We report here on the ability of IDRA 21 and aniracetam, two negative allosteric modulators of glutamateinduced DL-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization, to attenuate alprazolam-induced learning deficit in patas monkeys working in a complex behavioral task. In one component of a multiple schedule (repeated acquisition or "learning"), patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four discriminative stimuli (geometric forms or numerals). In the other component (performance) the four-response chain was the same each session. In the central nervous system, y-aminobutyric acid (GABA) is the most important and abundant inhibitory neurotransmitter, acting at GABAA and GABAB receptors (1, 2). Glutamate is the most potent and abundant excitatory neurotransmitter, acting at ionotropic DL-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl-Daspartate receptors, and on metabotropic receptors (3). Together these two neurotransmitters maintain a fragile balance between neuronal excitation and inhibition. Regulation of such balance establishes a time-related association of functional neuronal assemblies and changes the strength of neuronal circuits (i.e., long-term potentiation) underlying various forms of learning and memory processes (4, 5), thereby establishing functional neuronal maps in the neocortex and the limbic system attending cognitive and sensory-motor function expression (6-8). Drugs that up-regulate GABAergic or downregulate glutamatergic transmission in neocortical and limbic brain areas produce dramatic sensory-motor and learning impairments (9-13). For example, a facilitation of GABAergic transmission elicited at specific GABA receptors by benzodiazepines acting as full or selective positive allosteric modulators (i.e., alprazolam, triazolam, or diazepam) or an inhibition of glutamatergic transmission elicited by competitive and noncompetitive inhibitors of glutamate action at N-methyl-Daspartate receptors (phencyclidine, dizocilpine, etc.) reduces acquisition and retention in rodents and in human and nonhuman primates (9-13). These considerations are central to the working model that neuropharmacologists have recently adopted in order to develop animal models to evaluate potency and efficacy of cognition-enhancing drugs acting through neocortical or limbic glutamatergic or GABAergic neurons (5, 9, 10, 13).In the past several years in our and others' laboratories, attention has been focused on allosteric modulatory sites located on GABAergic and glutamatergic receptors that might be targets for the action of drugs (i.e., partial allosteric modulators) improving neurological or neuropsychiatric disorders, including learning and memory abnormalities, without or with minimal adverse side effects (1,5,9,(10)(11)(12)14).A role for the negative allosteric modulation of glutamateinduced AMPA receptor desensitization in long-term potentiation and cognition ...
