No abstract

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...

A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.

The present studies have examined whether the neuropeptide galanin can modulate brain serotoninergic (5-HT) neurotransmission in vivo and, particularly, 5-HT1A receptor-mediated transmission. For that purpose, we studied the ability of galanin (given bilaterally into the lateral ventricle, i.c.v.) to modify the impairment of passive avoidance retention induced by the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propyloamino)tetralin (8-OH-DPAT) when injected prior to training. This impairment appears to be mainly related to activation of 5-HT1A receptors in the CNS. Galanin dose-dependently (significant at 3.0 nmol/rat) attenuated the passive avoidance impairment (examined 24 h after training) induced by the 0.2 mg/kg dose of 8-OH-DPAT. This 8-OH-DPAT dose produced signs of the 5-HT syndrome indicating a postsynaptic 5-HT1A receptor activation. Furthermore, both the impairment of passive avoidance and the 5-HT syndrome were completely blocked by the 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg). Galanin (0.3 or 3.0 nmol) or WAY 100635 (0.1 mg/kg) failed by themselves to affect passive avoidance retention. 8-OH-DPAT given at a low dose 0.03 mg/kg, which presumably stimulates somatodendritic 5-HT1A autoreceptors in vivo, did not alter passive avoidance retention or induce any visually detectable signs of the 5-HT syndrome. Galanin (0.3 or 3.0 nmol) given i.c.v. in combination with the 0.03 mg/kg dose of 8-OH-DPAT, did not modify passive avoidance. The immunohistochemical study of the distribution of i.c.v. administered galanin (10 min after infusion) showed a strong diffuse labelling in the periventricular zone (100-200 microm) of the lateral ventricle. Furthermore, in the dorsal and ventral hippocampus galanin-immunoreactive nerve cells appeared both in the dentate gyrus and the CA1, CA2 and CA3 layers of the hippocampus. In the septum only endogenous fibres could be seen while in the caudal amygdala also galanin-immunoreactive nerve cells were visualized far away from the labelled periventricular zone. At the level of the dorsal raphe nucleus a thin periventricular zone of galanin immunoreactivity was seen but no labelling of cells. These results suggest that galanin can modulate postsynaptic 5-HT1A receptor transmission in vivo in discrete cell populations in forebrain regions such as the dorsal and ventral hippocampus and parts of the amygdala. The indication that galanin administered intracerebroventrically may be taken up in certain populations of nerve terminals in the periventricular zone for retrograde transport suggests that this peptide may also affect intracellular events.

3,3-Diphenylcyclobutylamine (4), N-methyl-3,3-diphenylcyclobutylamine (6), and N,N-dimethyl-3,3-diphenyl-cyclobutylamine (7) have been prepared and tested as potential antidepressant agents. The secondary (6) and tertiary (7) amines strongly decrease the accumulation of NA and 5-HT in brain slices in vitro and in vivo. The cyclobutylamines also cause motor stimulation. The most potent compound in this respect is the tertiary amine 7. The increase in locomotion is not blocked by pretreatment with phenoxybenzamine, methergoline, or alpha-methyltyrosine. Pretreatment with pimozide or reserpine reduces the hyperactivity induced by 7. This hyperstimulation seems to be caused by a mechanism of action which differs from that of amphetamine. 7 may cause increase in locomotion by release of dopamine from granular stores.