Piccolo is one of the components of the active zone at chemical synapses and regulates the transport of synaptic vesicles. The piccolo C2A domain is an important calcium sensor and binds with phosphatidylinositol or synaptotagmin-1. Recently, clinical studies suggested that a single nucleotide polymorphism in the piccolo C2A domain might be a causal risk factor for major depression. To clarify the association of piccolo with depression, we produced a transgenic mouse overexpressing the C2A domain of piccolo, and investigated the behavior of these mice. The mice exhibited depression-like behavior in both forced swim and tail suspension tests, suggesting that piccolo might regulate the depressive behavior.
More than half of methamphetamine (METH) users present with cognitive impairment, making it difficult for them to reintegrate into society. However, the mechanisms of METH-induced cognitive impairment remain unclear. METH causes neuronal hyperactivation in the nucleus accumbens (NAc) by aberrantly releasing dopamine, which triggers dependence. In this study, to clarify the involvement of hyperactivation of NAc in METH-induced cognitive impairment, mice were locally microinjected with METH into NAc (mice with METH (NAc)) and investigated their cognitive phenotype. Mice with METH (NAc) exhibited cognitive dysfunction in behavioral analyses and decreased long-term potentiation in the hippocampus, with NAc activation confirmed by expression of FosB, a neuronal activity marker. In the hippocampus of mice with METH (NAc), activated microglia, but not astroglia, and upregulated microglia-related genes, Il1b and C1qa were observed. Finally, administration of minocycline, a tetracycline antibiotic with suppressive effect on microglial activation, to mice with METH (NAc) ameliorated cognitive impairment and synaptic dysfunction by suppressing the increased expression of Il1b and C1qa in the hippocampus. In conclusion, activation of NAc by injection of METH into NAc elicited cognitive impairment by facilitating immune activation in mice. This study suggests that immunological intervention could be a therapeutic strategy for addiction-related cognitive disturbances.
Abstract Aim We previously reported that methamphetamine (METH)‐induced conditioned place preference was attenuated by Shati/Nat8l overexpression in the medial prefrontal cortex (mPFC). Shati/Nat8l overexpression in the mPFC expressed lower levels of both glutamate and dopamine (DA) in the nucleus accumbens (NAc) and attenuated METH‐induced DA elevation. We suggested a mechanism in which a decline of glutamate levels in the NAc decreases extracellular DA levels. However, the hypothesis has not confirmed. Methods We conducted a recovery experiments by pre‐microinjection of an mGluR group II antagonist, LY341495, into the NAc shell of mPFC‐Shati/Nat8l‐overexpressed mice followed by METH injection and DA levels measurement by in vivo microdialysis. Results Pretreatment with LY341495 was able to restore METH‐induced DA increase. Furthermore, mice injected with an adeno‐associated virus vector containing GFP (AAV‐GFP vector) in the mPFC expressed a colocalization of GFP with DARPP‐32 a medium spiny neuron (MSN) marker. Next, co‐immunostaining of DARPP‐32 and neuronal nitric oxide synthase (nNOS: expressed in a subtype of gamma‐Aminobutyric acid (GABA interneurons) in ventral tegmental area (VTA) showed a colocalization of nNOS and DARPP‐32. Conclusion These results provided a proof that Shati/Nat8l attenuation of METH‐induced DA increase is mediated by mGluR group II in the NAc. Moreover, immunohistochemical study showed a direct connection of mPFC projection neurons with NAc MSN and a connection of MSN projection neurons with a subtype of GABA interneurons in VTA.
Neurotrophins play a crucial role in the differentiation, maintenance, and survival of various types of peripheral and central neurons. However, the therapeutic use of neurotrophins is limited by their inability to cross the blood-brain barrier and their instability in the bloodstream. One of the promising approaches to utilize neurotrophic actions of these molecules in the therapy of neurodegenerative diseases is the stimulation of neurotrophin synthesis. Here we review the effects of 4-methylcatechol, a nonadrenergic catechol compound, on the synthesis of the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the peripheral and central nervous system. The neuroprotective potential of 4-methylcatechol in animal models of neurodegenerative disorders is discussed, and other agents that enhance neurotrophin synthesis are also mentioned. Biomedical Reviews 1999; 10: 45-54.
