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The cholinergic pathways, which originate in the basal forebrain and are responsible for the control of different cognitive processes including learning and memory, are also regulated by some neuropeptides. One of these neuropeptides, galanin (GAL), is involved in both neurotrophic and neuroprotective actions. The present study has evaluated in rats the effects on cognition induced by a subchronic treatment with GAL by analyzing the passive avoidance response, and the modulation of muscarinic cholinergic receptor densities and activities. [(3)H]-N-methyl-scopolamine, [(3)H]-oxotremorine, and [(3)H]-pirenzepine were used to quantify the density of muscarinic receptors (MRs) and the stimulation of the binding of guanosine 5'-(γ-[(35)S]thio)triphosphate by the muscarinic agonist, carbachol, to determine their functionality. Some cognitive deficits that were induced by the administration of artificial cerebrospinal fluid (aCSF) (i.c.v. aCSF 2 μl/min, once a day for 6 days) were not observed in the animals also treated with GAL (i.c.v. 1.5 mmol in aCSF, 2 μl/min, once a day for 6 days). GAL modulates the changes in M1 and M2 MR densities observed in the rats treated with aCSF, and also increased their activity mediated by G(i/o) proteins in specific areas of the dorsal and ventral hippocampus. The subchronic administration of the vehicle was also accompanied by an increased number of positive fibers and cells for GAL around the cortical tract of the cannula used, but that was not the case in GAL-treated rats. In addition, the increase of GAL receptor density in the ventral hippocampus and entorhinal cortex in the aCSF group was avoided when GAL was administered. The number of acetylcholinesterase (AChE)-positive neurons was decreased in the nucleus basalis of Meynert of both GAL- and aCSF-treated animals. In summary, GAL improves memory-related abilities probably through the modulation of MR density and/or efficacy in hippocampal areas., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

A high-fat diet (HFD) can increase hypothalamic galanin (GAL). GAL has recently been shown to inhibit opiate reward, which in turn, decreases cAMP response element-binding protein (CREB) in the nucleus accumbens (NAc). We hypothesized that injection of GAL into the paraventricular nucleus (PVN), or consumption of a HFD, would be associated with a decrease in NAc CREB. In Exp. 1, GAL in the PVN of naïve rats decreased phosphorylated-CREB (pCREB) which is the activated form of CREB, in the NAc compared to saline-injected controls. In Exp. 2, rats fed ad libitum HFD for 4 weeks had reduced NAc pCREB levels compared to rats with sporadic tastes of the HFD. Body weight, serum triglyceride and leptin levels were also raised in the chronic HFD-fed rats. These data suggest that PVN GAL or chronic intake of a HFD can decrease NAc pCREB. The implications of these findings may help to explain the lack of opiate-like withdrawal that has been reported in response to overeating a HFD, thereby providing a potential mechanism underlying behavioral differences seen with addiction-like overconsumption of different types of palatable foods., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

The cholinergic neurons in the septohippocampal projection are implicated in hippocampal functions such as spatial learning and memory. The aim of this study was to examine how septohippocampal cholinergic transmission is modulated by muscarinic inputs and by the neuropeptide galanin, co-localized with acetylcholine (ACh) in septohippocampal cholinergic neurons, and how spatial learning assessed by the Morris water maze test is affected. Muscarinic inputs to the septal area are assumed to be excitatory, whereas galanin is hypothesized to inhibit septohippocampal cholinergic function. To test these hypotheses, compounds were microinjected into the medial septum and hippocampal ACh release was assessed by microdialysis probes in the ventral hippocampus of the rat. Blockade of septal muscarinic transmission by intraseptal scopolamine increased hippocampal ACh release suggesting that septal cholinergic neurons are under tonic inhibition. Stimulation of septal muscarinic receptors by carbachol also increased hippocampal ACh release. Despite this increase, both scopolamine and carbachol tended to impair hippocampus-dependent spatial learning. This finding also suggests a revision of the simplistic notion that an increase in hippocampal ACh may be facilitatory for learning and memory. Galanin infused into the medial septum enhanced hippocampal ACh release and facilitated spatial learning, suggesting that septal galanin, contrary to earlier claims, does not inhibit but excites septohippocampal cholinergic neurons. Galanin receptor stimulation combined with muscarinic blockade in the septal area resulted in an excessive increase of hippocampal ACh release combined with an impairment of spatial learning. This finding suggests that the level of muscarinic activity within the septal area may determine the effects of galanin on hippocampal cognitive functions. In summary, a limited range of cholinergic muscarinic transmission may contribute to optimal hippocampal function, a finding that has important implications for therapeutic approaches in the treatment of disorders of memory function.

Galanin is widely distributed in the nervous system and is consistently upregulated in both dorsal root ganglion and spinal neurones by peripheral nerve injury. This study investigates the peripheral effects of galanin on nociceptive neurones using in vitro and in vivo electrophysiological techniques in naive and neuropathic rats. Using an in vitro skin-nerve preparation recording from single nociceptive fibres, galanin (1 microM) significantly inhibited firing induced by noxious heat in 65% of fibres examined. In the remaining 35% of fibres, galanin (1 microM) induced a facilitation of the responses to noxious heat. To examine the effect of peripheral galanin in vivo, extracellular recordings from convergent dorsal horn neurones were made in anaesthetised naive sham-operated and spinal nerve-ligated (SNL) rats. Injection of galanin (0.1-10 microg) into hindpaw receptive fields inhibited responses to innocuous mechanical, noxious mechanical and noxious heat stimuli in a proportion of neurones in each animal group and facilitated the remaining neurones. However, a higher proportion of neurones (80-90%) was inhibited by peripheral galanin administration in SNL rats compared with naive (45-55%) and sham (70-80%) rats. These results show that galanin can have both excitatory and inhibitory effects on peripheral sensory neurones, perhaps reflecting differential receptor activation, and that the proportion of these receptors may change following peripheral neuropathy.

A recent study has shown that ventral hippocampal galanin plays a role in spatial learning and that it has an inhibitory effect on basal acetylcholine release [Ogren S. O. et al. (1996) Neuroscience 75, 1127-1140]. The present studies were designed to compare the in vivo tissue distribution and kinetics of infused galanin (porcine) with the temporal effect of galanin on spatial learning in the rat. Daily bilateral microinfusions of galanin (1.5 nmol/side for five days) via chronic cannulae placed in the ventral hippocampus produced a significant impairment of acquisition of the spatial task when infused 20 min, but not 5 or 60 min, before the daily training session. No overall impairment of memory retention (examined 24 h after the last training session) was observed in the galanin-treated rats. These results indicate that galanin given in the ventral hippocampus produces a time-dependent effect on acquisition. Using an antibody to porcine galanin and immunohistochemistry, galanin infused in the ventral hippocampus was found to be distributed mainly within the ventral part of the hippocampus and around the infusion site. The infused galanin was rapidly cleared from the extracellular space between 5 and 20 min after infusion. Five minutes after infusion of galanin, a number of cells in the ventral hippocampus, both within and outside the zone of extracellularly located galanin, showed a positive galanin-like immunoreactivity. These cells appear morphologically to be medium-sized neurons with a similar position as cells showing neuropeptide Y-like immunoreactivity. At 20 and 60 min after infusion of galanin, no cells with detectable levels of galanin-like immunoreactivity could be seen. These results indicate that the temporal kinetics and distribution of infused galanin are of major importance for its behavioural effect in the ventral hippocampus. The rapid clearance of the infused galanin and its internalization by neuronal endocytotic mechanisms may be important for its effect on cognition.

The neuropeptide galanin coexists in the medial septum and diagonal band of Broca with a population of acetylcholine neurons which project mainly to the ventral hippocampus. The present studies investigated the role of ventral hippocampal galanin in spatial learning in the male rat using a spatial learning task. In addition, the effects of galanin on cholinergic function were monitored by in vivo microdialysis and high-performance liquid chromatography. Bilateral microinjections of galanin (3 nmol/ rat) via chronic cannulae placed into the ventral hippocampus (i.v.h.) produced a slight but significant impairment of acquisition of the spatial task, while the 1 nmol dose of galanin facilitated acquisition. The 6 nmol dose of galanin failed to affect performance. A trend for an impairment of long-term memory retention (examined seven days after the last training session) was observed after 3 nmol of galanin, while the 1 nmol dose facilitated retention performance. Scopolamine (0.1 mg/kg, s.c.) caused a marked impairment of acquisition. Galanin (3 nmol/rat) given i.v.h. failed to modify the acquisition impairment caused by scopolamine (0.1 mg/kg, s.c.). These results suggest that galanin given i.v.h. produces a biphasic dose-dependent effects on spatial learning. In freely moving rats, galanin (3 nmol/10 microliters) given into the lateral ventricle (i.c.v.) did not affect basal acetylcholine release. In contrast, perfusion (100 min) with galanin (0.1 or 0.3 nmol/1.25 microliters/min) through the ventral hippocampal probe resulted in a reduction of basal acetycholine release which was dose-dependent and reversible. Galanin given i.c.v. (3 nmol/10 microliters) or through the probe (0.3 nmol/1.25 microliters/min) attenuated the increase in acetylcholine release evoked by the muscarinic antagonist scopolamine (0.1 mg/kg, s.c.; 0.001 nmol/1.25 microliters/min through the probe). The galanin plus scopolamine combinations produced a 50% lower increase in the extracellular acetylcholine concentrations than scopolamine alone. This suggests that the mechanism(s) behind scopolamine- and galanin-induced stimulation of acetylcholine differ. These results indicate that ventral hippocampal galanin plays a role in cognition and that it has a powerful and modulatory effect on cholinergic transmission. However, the effects of exogenous galanin on spatial learning cannot be directly related to changes in in vivo cholinergic transmission in the ventral hippocampus. These discrepancies may relate to effects on subtypes of galanin receptors with different functional coupling. In addition, other hippocampal neurotransmitter systems (e.g. noradrenergic neurons) important for cognitive functions may also be modulated by ventral hippocampal galanin.