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The neurophysiology of alcohol use disorder (AUD) is complex, but a major contributor to addictive phenotypes is the tendency for drugs of abuse to increase tonic extracellular dopamine (DA) levels in the nucleus accumbens (NAc). Repeated exposure to substances of abuse such as ethanol results in the overstimulation of the mesolimbic pathway, causing an excessive release of DA from the ventral tegmental area (VTA) to target regions such as the NAc. This heightened DA signaling is associated with the reinforcing effects of substances, leading to a strong desire for continued use. Recent work has postulated that high frequency deep brain stimulation (DBS) of the ventral tegmental area may reduce dopamine transmission to the nucleus accumbens following acute drug of abuse exposure, thereby mitigating the drug's addictive potential. We first demonstrate ethanol's ability to decrease phasic DA release over time and to increase tonic extracellular DA concentrations in the nucleus accumbens. Next, we demonstrate the capability for high frequency VTA DBS to reverse this ethanol-associated surge in tonic DA concentrations in the nucleus accumbens to levels not significantly different from baseline. This study suggests a promising new avenue for investigating the mechanisms of alcohol use disorder. [ABSTRACT FROM AUTHOR]

External ventricular drainage (EVD) is an emergency neurosurgical procedure to decrease intracranial pressure through a catheter mediated drainage of cerebrospinal fluid. Most EVD catheters are placed using free hands without direct visualization of the target and catheter trajectory, leading to a high rate of complications- hemorrhage, brain injury and suboptimal catheter placement. Use of stereotactic systems can prevent these complications. However, they have found limited application for this procedure due to their long set-up time and expensive hardware. Therefore, we have developed and pre-clinically validated a novel 3D printed stereotactic system for rapid and accurate implantation of EVD catheters. Its mechanical and imaging accuracies were found to be at par with clinical stereotactic systems. Preclinical trial in human cadaver specimens revealed improved targeting accuracy achieved within an acceptable time frame compared to the free hand technique. CT angiography emulated using cadaver specimen with radio-opaque vascular contrast showed vessel free catheter trajectory. This could potentially translate to reduced hemorrhage rate. Thus, our 3D printed stereotactic system offers the potential to improve the accuracy and safety of EVD catheter placement for patients without significantly increasing the procedure time. [ABSTRACT FROM AUTHOR]

Rationale Aminoadamantanes represent a class of NMDA glutamate receptor antagonists that reduce alcohol consumption and may prevent alcohol-induced neuronal adaptations and side effects. Objective Behavioral specificity of memantine and amantadine on alcohol drinking in a schedule-induced polydipsia (SIP) task was investigated in mice. Methods Male C57BL/6J mice were food-deprived and divided into four groups: 5% alcohol SIP, water SIP, 1 h limited access regulatory water drinking, and a control group to determine if either drug altered ethanol drinking. Behavioral specificity of memantine (5, 10, and 25 mg/kg, ip) and amantadine (20, 40, and 60 mg/kg, ip) was determined by comparing alterations in alcohol or water consumption in SIP and regulatory water drinking. Drug effects on SIP drinking-specific measures (grams per kilogram consumption) were also compared to nondrinking measures (locomotion, head-entries for food, and lick efficiency). Results Compared to saline, memantine reduced alcohol SIP drinking (10 and 25 mg/kg). Memantine increased locomotion during alcohol SIP (25 mg/kg) and during water SIP (5 and 25 mg/kg). In contrast, amantadine reduced both alcohol SIP (40 mg/kg) and water SIP (40 and 60 mg/kg). Both drugs reduced regulatory water consumption over the entire dose range tested. Blood alcohol concentrations indicated consumption of physiologically meaningful amounts of alcohol during SIP, and that changes in alcohol metabolism did not account for drug-induced reductions in alcohol drinking. Conclusions In addition to reducing alcohol drinking, both drugs had other behavioral effects that included reductions in regulatory drinking. These results suggest that the therapeutic utility of these drugs for ameliorating human alcohol addiction remains questionable. [ABSTRACT FROM AUTHOR]

Abstract Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement. In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug. [ABSTRACT FROM AUTHOR]

There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy. [ABSTRACT FROM AUTHOR]