Persistent modification of forebrain networks and metabolism in rats following adolescent exposure to a 5-HT7 receptor agonist

Canese, Rossella; Zoratto, Francesca; Altabella, Luisa; Porcari, Paola; Mercurio, Laura; Pasquale, Francesco de; Butti, Erica; Martino, Gianvito; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Adriani, Walter

doi:10.1007/s00213-014-3639-6

Cited by 36 publications

(63 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One clue is given by the fact that 5-HT7 is found to be functionally linked to forebrain limbic networks, which comprise the amygdala, VS, orbital PFC, and thalami [33]. Moreover, a recent report [56] demonstrated that serotonin acts on inhibitory interneurons in the PFC through Gs proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, this positive effect might be explained by more complex circuits, leading - eventually - to the re-modeling of cognitive maps: in this context, recent findings [33] point to enhanced transmission between limbic networks including the hippocampus, that might explain the improved SSA (essential to build spatial maps). Furthermore, the same approach has confirmed the hypothesis that the mesocortical DA branch is, in the NHE rat model, at a higher functional state [14], [16], [17].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prepuberal Stimulation of 5-HT7-R by LP-211 in a Rat Model of Hyper-Activity and Attention-Deficit: Permanent Effects on Attention, Brain Amino Acids and Synaptic Markers in the Fronto-Striatal Interface

et al. 2014

Self Cite

View full text Add to dashboard Cite

The cross-talk at the prefronto-striatal interface involves excitatory amino acids, different receptors, transducers and modulators. We investigated long-term effects of a prepuberal, subchronic 5-HT7-R agonist (LP-211) on adult behaviour, amino acids and synaptic markers in a model for Attention-Deficit/Hyperactivity Disorder (ADHD). Naples High Excitability rats (NHE) and their Random Bred controls (NRB) were daily treated with LP-211 in the 5th and 6th postnatal week. One month after treatment, these rats were tested for indices of activity, non selective (NSA), selective spatial attention (SSA) and emotionality. The quantity of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and L-Leucine (L-Leu), dopamine transporter (DAT), NMDAR1 subunit and CAMKIIα, were assessed in prefrontal cortex (PFC), dorsal (DS) and ventral striatum (VS), for their role in synaptic transmission, neural plasticity and information processing. Prepuberal LP-211 (at lower dose) reduced horizontal activity and (at higher dose) increased SSA, only for NHE but not in NRB rats. Prepuberal LP-211 increased, in NHE rats, L-Glu in the PFC and L-Asp in the VS (at 0.250 mg/kg dose), whereas (at 0.125 mg/kg dose) it decreased L-Glu and L-Asp in the DS. The L-Glu was decreased, at 0.125 mg/kg, only in the VS of NRB rats. The DAT levels were decreased with the 0.125 mg/kg dose (in the PFC), and increased with the 0.250 mg/kg dose (in the VS), significantly for NHE rats. The basal NMDAR1 level was higher in the PFC of NHE than NRB rats; LP-211 treatment (at 0.125 mg/kg dose) decreased NMDAR1 in the VS of NRB rats. This study represents a starting point about the impact of developmental 5-HT7-R activation on neuro-physiology of attentive processes, executive functions and their neural substrates.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prepuberal Stimulation of 5-HT7-R by LP-211 in a Rat Model of Hyper-Activity and Attention-Deficit: Permanent Effects on Attention, Brain Amino Acids and Synaptic Markers in the Fronto-Striatal Interface

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Accordingly, stimulation of 5-HT7R in adolescent rats by intraperitoneal administration of LP-211 (0.25 mg/kg/day for 5 days), induces plastic rearrangements within forebrain networks, accounting for long-lasting behavioral changes in the adulthood (Canese et al, 2014). Similar results were obtained in a rat model for Attention Deficit Hyperactivity Disorder (ADHD) in which prepuberal stimulation of 5-HT7R by intraperitoneal administration of LP-211 (up to 0.5 mg/kg/day for 14 days), has long-term effects on adult behavior, improving spatial attention and resulting in modified expression of pre- and post-synaptic markers (Ruocco et al, 2014a), while the same treatment, during adolescence, modulates the emotional responses (Ruocco et al, 2014b).…”

Section: The Serotonin Receptor 7 Modulates Connectivity In Adolescenmentioning

confidence: 99%

The serotonin receptor 7 and the structural plasticity of brain circuits

Volpicelli

Speranza

Porzio

et al. 2014

Front. Behav. Neurosci.

View full text Add to dashboard Cite

Serotonin (5-hydroxytryptamine, 5-HT) modulates numerous physiological processes in the nervous system. Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R) in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration.

show abstract

“…Animal models suggest several possible indications of 5-HT 7 R agonists as therapeutics. The stimulation of 5-HT 7 R in adolescent rats by LP-211 causes plastic rearrangements within the forebrain networks, accounting for long-lasting behavioural changes in adulthood 34 . The activation of 5-HT 7 R was found to be beneficial in mouse models of Rett syndrome 35 and fragile X syndrome 36 .…”

Section: Introductionmentioning

confidence: 99%

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Hogendorf

Kurczab

et al. 2017

Sci Rep

View full text Add to dashboard Cite

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT 7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K i 5-HT7 = 6 nM, EC 50 = 19 nM, 176-fold selectivity over 5-HT 1A R) and 1e (5-methoxy analogue, K i 5-HT7 = 30 nM, EC 50 = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C max = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT 7 R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT 1A R selectivity.Within the serotonergic system, 5-HT 7 , the last identified serotonin receptor, is one of the most valuable drug targets 1 . Discovered independently by three laboratories in 1993 2-4 , 5-HT 7 R was thought to function by being coupled to G s to stimulate intracellular production of cAMP, but it was later found to also be coupled to G 12 which is an alternative signal transduction pathway 5 . 5-HT 7 R is expressed in the central nervous system (thalamus, hypothalamus, hippocampus and cortex) as well as peripherally (pancreas, spleen, coronary artery, ileum and intestine) [3][4][5][6] . Experiments using animal models have shown that the receptor is involved in many physiological processes, i.e. the regulation of body temperature 7 , smooth muscle relaxation of cerebral arteries 8 , circadian rhythm, learning and memory 9-13 , as well as pathophysiological processes such as mood disorders, anxiety 14 , inflammatory processes in the CNS 15 , schizophrenia 16 and pain 17,18 . 5-HT 7 R antagonists have been proposed as potential drugs targeting depression 19,20 . There have been less conclusive reports on potential anxiolytic 21,22 , analgesic 17 and antipsychotic properties of the receptor ligands 23,24 . It was established that 5-HT 7 R blockade can induce promnesic effects indicating the possibility of developing atypical procognitive antidepressants 25 .There are several 5-HT 7 R agonists available to serve as molecular probes. These include small, low-weight molecules, e.g. AS-19 26 , RA-7 7 , 5-carboxyamidotryptamine (5-CT), 5-methoxytryptamine, 8-OH-DPAT 27 , and lysergic acid derivatives 28 and long-chain diphenylpiperazines (LP-12, LP-44, LP-211) developed by . None of these compounds qualify as perfect...

show abstract

Persistent modification of forebrain networks and metabolism in rats following adolescent exposure to a 5-HT7 receptor agonist

Abstract: Persistent MR-detectable modifications indicate a rearrangement within forebrain networks, accounting for long-lasting behavioural changes as a function of developmental 5-HT7-R stimulation.

Cited by 36 publications

References 88 publications

Prepuberal Stimulation of 5-HT7-R by LP-211 in a Rat Model of Hyper-Activity and Attention-Deficit: Permanent Effects on Attention, Brain Amino Acids and Synaptic Markers in the Fronto-Striatal Interface

Prepuberal Stimulation of 5-HT7-R by LP-211 in a Rat Model of Hyper-Activity and Attention-Deficit: Permanent Effects on Attention, Brain Amino Acids and Synaptic Markers in the Fronto-Striatal Interface

The serotonin receptor 7 and the structural plasticity of brain circuits

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Contact Info

Product

Resources

About