This paper presents a 3.3 × 3.2mm2 system-on-chip (SoC) fabricated in AMS 0.35µm 2P/4M CMOS for closed-loop regulation of brain dopamine. The SoC uniquely integrates neurochemical sensing, on-the-fly chemometrics, and feedback-controlled electrical stimulation to realize a “neurochemostat” by maintaining brain levels of electrically evoked dopamine between two user-set thresholds. The SoC incorporates a 90µW, custom-designed, digital signal processing (DSP) unit for real-time processing of neurochemical data obtained by 400V/s fast-scan cyclic voltammetry (FSCV) with a carbon-fiber microelectrode (CFM). Specifically, the DSP unit executes a chemometrics algorithm based upon principal component regression (PCR) to resolve in real time electrically evoked brain dopamine levels from pH change and CFM background-current drift, two common interferents encountered using FSCV with a CFM in vivo. Further, the DSP unit directly links the chemically resolved dopamine levels to the activation of the electrical microstimulator in on-off-keying (OOK) fashion. Measured results from benchtop testing, flow injection analysis (FIA), and biological experiments with an anesthetized rat are presented.

Modafinil (MOD) exhibits therapeutic efficacy for treating sleep and psychiatric disorders; however, its mechanism is not completely understood. Compared with other psychostimulants inhibiting dopamine (DA) uptake, MOD weakly interacts with the dopamine transporter (DAT) and modestly elevates striatal dialysate DA, suggesting additional targets besides DAT. However, the ability of MOD to induce wakefulness is abolished with DAT knockout, conversely suggesting that DAT is necessary for MOD action. Another psychostimulant target, but one not established for MOD, is activation of phasic DA signaling. This communication mode during which burst firing of DA neurons generates rapid changes in extracellular DA, the so-called DA transients, is critically implicated in reward learning. Here, we investigate MOD effects on phasic DA signaling in the striatum of urethane-anesthetized rats with fast-scan cyclic voltammetry. We found that MOD (30-300 mg/kg i.p.) robustly increases the amplitude of electrically evoked phasic-like DA signals in a time- and dose-dependent fashion, with greater effects in dorsal versus ventral striata. MOD-induced enhancement of these electrically evoked amplitudes was mediated preferentially by increased DA release compared with decreased DA uptake. Principal component regression of nonelectrically evoked recordings revealed negligible changes in basal DA with high-dose MOD (300 mg/kg i.p.). Finally, in the presence of the D2 DA antagonist, raclopride, low-dose MOD (30 mg/kg i.p.) robustly elicited DA transients in dorsal and ventral striata. Taken together, these results suggest that activation of phasic DA signaling is an important mechanism underlying the clinical efficacy of MOD.

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In an effort to combat diseases and disorders that impede our health, comfort and well-being, an abundance of prescription drugs have emerged in the past 60 years. Many prescription drugs have remarkable efficacy for treating the primary symptoms of these diseases and disorders; however, some drugs carry negative side effects that impose their own adverse symptoms, albeit, often to a lesser degree than the primary symptoms. Thus, one of the main objectives of the pharmaceutical industry is to innovate and develop novel therapeutics, which remediate the primary symptoms of disease and lack undesirable negative side effects. However, in order to develop effective novel therapeutics, a comprehensive understanding of the underlying mechanisms of current drugs is critical. The work within this thesis investigates the mechanisms of two neuroactive drugs, which are commonly prescribed by physicians. Chapter I investigates modafinil (Provigil®), which is therapeutic for sleep and psychiatric disorders, and drug addiction therapy. Chapter II investigates atomoxetine (Strattera®), which is prescribed for attention deficit hyperactivity disorder (ADHD) and possesses limited abuse potential, in contrast to current ADHD medications, Adderall® and Ritalin®, which are addictive.The effects of modafinil and atomoxetine on phasic dopamine signaling were investigated. Phasic dopamine signaling has been identified critical for reward learning and seeking, and is hypothesized to contribute to deficits in ADHD and drug addiction.The results herein suggest that alterations in phasic dopamine signaling are involved in the underlying mechanism of modafinil and atomoxetine action and may ultimately contribute to their therapeutic efficacy.