RESUMEN
Animals often behave repetitively and predictably. These repetitive behaviors can have a component that is learned and ingrained as habits, which can be evolutionarily advantageous as they reduce cognitive load and the expenditure of attentional resources. Repetitive behaviors can also be conscious and deliberate, and may occur in the absence of habit formation, typically when they are a feature of normal development in children, or neuropsychiatric disorders. They can be considered pathological when they interfere with social relationships and daily activities. For instance, people affected by obsessive-compulsive disorder, autism spectrum disorder, Huntington's disease and Gilles de la Tourette syndrome can display a wide range of symptoms like compulsive, stereotyped and ritualistic behaviors. The striatum nucleus of the basal ganglia is proposed to act as a master regulator of these repetitive behaviors through its circuit connections with sensorimotor, associative, and limbic areas of the cortex. However, the precise mechanisms within the striatum, detailing its compartmental organization, cellular specificity, and the intricacies of its downstream connections, remain an area of active research. In this review, we summarize evidence across multiple scales, including circuit-level, cellular, and molecular dimensions, to elucidate the striatal mechanisms underpinning repetitive behaviors and offer perspectives on the implicated disorders. We consider the close relationship between behavioral output and transcriptional changes, and thereby structural and circuit alterations, including those occurring through epigenetic processes.
RESUMEN
Polyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-d-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. The bilateral intra-hippocampal administration of exogenous spermidine (2 nmol/site) immediately after, but not 6h after extinction training, facilitated the extinction of fear conditioning. The injection of the NMDAr antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction and, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development.
Asunto(s)
Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Nootrópicos/farmacología , Espermidina/farmacología , Animales , Biguanidas/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Extinción Psicológica/fisiología , Miedo/fisiología , Reacción Cataléptica de Congelación , Masculino , Pruebas Neuropsicológicas , Piperidinas/farmacología , Poliaminas/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
In Alzheimer's disease (AD), the ß-amyloid peptide (Aß) has been causally linked to synaptic dysfunction and cognitive impairment. Several studies have shown that N-Methyl-D-Aspartate receptors (NMDAR) activation is involved in the detrimental actions of Aß. Polyamines, like spermidine and spermine, are positive modulators of NMDAR function and it has been shown that their levels are regulated by Aß. In this study we show here that interruption of NMDAR modulation by polyamines through blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aß25-35-induced memory impairment in mice in a novel object recognition task. Incubation of hippocampal cell cultures with Aß25-35 (10 µM) significantly increased the nuclear accumulation of Jacob, which is a hallmark of NMDAR activation. The Aß-induced nuclear translocation of Jacob was blocked upon application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM), suggesting that activation of the polyamine binding site at NMDAR located probably at extrasynaptic sites might underlie the cognitive deficits of Aß25-35-treated mice. Extrasynaptic NMDAR activation in primary neurons results in a stripping of synaptic contacts and simplification of neuronal cytoarchitecture. Aß25-35 application in hippocampal primary cell cultures reduced dendritic spine density and induced alterations on spine morphology. Application of traxoprodil (4 nM), arcaine (4 µM) or DFMO (5 µM) reversed these effects of Aß25-35. Taken together these data provide evidence that polyamine modulation of extrasynaptic NMDAR signaling might be involved in Aß pathology.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/patología , Fragmentos de Péptidos/toxicidad , Poliaminas/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Animales , Biguanidas/farmacología , Sitios de Unión , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Conducta Exploratoria/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Proteínas del Tejido Nervioso/metabolismo , Piperidinas/farmacología , Poliaminas/metabolismo , Espermidina/administración & dosificación , Espermidina/farmacología , Sinapsis/efectos de los fármacosRESUMEN
Venoms peptides have produced exceptional sources for drug development to treat pain. In this study we examined the antinociceptive and side effects of Tx3-3, a peptide toxin isolated from Phoneutria nigriventer venom, which inhibits high-voltage-dependent calcium channels (VDCC), preferentially P/Q and R-type VDCC. We tested the effects of Tx3-3 in animal models of nociceptive (tail-flick test), neuropathic (partial sciatic nerve ligation and streptozotocin-induced diabetic neuropathy), and inflammatory (intraplantar complete Freund's adjuvant) pain. In the tail-flick test, both intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of Tx3-3 in mice caused a short-lasting effect (ED(50) and 95% confidence intervals of 8.8 [4.1-18.8] and 3.7 [1.6-8.4] pmol/site for i.t. and i.c.v. injection, respectively), without impairing motor functions, at least at doses 10-30 times higher than the effective dose. By comparison, ω-conotoxin MVIIC, a P/Q and N-type VDCC blocker derived from Conus magus venom, caused significant motor impairment at doses close to efficacious dose in tail flick test. Tx3-3 showed a long-lasting antinociceptive effect in neuropathic pain models. Intrathecal injection of Tx3-3 (30 pmol/site) decreased both mechanical allodynia produced by sciatic nerve injury in mice and streptozotocin-induced allodynia in mice and rats. On the other hand, i.t. injection of Tx3-3 did not alter inflammatory pain. Taken together, our data show that Tx3-3 shows prevalent antinociceptive effects in the neuropathic pain models and does not cause adverse motor effects at antinociceptive efficacious doses, suggesting that this peptide toxin holds promise as a novel therapeutic agent for the control of neuropathic pain. The Brazilian armed spider Tx3-3, a new P/Q and R-type calcium channel blocker, effectively alleviates allodynia in animal neuropathic pain models.