Compounds that enhance cognitive function

The term 'nootropics' (from Greek, noos—mind, tropos—turn) was originally coined to denote chemical compounds that were reported to enhance cognitive function, including learning and memory, without possessing other significant effects (Giurgea 1973). The best known are piracetam and structurally related compounds (Giurgea 1973; Gouliaev and Senning 1994). Over the years, however, the term has acquired a peculiar flavour. Many authors reserve it for compounds that are reputed to boost cognition, but were not rigorously proven to do so. Others use it to refer to compounds that have proven beneficial effects on cognition but whose mechanism of action is yet unknown. There is actually no reason why 'nootropics' shouldn't be used as a generic term to denote compounds that enhance cognition, whether their mechanism of action is known or not. But this is a matter oftaste.

The search for a memory potion clearly antedated the introduction of the term 'nootropics'. It was mostly disappointing. Even the literary imagination did not come up with a simple solution. To learn the fine details of the collective past, the poet in the oivine Comedy, much like Odyssey before him, had to go through Hell

(Dante 1314; "limbic system); and in modern times, Borges' Funes, the ultimate memorizer, was endowed with limitless memory only after knocking his head in an almost fatal horse accident (Borges 1944; "mnemonics). A more realistic and systematic approach to memory enhancement began by the same Lashley who was searching for the "engram. He found that strychnine (a poison that interacts with the "receptor for the "neurotransmitter glycine) accelerates the learning "performance of rats in a maze, albeit only in concentrations that produce tremor and motor incoordination (Lashley 1917). More recent research has provided evidence that other stimulants as well could enhance memory if administered around the time of training (McGaugh 1966; McGaugh et al. 1993), but toxicity prevents these drugs from being used as cognitive enhancers.

In the late 1960s, a new compound with a structural resemblance to the inhibitory neurotrans-mitter y-aminobutyric acid (GABA), piracetam (2-pyrrollidoneacetamide), was tested for its effects on motion sickness, and subsequently reported to enhance learning and protect against "amnesic treatments in rats (Giurgea 1973; Gouliaev and Senning 1994). Soon afterwards, additional pyrrollidone derivatives were synthesized and tested, and some reported to improve learning and memory in both rats and humans (Mondadori 1993; Deberdt 1994; Gouliaev and Senning 1994). In parallel, compounds unrelated to the piracetam family were also added to the nootropic list, among them newly synthesized chemicals (e.g. Mondadori et al. 1991), and natural preparations with a respectable history in traditional medicines (e.g. ginkgo biloba extracts; Deberdt 1994). The nootropic efficacy of most of these compounds was, however, debated from the outset. Furthermore, no agreement has been reached on their mechanism of action in the brain. Interactions with neurotransmitter and neuromodula-tory systems (and see below), "ion channels, membrane fluidity, steroid hormones, and neuronal energy supply, have all been suggested (Olpe and Lynch 1982; Mondadori 1993; Gouliaev and Senning 1994).

Meanwhile, rational design has led to the development and identification of new classes of cognitive boosters (Staubli et al. 1994; Ingram et al. 1996; Giacobini and McGeer 2000). The first drugs to be approved for alleviating some early symptoms of "dementia act by enhancing transmission via

"acetylcholine (Crimson 1994; Giacobini and McGeer 2000). The identification of the role of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) type of "glutamatergic receptors in "plasticity resulted in the synthesis of ampakines, AMPA agonists that cross the blood-brain barrier, enhance excitatory synaptic response and "LTP, and improve memory in rats (Staubli et al. 1994) and humans (Ingvar et al. 1997). In the latter, an ampakine was reported to improve performance on several sensory and spatial learning tasks, but not on cued "recall of verbal information and on tasks that measure arousal and "attention only. Interestingly, facilitation ofAMPA receptors is one ofthe effects seen with piracetams (Gouliaev and Senning 1994). In vivo this glutamatergic effect is probably limited because of the rapid metabolism of piracetam in peripheral tissues (Staubli et al. 1994). Research on agonists of the benzodiazepine binding sites on GABAergic receptors was also considered (Raffalli-Sebille et al. 1990; Izquierdo and Medina 1991; "lotus). The anxio-genic effects ofthese compounds could pose, however, a severe problem.

Drugs that interact with the cholinergic, glutamater-gic, and additional neurotransmitter systems are expected to enhance "acquisition and possibly "retrieval of learned information. Other compounds might boost "consolidation. An appealing target for consolidation boosters is the "CREB system. Other transcription factors and "immediate early genes could be targeted as well. At the time of writing, nootropics that act on these targets are still unavailable. To develop them is not an easy task, because one must identify those elements of the transcriptional and translational regulatory systems in neurons that are critical for learning and memory, but not for other essential cellular processes (e.g. "homeostasis).

Whichever their mechanism of action, either on acquisition, on consolidation or on retrieval, it is likely that safe and effective nootropics will ultimately become available, even as over-the-counter medications. Their effect on the "capacity of "real-life memory, on cognitive functions such as categorization and decision making, and on emotion, should make an interesting topic for countless PhD theses.

Selected associations: CREB, Glutamate, Lotus, Mnemonics, Nutrient


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