Farmacobiología

Hippocampal high frequency electrical stimulation (HFS) at 130 Hz has been proposed as a therapeutical strategy to control neurological disorders such as intractable temporal lobe epilepsy (TLE). This study was carried out to determine the effects of hippocampal HFS on the memory process and the probable involvement of amino acids. Using the autoshaping task, we found that animals receiving hippocampal HFS showed augmented short-term, but not long-term memory formation, an effect blocked by bicuculline pretreatment and associated with enhanced tissue levels of amino acids in hippocampus. In addition, microdialysis experiments revealed high extracellular levels of glutamate, aspartate, glycine, taurine, and alanine during the application of hippocampal HFS. In contrast, GABA release augmented during HFS and remained elevated for more than 1 h after the stimulation was ended. HFS had minimal effects on glutamine release. The present results suggest that HFS has an activating effect on specific amino acids in normal hippocampus that may be involved in the enhanced short-term memory formation. These data further provide experimental support for the concept that hippocampus may be a promising target for focal stimulation to treat intractable seizures in humans.

It has been established that serotonergic pathways project to cerebral areas involved in learning and memory and that serotonin (5-HT) receptor agonists and antagonists modify these processes. Indeed, most of the 5-HT receptors characterized so far, i.e., 5-HT(1) through 5-HT(7), show a regional distribution in brain areas involved in learning and memory, such as hippocampal formation (HF), amygdala and cortex. Although 5-HT(7) receptor biological functions are still to be clarified, it was recently suggested that it may play a role in the control of learning and memory processes. The aim of our study was to assess the role of 5-HT(7) receptors antagonist SB-269970 on working and reference memory in a radial arm maze task, utilizing a two-phase procedure, comprising an acquisition and test phase, conducted to evaluate working and reference memory, respectively. Our results showed that 5-HT(7) receptors antagonist SB-269970 improved memory, decreasing the number of errors in test phase and, thus, affecting reference memory, while no effects were observed in working memory. These results could be explained taking into consideration the specific localization of 5-HT(7) receptors in the CNS. In fact, high concentrations of 5-HT(7) receptors were found in the HF, which exerts an important role on reference memory, while relatively low concentrations were present in the prefrontal cortex, involved in working memory. Thus, 5-HT(7) receptor blockade had procognitive effect, when the learning task implicated a high degree of difficulty. This conclusion has a major implication in the context that 5-HT receptors play an important role under amnesia states (e.g., Alzheimer's disease) or when the learning is complex.

The cyclic adenosine monophosphate (cAMP) is a second messenger and a central component of intracellular signaling pathways that regulate a wide range of biological functions, including memory. Hence, in this work, firstly the time-course of memory formation was determined in an autoshaping learning task, which had allowed the identification of testing times for increases or decreases in performance. Next, untrained, trained and overtrained groups were compared in cAMP production. Moreover, selective stimulation and antagonism of 5-HT(1A) and 5-HT(7) receptors during memory formation and cAMP production were determined. Finally, since there is scarce information about how pharmacological models of amnesia affect cAMP production, the cholinergic or glutamatergic antagonists, scopolamine and dizocilpine, were tested. The major findings of this work showed that when the time-course was determined inasmuch as training and testing sessions occurred, memory performance was graduate and progressive. Notably, for the fourth to seventh (i.e., 48-120 h following autoshaping training session) testing session performance was significantly higher from the previous ones. When animals received 5-HT(1A) and 5-HT(7) receptor agonists and antagonists or amnesic drugs significant increases or decrements in memory performance were observed at 24 and 48 h. Moreover, when ex vivo cAMP production from trained and overtrained groups were compared to untrained ones, significant differences were observed among groups and brain areas. Trained animals treated with 8-OHDPAT, AS19, 8-OHDPAT plus AS19, WAY100635, SB-269970, scopolamine or dizocilpine were compared to similar untrained groups, and eightfold-reduced cAMP production was evident, showing the importance of cAMP production in the signaling case in mammalian memory formation.

Diverse studies indicate that the attention deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short-term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Here SHR-saline group showed significantly poor STM and LTM relative to SD and WKY saline rats. SD and WKY rats treated with d-amphetamine displayed better STM and LTM, compared to SD-vehicle, WKY-vehicle or SHR-d-amphetamine groups.