Galnon

Galnon facilitates extinction of morphine-conditioned place preference but also potentiates the consolidation process.[Pubmed:24146862]

PLoS One. 2013 Oct 11;8(10):e76395.

Learning and memory systems are intimately involved in drug addiction. Previous studies suggest that galanin, a neuropeptide that binds G-protein coupled receptors, plays essential roles in the encoding of memory. In the present study, we tested the function of Galnon, a galanin receptor 1 and 2 agonist, in reward-associated memory, using conditioned place preference (CPP), a widely used paradigm in drug-associated memory. Either before or following CPP-inducing morphine administration, Galnon was injected at four different time points to test the effects of galanin activation on different reward-associated memory processes: 15 min before CPP training (acquisition), immediately after CPP training (consolidation), 15 min before the post-conditioning test (retrieval), and multiple injection after post-tests (reconsolidation and extinction). Galnon enhanced consolidation and extinction processes of morphine-induced CPP memory, but the compound had no effect on acquisition, retrieval, or reconsolidation processes. Our findings demonstrate that a galanin receptor 1 and 2 agonist, Galnon, may be used as a viable compound to treat drug addiction by facilitating memory extinction process.

The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.[Pubmed:25053279]

Addict Biol. 2015 Jul;20(4):701-13.

Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, Galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of Galnon on cocaine-induced behaviors and neurochemistry in rats. We found that Galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, Galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that Galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex.

Anxiolytic-like activity of the non-selective galanin receptor agonist, galnon.[Pubmed:17637475]

Neuropeptides. 2007 Oct;41(5):307-20.

Galanin's influence on monoaminergic neurotransmission, together with its discrete CNS distribution in corticolimbic brain areas, points to a potential role for this neuropeptide in mediating anxiety- and depression-like responses. To evaluate this hypothesis, the non-selective galanin receptor agonist, Galnon, was tested in multiple preclinical models of anxiolytic- and antidepressive-like activity. Acute administration of Galnon (0.03-1mg/kg, i.p.) dose-dependently increased punished crossings in the four plate test, with magnitude similar to the effects of the endogenous ligand, galanin (0.1-1.0 microg, i.c.v.). Moreover, the effects of Galnon and galanin were blocked by central administration of the non-selective galanin receptor antagonist, M35 (10 microg, i.c.v.). Interestingly, the benzodiazepine receptor antagonist, flumazenil (1mg/kg, i.p.), reversed Galnon's effect in the four plate test, implicating GABAergic neurotransmission as a potential mechanism underlying this anxiolytic-like response. In the elevated zero maze, Galnon (0.3-3.0mg/kg, i.p.) and galanin (0.03-0.3 microg, i.c.v.) increased the time spent in the open arms, while in the stress-induced hyperthermia model, Galnon (0.3-30 mg/kg, i.p.) attenuated stress-induced changes in body temperature. Consistent with these anxiolytic-like effects, in vivo microdialysis showed that acute Galnon (3mg/kg, i.p.) treatment preferentially elevated levels of GABA in the rat amygdala, a brain area linked to fear and anxiety behaviors. In contrast to the effects in anxiety models, neither Galnon (1-5.6 mg/kg, i.p.) nor galanin (0.3-3.0 microg, i.c.v.) demonstrated antidepressant-like effects in the mouse tail suspension test. Galnon (1-10mg/kg, i.p.) also failed to reduce immobility time in the rat forced swim test. In vitro, Galnon and galanin showed affinity for human galanin receptors expressed in Bowes melanoma cells (K(i)=5.5 microM and 0.2 nM, respectively). Galanin displayed high affinity and functional potency for membranes expressing rat GALR1 receptors (K(i)=0.85 nM; EC(50)=0.6 nM), while Galnon (10 microM) failed to displace radiolabeled galanin or inhibit cAMP production in the same GALR1 cell line. Galnon (10 microM) showed affinity for NPY1, NK2, M5, and somatostatin receptors but no affinity for galanin receptors expressed in rat hippocampal membranes. Taken together, the present series of studies demonstrate novel effects of Galnon in various preclinical models of anxiety and highlight the galaninergic system as a novel therapeutic target for the treatment of anxiety-related disorders. Moreover, these data indicate rodent GALR1 receptors do not mediate Galnon's in vivo activity.

Galnon, a galanin receptor agonist, improves intrinsic cortical bone tissue properties but exacerbates bone loss in an ovariectomised rat model.[Pubmed:24879020]

J Musculoskelet Neuronal Interact. 2014 Jun;14(2):162-72.

OBJECTIVES: Previous studies have shown galanin (GAL) injections onto mouse calvaria increased bone thickness and osteoblast number. This study investigated the effects of the GAL receptor agonist Galnon on bone loss using the ovariectomised (OVX) rat model. METHODS: OVX rats were treated with either vehicle or Galnon for 6 weeks via mini-osmotic pumps. Plasma osteocalcin concentrations, osseous cell gene expression, morphological and biomechanical properties of the skeleton were compared between the two groups. RESULTS: Treatment with Galnon increased RANKL:OPG gene ratio (p<0.001) plus expression of TNF-alpha (p<0.05) and cathepsin K (p<0.05). muCT analyses revealed Galnon-treated OVX animals had reduced trabecular and cortical morphology compared to control animals. Biomechanically, Galnon OVX animals required similar peak force to failure to that of control OVX animals although Galnon treatment did enhance the mechanical properties of Young's modulus and ultimate tensile stress. CONCLUSIONS: Our research suggests that Galnon, a GAL receptor agonist, may enhance osteoclastic bone resorption in OVX rats. Although Galnon reduced bone volume, biomechanical testing revealed that bone of Galnon-treated animals was mechanically superior per unit area. Taken together, Galnon simultaneously improves the intrinsic quality of cortical bone whilst stimulating osteoclastic activity in the OVX rat model.

A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus.[Pubmed:15647369]

Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):874-9.

Selective serotonin reuptake inhibitors, such as fluoxetine (FLX), are the most commonly used drugs in the treatment of major depression. However, there is a limited understanding of their molecular mechanism of action. Although the acute effect of selective serotonin reuptake inhibitors in elevating synaptic serotonin concentrations is well known, the clinical amelioration of depressive symptoms requires 14-21 days of treatment, suggesting that numerous other rearrangements of function in the CNS must take place. In the present study, we demonstrated that 14 days of FLX treatment up-regulated galanin mRNA levels by 100% and GalR2-binding sites by 50%, in the rat dorsal raphe nucleus, where galanin coexists with serotonin. Furthermore, a galanin receptor antagonist, M40, attenuated the antidepressant-like effect of FLX in the forced swim test, a rodent preclinical screen commonly used to evaluate antidepressant-like efficacy. Direct activation of galanin receptors by a galanin receptor agonist, Galnon, was found to produce an antidepressant-like effect in the same task. Two other antidepressant treatments also affected the galaninergic system in the monoaminergic nuclei: Electroconvulsive shock elevated galanin mRNA levels in dorsal raphe nucleus, whereas sleep deprivation increased galanin mRNA levels in the locus coeruleus, further underlining the connection between activation of the galaninergic system and antidepressant action of various clinically proven treatments.

Effects of galnon, a non-peptide galanin-receptor agonist, on insulin release from rat pancreatic islets.[Pubmed:15670772]

Biochem Biophys Res Commun. 2005 Mar 4;328(1):213-20.

Galanin is a neurotransmitter peptide that suppresses insulin secretion. The present study aimed at investigating how a non-peptide galanin receptor agonist, Galnon, affects insulin secretion from isolated pancreatic islets of healthy Wistar and diabetic Goto-Kakizaki (GK) rats. Galnon stimulated insulin release potently in isolated Wistar rat islets; 100 microM of the compound increased the release 8.5 times (p<0.001) at 3.3 mM and 3.7 times (p<0.001) at 16.7 mM glucose. Also in islet perifusions, Galnon augmented several-fold both acute and late phases of insulin response to glucose. Furthermore, Galnon stimulated insulin release in GK rat islets. These effects were not inhibited by the presence of galanin or the galanin receptor antagonist M35. The stimulatory effects of Galnon were partly inhibited by the PKA and PKC inhibitors, H-89 and calphostin C, respectively, at 16.7 but not 3.3 mM glucose. In both Wistar and GK rat islets, insulin release was stimulated by depolarization of 30 mM KCl, and 100 microM Galnon further enhanced insulin release 1.5-2 times (p<0.05). Cytosolic calcium levels, determined by fura-2, were increased in parallel with insulin release, and the L-type Ca2+-channel blocker nimodipine suppressed insulin response to glucose and Galnon. In conclusion, Galnon stimulates insulin release in islets of healthy rats and diabetic GK rats. The mechanism of this stimulatory effect does not involve galanin receptors. Galnon-induced insulin release is not glucose-dependent and appears to involve opening of L-type Ca2+-channels, but the main effect of Galnon seems to be exerted at a step distal to these channels, i.e., at B-cell exocytosis.

Regulation of feeding by galnon.[Pubmed:15003717]

Neuropeptides. 2004 Feb;38(1):55-61.

Galanin is a neuropeptide that has been implicated in multiple bioactivities, inter alia eating disorders. In this study, we have examined the effects of Galnon, a novel low molecular weight galanin receptor ligand. Previous studies have shown that Galnon acts as a systemically active, blood-brain barrier crossing agonist on galanin signaling both in vitro and in vivo, inhibiting pentylenetetrazole-induced seizures. Here, intracerebroventricular (10-20 microg) and intraperitoneal (1.5-5 mg/kg) administration of Galnon induced a strong, dose-dependent reduction of food intake in rats and mice. This reduction in feeding occurred without reducing general activity and was shown to be attenuated by an intracerebroventricular administration of M35, a peptide galanin antagonist. These data demonstrate that Galnon is a promising tool for studies of the involvement of galanin in feeding disorders and other behavioral processes.

Anticonvulsant activity of a nonpeptide galanin receptor agonist.[Pubmed:12011470]

Proc Natl Acad Sci U S A. 2002 May 14;99(10):7136-41.

Galanin is a neuropeptide with a wide variety of biological functions, including that of a strong endogenous anticonvulsant. No nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin, a combinatorial library was designed, synthesized, and screened at the rat hippocampal galanin receptor. A low molecular weight galanin receptor agonist, 7-((9-fluorenylmethoxycarbonyl)cyclohexylalanyllysyl)amino-4-methylcoumarin (Galnon) was found to displace (125)I-galanin with micromolar affinity at Bowes cellular and rat hippocampal membranes. Autoradiographic binding assay on rat spinal cord sections confirmed the ability of Galnon to displace (125)I-galanin from its binding sites. Galnon inhibited adenylate cyclase activity, suggesting an agonist action at galanin receptors. When injected i.p. Galnon reduced the severity and increased the latency of pentylenetetrazole-induced seizures in mice and reversed the proconvulsant effects of the galanin receptor antagonist M35, injected into a lateral ventricle. Intrahippocampal injection of Galnon also shortened the duration of self-sustaining status epilepticus in rats, confirming its agonist properties in vivo. Pretreatment of rats with antisense peptide nucleic acid targeted to galanin receptor type 1 mRNA abolished the effect of Galnon, suggesting mediation of its anticonvulsant properties through this receptor subtype. These findings introduce a systemically active nonpeptide galanin agonist anticonvulsant.