1998;Descarries et al. 1990;Descarries et al. 1975;Dewar et al. 1991;Jansson et al. 1998). Thus, released 5-HT can act at a distance at multiple 5-HT receptors far away from the synaptic cleft, whereas selective 5-HT agonists act on all receptors of a specific subtype.Earlier studies have shown that treatments that increase 5-HT activity in the brain, such as 5-HT-releasing compounds [p-chloroamphetamine (PCA), MDMA, and MMAI] (Marona- Lewicka et al. 1996;McNamara et al. 1995;Ögren 1985b;Romano and Harvey 1994;Santucci et al. 1996) as well as the selective 5-HT reuptake inhibitors (SSRIs) (Altman et al. 1984;Lalonde and Vikis-Freibergs 1985;Lucki and Nobler 1985;McElroy et al. 1982;Meneses and Hong 1995;Ögren 1985b) can both enhance and impair performance in aversive learning tasks. Pretraining administration of PCA has been found to produce a marked impairment of both one-and two-way active avoidance acquisition and retention in the rat (Ögren 1982).Although PCA also causes an acute release of dopamine (DA) (Crespi et al. 1997;Henderson et al. 1993;Johnson et al. 1990;Ögren 1985b;Sharp et al. 1986) as well noradrenaline (NA) (Ögren 1982; Ögren 1985a) in the rat brain, its behavioral effects are mediated primarily via serotonergic mechanisms (Adell et al. 1989;Geyer 1996;Hutson and Curzon 1989;Trulson and Jacobs 1976). In support of this, the one-way active avoidance deficit by PCA was completely blocked when the rats were pretreated with 5-HT reuptake inhibitors zimeldine and fluoxetine but not by the NA uptake inhibitor desipramine (Ögren 1982). Zimeldine also blocked the 5-HT release induced by PCA (Ögren et al. 1982). Several nonselective 5-HT 2 antagonists, which, by themselves, did not impair avoidance learning, also produced a dose-dependent blockade of the PCAinduced deficit (Ögren 1986b). This finding suggested that the impairment of active avoidance acquisit...