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Background Methylphenidate (MPH) has long been used to treat attention deficit-hyperactivity disorder (ADHD); however, its cellular mechanisms of action and potential effects on prefrontal cortical circuitry are not well understood, particularly in the developing brain system. A clinically-relevant dose range for rodents has been established in the adult animal; however, how this range will translate to juvenile animals has not been established. Methods Juvenile (P15) and adult (P90) SD rats were treated with MPH or saline. Whole-cell patch clamp recording was used to examine the neuronal excitability and synaptic transmission in pyramidal neurons of prefrontal cortex. Recovery from MPH treatment was also examined at 1, 5 and 10 weeks following drug cessation. Results 1 mg/kg i.p. dose of MPH, either single dose or chronic treatment (well within the accepted therapeutic range for adults) produced significant depressive effects on pyramidal neurons by increasing hyperpolarization-activated currents in juvenile rat prefrontal cortex, while exerting excitatory effects in adult rats. Minimum clinically-relevant doses (0.03 to 0.3 mg/kg) also produced depressive effects in juvenile rats, in a linear dose-dependent manner. Function recovered within 1 week from chronic 1 mg/kg treatment, chronic treatment with 3 and 9 mg/kg resulted in depression of prefrontal neurons lasting 10 weeks and beyond. Conclusions These results suggest that the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults is an overshoot. Juvenile treatment with MPH may result in long-lasting, potentially permanent, changes to excitatory neuron function in the prefrontal cortex of juvenile rats.

Cognitive enhancement is perhaps one of the most intriguing and controversial topics in neuroscience today. Currently, the main classes of drugs used as potential cognitive enhancers include psychostimulants (methylphenidate (MPH), amphetamine), but wakefulness-promoting agents (modafinil) and glutamate activators (ampakine) are also frequently used. Pharmacologically, substances that enhance the components of the memory/learning circuits—dopamine, glutamate (neuronal excitation), and/or norepinephrine—stand to improve brain function in healthy individuals beyond their baseline functioning. In particular, non-medical use of prescription stimulants such as MPH and illicit use of psychostimulants for cognitive enhancement have seen a recent rise among teens and young adults in schools and college campuses. However, this enhancement likely comes with a neuronal, as well as ethical, cost. Altering glutamate function via the use of psychostimulants may impair behavioral flexibility, leading to the development and/or potentiation of addictive behaviors. Furthermore, dopamine and norepinephrine do not display linear effects; instead, their modulation of cognitive and neuronal function maps on an inverted-U curve. Healthy individuals run the risk of pushing themselves beyond optimal levels into hyperdopaminergic and hypernoradrenergic states, thus vitiating the very behaviors they are striving to improve. Finally, recent studies have begun to highlight potential damaging effects of stimulant exposure in healthy juveniles. This review explains how the main classes of cognitive enhancing drugs affect the learning and memory circuits, and highlights the potential risks and concerns in healthy individuals, particularly juveniles and adolescents. We emphasize the performance enhancement at the potential cost of brain plasticity that is associated with the neural ramifications of nootropic drugs in the healthy developing brain.

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Using an adaptation of published behavioral protocols, we determined that acute exposure to the cholinergic compounds nicotine and carbamylcholine decreased planarian motility in a concentration-dependent manner. A tobacco cembranoid (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R-cembranoid), also decreased planarian motility. Experiments in the presence of 1 μM 4R-cembranoid did increase the IC 50 for nicotine-but not carbamylcholine-induced decrease in planarian motility. When planarians were exposed for 24 h to either nicotine or carbamylcholine at concentrations near their respective IC 50 values and then transferred to plain media, nicotineexposed, but not carbamylcholine-or cembranoid-exposed worms displayed withdrawal-like distress behaviors. In experiments where planarians were pre-exposed to 100 μM nicotine for 24 h in the presence of 1 μM 4R-cembranoid, the withdrawal-like effects were significantly reduced. These results indicate that the 4R-cembranoid might have valuable applications for tobacco abuse research. This experimental approach using planarians is useful for the initial screening of compounds relevant to drug abuse and dependence.