Tetrahydrobiopterin improves hippocampal nitric oxide-linked long-term memory.

Tetrahydrobiopterin (BH4) is synthesized by the combined action of three metabolic pathways, namely de novo synthesis, recycling, and salvage pathways. The best-known function of BH4 is its mandatory action as a natural cofactor of the aromatic amino acid hydroxylases and nitric oxide synthases. Thus, BH4 is essential for the synthesis of nitric oxide, a retrograde neurotransmitter involved in learning and memory. We investigated the effect of BH4 (4-4000 pmol) intracerebroventricular administration on aversive memory, and on BH4 metabolism in the hippocampus of rodents. Memory-related behaviors were assessed in Swiss and C57BL/6 J mice, and in Wistar rats. It was consistently observed across all rodent species that BH4 facilitates aversive memory acquisition and consolidation by increasing the latency to step-down in the inhibitory avoidance task. This effect was associated with a reduced threshold to generate hippocampal long-term potentiation process. In addition, two inhibitors of memory formation (N(ω)-nitro-L-arginine methyl ester - L-Name - and dizocilpine - MK-801 -) blocked the enhanced effect of BH4 on memory, while the amnesic effect was not rescue by the co-administration of BH4 or a cGMP analog (8-Br-cGMP). The data strongly suggest that BH4 enhances aversive memory by activating the glutamatergic neurotransmission and the retrograde activity of NO. It was also demonstrated that BH2 can be converted into BH4 by activating the BH4 salvage pathway under physiological conditions in the hippocampus. This is the first evidence showing that BH4 enhances aversive memory and that the BH4 salvage pathway is active in the hippocampus.

Temporal development of neurochemical and cognitive impairments following reserpine administration in rats.

The systemic administration of low reserpine (RES) doses (0.1-1.0 mg/kg) has been proposed as a valuable rat model for the study of non-motor symptoms of Parkinson's disease (PD). Here, we investigated the temporal-dependent effects of RES (1 mg/kg, s.c.) on short-term memory and locomotion, as well as, the levels of dopamine, serotonin and its metabolites in the striatum, hippocampus and prefrontal cortex at 3, 24 or 72 h after RES administration. RES administrations resulted in social and object recognition memory impairment and increased dopamine turnover in the striatum, without changes in the rat spontaneous locomotor activity, 3 h after RES administration. Altogether, these results provide new insights for the use of RES administration as an experimental design for the study of PD non-motor symptoms in rats.