Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo.

Abstract

An experimental drug, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine, that facilitates glutamatergic transmission in brain after systemic administration was tested for its effects on the induction of long-term potentiation in the hippocampus of rats. Intraperitoneal injections of the drug markedly increased the degree and duration of long-term potentiation; similar results were obtained with an analogue of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine that was also found to improve retention of memory in a radial maze task and in an odor-matching problem. These results define tools for enhancing long-term potentiation in vivo and confirm an important prediction from the hypothesis that long-term potentiation is a substrate of memory.Long-term potentiation (LTP) is a stable increase in synaptic strength known to occur at a variety of sites in the forebrain after brief periods of high-frequency afferent stimulation (1-3). The characteristics of LTP, including rapid development (4), persistence (5, 6), and synapse specificity (7,8), are suggestive of a memory-encoding process; moreover, patterns of physiological activity that have a strong relationship with LTP induction (9-11) have been recorded from neurons during learning (12). The hypothesis, arising from these observations, that LTP is a substrate of memory predicts that manipulations that block the potentiation effect will cause anterograde amnesia and that manipulations that promote it will result in memory enhancement. While there have been a number of tests of the first prediction (13-16), the absence of drugs that facilitate LTP in vivo have precluded tests of the second.Previous work (17) has shown that 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine (BDP) increases the amplitude and duration of field excitatory postsynaptic potentials (EPSPs) recorded in vitro in slices of hippocampus while having little effect on the slope of responses. Studies with outside-out patches indicate that BDP modulates a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor-gated currents (18). After intraperitoneal (i.p.) injections and for 2-3 h, the drug influences monosynaptic responses in the dentate gyrus in vivo in a manner similar to that observed in slices (17). Since compounds that facilitate AMPA-receptormediated responses promote the induction of LTP in hippocampal slices (19), BDP is a candidate for an enhancer of the potentiation effect in vivo. The experiments described in the present paper indicate that i.p. injections of BDP or a related compound have a marked influence on LTP in freely moving rats and, as expected from the LTP-memory hypothesis, improve retention of spatial and olfactory information. MATERIALS AND METHODSTo assess the time course of biodistribution of BDP (Cortex Pharmaceuticals, Irvine, CA), the drug was radiolabeled with carbon-11 as described (20) and injected into rats under conditions that simulated the dosage and mode of administration to be used (see below) in testing its effects on LTP. Biodistribution and pharmacokinetics ...

Synaptic plasticity in early aging

“…Current efforts appear to be focused on induction and consolidation. The introduction of drugs ('ampakines') that positively modulate AMPA receptors in brain (Staubli et al, 1994a,b) is of interest because ampakines increase and prolong the EPSPs needed to unblock NMDA receptors, and thereby facilitate LTP induction (Staubli et al, 1994b). Moreover, acute administration of ampakines restores LTP to the basal dendrites of middle-aged slices (Rex et al, 2005) and improves memory scores in middle age rats (Granger et al, 1996) as well as elderly humans .…”

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

“…Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions.…”

7-Chloro-3-methyl-3,4-dihydro-2 H -1,2,4-benzothiadiazine S , S -dioxide: A partial modulator of AMPA receptor desensitization devoid of neurotoxicity

“…Moreover, in monkeys IDRA-21 antagonizes the cognitive deficit elicited by alprazolam, a benzodiazepine with full positive allosteric modulatory activity on GABA A receptors (8), by a mechanism independent from the benzodiazepine action on GABA A receptors (6,8). In addition, IDRA-21 facilitates the induction of long-term potentiation by lowering its threshold in rat hippocampal slices (15).…”

“…Pyrrolidinone derivatives, such as aniracetam (9); benzoylpiperidine derivatives, such as BDP-12 or BDP-20 (6,10); and benzothiadiazine derivatives such as cyclothiazide, diazoxide, and 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA-21) (11-13) attenuate the desensitization rate of AMPA-gated Na ϩ currents.…”

“…The discovery that the rapid spontaneous agonist-dependent desensitization of ␣-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA)-gated ion channels can be reduced by drugs that act on specific allosteric sites present within or in the proximity of the flip-flop 38-amino acid region of the AMPA receptor subunits (1)(2)(3)(4)(5) has become an interesting model to assist discovery of drugs that might ameliorate learning, memory, and attention deficits via a facilitation of AMPA-selective glutamatergic synaptic function (6)(7)(8). Pyrrolidinone derivatives, such as aniracetam (9); benzoylpiperidine derivatives, such as BDP-12 or BDP-20 (6,10); and benzothiadiazine derivatives such as cyclothiazide, diazoxide, and 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide (IDRA-21) (11-13) attenuate the desensitization rate of AMPA-gated Na ϩ currents.…”