Galanin (1-29) (rat, Mouse)

Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT(4) receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT(4) receptors in different experimental models of amnesia in male Swiss mice or in male Sprague-Dawley rats, tested in learning and memory tasks. Amnesia was induced in mice by intracerebroventricular (i.c.v.) injection of beta-amyloid 1-42 fragment (BAP 1-42; 400 pmol/mouse) or of galanin (GAL) 1-29 (3 microg/mouse). Another group of animals was exposed to carbon monoxide (CO). Treatments were made 14 days, 15 min or 8 days prior to the learning trial of a step-through passive avoidance paradigm, respectively. Latency to re-enter the dark box appeared to be reduced in all treatment groups. Intraperitoneal (i.p.) administration of SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one-monohydrochloride), a serotonin 5-HT(4) receptor partial agonist (1 mg/kg/day), for 7 days prior to the learning trial, inhibited the amnesic effect of both peptides increasing the latency to re-enter the dark box also in mice exposed to CO. In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1 mg/kg/day, i.p.) administered for 7 days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests. These findings give further support to the hypothesis of SL65.0155 cognition-enhancing activity across a range of tasks.

The impairment of cognitive performance by galanin administration in rodents indicates a possible modulating effect of this neuropeptide on long-term potentiation (LTP) induction in the hippocampal formation. Galnon is a non-peptide, systemically active galanin receptor agonist which has been tested in feeding, seizure and forced swim task in in vivo rodent experimental models. Similarly to galanin (1-29) (i.c.v.), galnon (i.p.) has exhibited anticonvulsant effects in rats. We have investigated the effect of galnon on the synaptic transmission and plasticity in hippocampal dentate gyrus (DG) of C57Bl/6 mice and compared the galnon effects to the effect of galanin (1-29) and galmic, a non-peptide galanin receptor agonist. Similarly to galanin (1-29) and galmic, superfusion of galnon did not alter the input-output responses in DG. Administration of galnon (1 microM) significantly attenuated the LTP induction by 85.5 +/- 1% by 51 min after high frequency trains stimulation. This result was very similar to the effect of galanin (1-29) and galmic, which caused an 80 +/- 1.5% and 94 +/- 2% reduction in the level of field potentiation, respectively. The PPF responses, however, were not altered due to galnon superfusion which is in contrast to the effect of galanin (1-29) or galmic. In summary, these data indicate that the systemically active, non-peptide galanin receptor agonist, galnon can exert similar effects to galanin (1-29) in attenuation of DG LTP in mice.

In mammals, the neuropeptide galanin exerts a variety of physiological roles in the neuroendocrine system through its interactions with three galanin receptor subtypes (GalR1, GalR2 and GalR3). However, little is known about the characteristics of galanin receptors in birds, and it is only recently that avian GalR1 and a novel GalR1-like receptor were first identified in chickens. In this study, we report the cDNA cloning and characterization of the other two chicken galanin receptors, the galanin type II receptor (cGalR2) and a novel GalR2-like receptor (GalR2-L), which share high degrees of similarity in sequence identity, gene structure and signaling properties. cGalR2 and cGalR2-L cDNAs encode two putative receptors of 371 and 370 amino acids, in which they show considerable amino acid sequence identities (65-67%, and 53-55%, respectively) with the mammalian GalR2. RT-PCR assays revealed that cGalR2 and cGalR2-L mRNA were widely expressed in the adult chicken tissues including the whole brain, intestine, lung, ovary, pituitary and different regions of the oviduct. As assayed with different luciferase reporter systems, chicken galanin (cGal 1-29) and human galanin-like peptide (hGALP 1-60) were demonstrated to stimulate the luciferase activities in Chinese hamster ovary cells expressing cGalR2 and cGalR2-L through the activations of cAMP/PKA, Ca(2+)/calcineurin and MAPK/ERK signaling pathways, hence suggesting that both receptors are functionally coupled to the G(s) and G(q) proteins. Furthermore, the previously identified cGalR1 and cGalR1-L were found to be solely coupled to the G(i/o) proteins, and the hGALP (1-60) exhibited only a low potency to cGalR1, cGalR1-L, cGalR2 and cGalR2-L activations.

The neuropeptide galanin suppresses seizure activity in the hippocampus by inhibiting glutamatergic neurotransmission. Galanin may also modulate limbic seizures through interaction with other neurotransmitters in neuronal populations that project to the hippocampus. We examined the role of galanin receptors types 1 and 2 in the dorsal raphe (DR) in the regulation of serotonergic transmission and limbic seizures. Infusion of a mixed agonist of galanin receptors types 1 and 2 [galanin (1-29)] into the DR augmented the severity of limbic seizures in both rats and wild-type mice and concurrently reduced serotonin concentration in the DR and hippocampus as measured by immunofluorescence or HPLC. In contrast, injection of the galanin receptor type 2 agonist galanin (2-11) mitigated the severity of seizures in both species and increased serotonin concentration in both areas. Injection of both galanin fragments into the DR of galanin receptor type 1 knockout mice exerted anticonvulsant effects. Both the proconvulsant activity of galanin (1-29) and seizure suppression by galanin (2-11) were abolished in serotonin-depleted animals. Our data indicate that, in the DR, galanin receptors types 1 and 2 modulate serotonergic transmission in a negative and a positive fashion, respectively, and that these effects translate into either facilitation or inhibition of limbic seizures.