Resumen:

Acción de distintos agonistas y antagonistas del GABA sobre la memoria. El ritmo θ. El muscimol puede alterar directamente la memoria. Recientemente, se empleó un paradigma modificado dirigido a equiparar una respuesta con una posición dada ("matching to position", MTP) con el fin de influenciar el tipo de asociaciones que una rata podría usar para resolver dicha tarea. La principal manipulación conductual fue la aplicación de un procedimiento de resultados diferenciales (DOP). El DOP implica correlacionar cada evento que deba ser recordado con una condición distinta de recompensa. Este procedimiento dará como resultado el desarrollo de esperanzas específicas de recompensa que incrementarán y guiarán a la conducta selectiva. Tales esperanzas distintas de recompensa no se presentarán cuando sea empleada una asignación ya sea común o al azar de la recompensa (procedimiento de resultados no diferenciales, NOP).

La infusión intraventricular de muscimol o de líquido cefalorraquídeo (LCR) en ratas que ejecuten un MTP con retraso dentro de un protocolo de DOP o de NOP, dañará a ambos grupos de ratas pero la naturaleza del déficit diferirá según las contingencias de refuerzo. Las ratas entrenadas con DOP mostrarán un daño general, no mnemónico, independiente del retraso, esto es, el desempeño se afectará en todos los intervalos de retraso que se empleen. Por el contrario, las ratas entrenadas con NOP mostrarán un daño que sí dependerá del retraso. Esto parece demostrar que el muscimol también puede tener efectos adversos contra la memoria, lo que indica, además, que la activación de los receptores del GABA afectará a un conjunto de asociaciones y funciones mnemónicas.

Las dificultades que se han tenido en el pasado para inducir LTP a nivel de la conexión CA3-CA1, a través de las colaterales de Schäffer, con protocolos basados en el orden temporal de presentación de los potenciales de acción, han sido desconcertantes dada la preeminencia de estas sinapsis como sistema modelo para el estudio de la plasticidad sináptica. Los resultados descritos anteriormente de experimentos que emplean picrotoxina como inhibidor del GABA sugieren que estas dificultades provienen del requerimiento de que, para que la LTP sea inducida, las dendritas de CA1 deberán estar persistente y totalmente activadas. Los "dobletes" usados en ese caso representarían a un séquito ("burst") mínimo, o un nivel de estimulación post-sináptica para la inducción de LTP que resumiera a mayores despolarizaciones. In vitro, los séquitos de potenciales inducidos sinápticamente corresponderían a eventos eléctricos regenerativos en las dendritas apicales de las neuronas piramidales. Tales requerimientos para la activación dendrítica serían satisfechos in vivo durante el ritmo θ, que se presenta durante la exploración activa. Por lo tanto, el GABA podría servir como modulador del engrama a través de la activación del ritmo θ hipocámpico.

Cannabis indica y memoria. Los canabinoides (derivados de la Cannabis indica, o marihuana) trastornan los procesos de memoria en los mamíferos. A pesar de que el receptor canabinoide neuro-nal CB1 se identificó hace ya varios años, los mecanismos en las redes neuronales que median estos efectos son todavía motivo de controversia. Se han usado experimentos de liberación de GABA marcado con tritio para comprobar la localización de este receptor a nivel celular y subcelular en el hipocampo humano. La expresión que se pudo detectar de CB1 con esta técnica estaba limitada a las interneuronas del hipocampo. Se determinó que la mayor parte de ellas eran neuronas en canasta que contenían cole-quistocinina. Los somas neuronales positivos a CB1 mostraban tinción inmune en su citoplasma perinuclear, pero no en su membrana plasmática somatodendrítica. Las terminales axónicas in-munorreactivas a CB1 cubrían densamente al hipocampo entero, y formaban sinapsis simétricas características de los botones neu-ronales GABAérgicos. Se pudo así observar que WIN 55,212-2, agonista del receptor CB1, reducía considerablemente la liberación del GABA marcado con ³H, y que este efecto era prevenible con el antagonista SR 141716A del receptor. Este patrón único de expresión, y la modulación pre-sináptica de la liberación del GABA, sugieren la existencia de un papel conservado de los receptores CB1 en el control de las redes inhibitorias del hipocampo que son responsables de la generación y el mantenimiento de patrones de oscilación rápidos y lentos. Por lo tanto, un mecanismo probable a través del cual los canabinoides llegarían a afectar a los procesos de asociación en la memoria podría ser una alteración de la sincronía de eventos rítmicos en distintas poblaciones neuronales.

Palabras clave: Acido γ-aminobutírico; memoria; agonistas y antagonistas; ritmo θ; receptores μ opiáceos; canabinoides; envejecimiento; interneuronas

Summary:

Action of GABA agonists and antagonists on memory. The θ rhythm. Muscimol may directly alter memory. Recently, a modified matching to position (MTP) paradigm was employed aimed at influencing the type of associations a rat may use to solve the task. The main behavioral manipulation was the application of a differential outcomes procedure (DOP). DOP implies correlating each event to be remembered with a different reward condition. This procedure will result in the development of specific reward expectations which will in turn increase and guide choice behavior. Such different reward expectations will not be present when the reward assignation used is either common or random (non-differential outcomes procedure, NOP).

Intraventricular infusion of muscimol or CSF in rats carrying out a delayed MTP using either a MOP or an NOP protocol will affect both groups of rats, but the nature of the deficit will differ depending on the reinforcement contingencies. Rats trained in DOP will show general non-mnemonic damage independent of delay, i.e., performance will be affected at all delay intervals employed. On the contrary, rats trained in NOP will show delay-dependent damage. This appears to demonstrate that muscimol may also have untoward memory effects, which further indicates that activation of GABA receptors will affect a set of memory associations and functions.

Difficulties experienced in the past regarding LTP induction at the level of the CA3-CA1 synapse using time-based spike presentation protocols have been disconcerting given the preeminence of these synapses as a model system for the study of synaptic plasticity. Results previously discussed in experiments using picrotoxin as a GABA inhibitor have suggested that such difficulties arise from the requirement that, for LTP to be induced, CA1 dendrites must be persistently and totally activated. Doublets used in this case represent a minimal burst, or level of post-synaptic stimulation for LTP induction that subsumes greater depolarizations. In vitro, synaptically induced bursts would correspond to regenerative electrical events in apical dendrites of pyramidal neurons. The same requirements for dendritic activation would be satisfied in vivo during the θ rhythm, which is present during active exploration. Therefore, GABA might serve as an engram modulator through the activation of the hippocampal θ rhythm.

Effect of μ-opioid receptors on hippocampal memory activity. Hippocampal μ-opioid receptors (MOR) have been involved in the formation of memory associated with the abuse of opioid drugs. When chronically activated, and during programmed drug abstinence, MORs acutely modulate hippocampal synaptic plasticity At the level of neuronal networks, MORs increase excitability of area CA1 by means of a disinhibition of pyramidal cells. The specific inhibitory interneuronal subtypes which become affected by activation of MORs are not known. Nevertheless, not all subtypes are inhibited and some subtypes preferentially express these receptors. In one study, the effect of activation of MORs on inhibitory patterns and propagation of excitatory activity in CA1 of rat hippocampus was investigated through cortical images created using voltage-sensitive dyes.

MOR activation increased excitatory activity originated by the increased stimulating input to stratum oriens (i.e., Schäffer collateral and commissural [SCC] fibers, as well as the retrograde pathway), to stratum radiatum (i.e., SCC fibers) and to stratum lacunosum-moleculare (i.e., the perforant pathway and the thalamus). Increased excitatory activity was additionally facilitated by propagation through the neural network of area CA1. This was observed as a proportionally greater increment of amplitudes of excitatory activity in sites distant from the originally evoked activity. Such facilitation was noted in excitatory activity propagating from three sites of stimulation. The increment and facilitation were prevented with GABA_A receptor antagonists (bicuculline, 30 μM), but not with GABA_B receptor antagonists (CGP, 10 μM). Besides, MOR activation inhibited inhibitory post-synaptic potentials (IPSPs) in every layer of area CA1. These findings suggest that MOR-originated suppression of GABA release to GABA_A receptors increases every type of input to pyramidal CA1 neurons and facilitates propagation of excitatory activity through the neural network of area CA1.

Cannabis indica and memory. Cannabinoids (derived from Cannabis indica, or marihuana) disturb memory processes in mammalians. In spite of the fact that the neuronal cannabinoid CB1 receptor was identified several years ago, the neuronal network mechanisms mediating these effects are still controversial. Tritium-labeled GABA-releasing experiments have been used to test for the localization of this receptor at a cellular and subcellular level in the human hippocampus. CB1 expression detected with this technique is limited to hippocampal interneurons, most of which, it could be determined, are cholecystokinin-containing basket neurons. The CB1-positive neuronal somata show immune staining of their cytoplasm, but not of their somatodendritic plasma membrane. CB1-immunoreactive axonic terminals densely cover the entire hippocampus and form symmetrical synapses, characteristic of GABAergic neuronal boutons. It could thus be observed that WIN 55,212-2, a CB1-receptor agonist, considerably reduces the release of tritium-labeled GABA, and that this effect is preventable using the receptor antagonist, SR 141716A. This single pattern of expression and pre-synaptic modulation of GABA release suggests the existence of a preserved role of CB1 receptors in the control of inhibitory hippocampal networks responsible for the generation and maintenance of fast and slow oscillation patterns. Therefore, a probable mechanism whereby cannabinoids could affect associational processes in memory might be a disturbance of synchrony of rhythmical events in distinct neuronal populations.

GABA effects against aging. Certain components which stimulate GABAergic neurotransmission might prevent the hippocampal and striatal degeneration which typically appears with old age and causes memory deterioration. On using a 4-vessel occlusion model in animals to study the effect of ischemia on expression of GABA_A receptor subunits, which are vulnerable in region CA1 and resistant in region CA3 of Amnion's horn, an increment in expression of GABA_A2, GABA _B2, GABA _G2 units and a decrement in expression of GABA _A1 and GABA _A3 subunits in region CA3 were obtained. On the contrary, there was no change in region CA1 or the dentate gyrus under the same conditions. These data speak in favor of the stimulation of type 2 receptor GABAergic subunits which might protect certain hippocampal areas against a harmful neurodegenerative effect, for example, of memory activities during old age.

Key words: γ-aminobutyric acid; agonists and antagonists; θ rhythm; cannabinoids; aging; interneurons