Alcoholism is a progressive disorder that involves the amygdala. Mice lacking protein kinase C epsilon (PKCe) show reduced ethanol consumption, sensitivity and reward. We therefore investigated whether PKCe signaling in the amygdala is involved in ethanol consumption. Local knockdown of PKCe in the amygdala reduced ethanol consumption and preference in a limited-access paradigm. Further, mice that are heterozygous for the PKCe allele consume less ethanol compared with wildtype mice in this paradigm. These mice have a >50% reduction in the abundance of PKCe in the amygdala compared with wild-type mice. We conclude that amygdala PKCe is important for ethanol consumption in mice.

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This review gives a basic introduction to the biology of protein kinase C, one of the first calcium-dependent kinases to be discovered. We review the structure and function of protein kinase C, along with some of the substrates of individual isoforms. We then review strategies for inhibiting PKC in experimental systems and finally discuss the therapeutic potential of targeting PKC. Each aspect is covered in summary, with links to detailed resources where appropriate.

Neuropathic pain (NeuP) is a syndrome that results from damaged nerves and/or aberrant regeneration. Common etiologies of neuropathy include chronic illnesses and medication use. Chronic disorders, such as diabetes and alcoholism, can cause neuronal injury and consequently NeuP. Certain medications with antineoplastic effects also carry an exquisitely high risk for neuropathy. These culprits are a few of many that are fueling the NeuP epidemic, which currently affects 7%–10% of the population. It has been estimated that approximately 10% and 7% of US adults carry a diagnosis of diabetes and alcohol disorder, respectively. Despite its pervasiveness, many physicians are unfamiliar with adequate treatment of NeuP, partly due to the few reviews that are available that have integrated basic science and clinical practice. In light of the recent Centers for Disease Control and Prevention guidelines that advise against the routine use of μ-opioid receptor-selective opioids for chronic pain management, such a review is timely. Here, we provide a succinct overview of the etiology and treatment options of diabetic and alcohol- and drug-induced neuropathy, three different and prevalent neuropathies fusing the combined clinical and preclinical pharmacological expertise in NeuP of the authors. We discuss the anatomy of pain and pain transmission, with special attention to key ion channels, receptors, and neurotransmitters. An understanding of pain neurophysiology will lead to a better understanding of the rationale for the effectiveness of current treatment options, and may lead to better diagnostic tools to help distinguish types of neuropathy. We close with a discussion of ongoing research efforts to develop additional treatments for NeuP.

There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.

Dementia is an important risk factor for delirium, but the optimal strategy for incorporating cognitive impairment into delirium risk assessment at the time of hospital admission is unknown. We compared two informant-based screening tools for dementia and mild cognitive impairment (AD8 and D=(MC)2) to the Mini Mental State Exam (MMSE) and Mini-cog in predicting hospital-acquired delirium. This prospective cohort study at an academic medical center consisted of 162 medical inpatients over age 50 without delirium upon admission. Each participant was evaluated using the MMSE, Mini-cog, AD8, and D=(MC)2 upon admission and was assessed daily for delirium. An MMSE ≤ 24 carried a 5.5 (95% CI 2.7 – 11.1) relative risk for delirium, whereas cognitive impairment detected by the Mini-cog, D=(MC)2 or AD8 carried a 2-fold risk. Adding the D=(MC)2 to the MMSE increased the sensitivity for predicting delirium from 52% (32 – 73) for the MMSE alone to 65% (46 – 85) if either test was positive. If both were positive, specificity was maximized at 97% (94 – 100) but sensitivity was 17% (2 – 33). The MMSE and Mini-cog identify a large proportion of patients at risk for hospital-acquired delirium, but the combination of performance- and an informant-based screens may maximize specificity and sensitivity.

Mechanisms driving adaptive developmental responses to chronic high altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and post-natal timeframe. We assessed lung growth and cardiopulmonary structure and function, and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 feet elevation). Mating, pregnancy and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNAseq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, RV systolic pressure as well as increased pulmonary artery remodeling. RNAseq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. While there was considerable similarity between hypoxic lungs and RVs compared to RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune down-regulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.