Alzheimer’s dementia (AD) is a progressive, neurodegenerative disease often accompanied by neuropsychiatric symptoms that profoundly impact both patients and caregivers. Agitation is among the most prevalent and distressing of these symptoms and often requires treatment. Appropriate therapeutic interventions depend on understanding the biological basis of agitation and how it may be affected by treatment. This narrative review discusses a proposed pathophysiology of agitation in Alzheimer’s dementia based on convergent evidence across research approaches. Available data indicate that agitation in Alzheimer’s dementia is associated with an imbalance of activity between key prefrontal and subcortical brain regions. The monoamine neurotransmitter systems serve as key modulators of activity within these brain regions and circuits and are rendered abnormal in AD. Patients with AD who exhibited agitation symptoms during life have alterations in neurotransmitter nuclei and related systems when the brain is examined at autopsy. The authors present a model of agitation in Alzheimer’s dementia in which noradrenergic hyperactivity along with serotonergic deficits and dysregulated striatal dopamine release contribute to agitated and aggressive behaviors.

The impairment of endothelial function by reduced endothelial production of nitric oxide (NO) may contribute to the increased risk of developing cardiovascular disease in patients with depression. NO also plays an essential role in the efficacy of antidepressants. The present study aimed to confirm our previous preliminary findings using a larger sample and different antidepressants. We enrolled 100 patients with major depressive disorder (MDD) and 50 healthy controls. Patients were administered sertraline, duloxetine or mirtazapine and were followed up for 8 weeks. We also compared the rate of increase in plasma levels of metabolites of NO (NOx) among the three antidepressant treatments. Baseline plasma NOx levels were significantly lower in the MDD group than in the control group. A negative correlation was found between plasma NOx levels and the severity of MDD. Treatment with duloxetine significantly increased plasma NOx levels, whereas sertraline treatment caused no significant increase.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Objectives: Amphetamine improves vigilance as assessed by continuous performance tests (CPT) in children and adults with attention deficit hyperactivity disorder (ADHD). Less is known, however, regarding amphetamine effects on vigilance in healthy adults. Thus, it remains unclear whether amphetamine produces general enhancement of vigilance or if these effects are constrained to the remediation of deficits in patients with ADHD. Methods: We tested 69 healthy adults (35 female) on a standardized CPT (Conner’s CPT-2) after receiving 10- or 20-mg d-amphetamine or placebo. To evaluate potential effects on learning, impulsivity, and perseveration, participants were additionally tested on the Iowa Gambling Task (IGT) and Wisconsin Card Sorting Task (WCST). Results: Participants receiving placebo exhibited the classic vigilance decrement, demonstrated by a significant reduction in attention (D’) across the task. This vigilance decrement was not observed, however, after either dose of amphetamine. Consistent with enhanced vigilance, the 20-mg dose also reduced reaction time variability across the task and the ADHD confidence index. The effects of amphetamine appeared to be selective to vigilance since no effects were observed on the IGT, WCST, or response inhibition/perseveration measures from the CPT. Conclusions: The present data support the premise that amphetamine improves vigilance irrespective of disease state. Given that amphetamine is a norepinephrine/dopamine transporter inhibitor and releaser, these effects are informative regarding the neurobiological substrates of attentional control. (JINS, 2018, 24, 283–293)

Emotional arousal enhances perception and memory of high-priority information but impairs processing of other information. Here, we propose that, under arousal, local glutamate levels signal the current strength of a representation and interact with norepinephrine (NE) to enhance high priority representations and out-compete or suppress lower priority representations. In our "glutamate amplifies noradrenergic effects" (GANE) model, high glutamate at the site of prioritized representations increases local NE release from the locus coeruleus (LC) to generate “NE hotspots.” At these NE hotspots, local glutamate and NE release are mutually enhancing and amplify activation of prioritized representations. In contrast, arousal-induced LC activity inhibits less active representations via two mechanisms: 1) Where there are hotspots, lateral inhibition is amplified; 2) Where no hotspots emerge, NE levels are only high enough to activate low-threshold inhibitory adrenoreceptors. Thus, LC activation promotes a few hotspots of excitation in the context of widespread suppression, enhancing high priority representations while suppressing the rest. Hotspots also help synchronize oscillations across neural ensembles transmitting high-priority information. Furthermore, brain structures that detect stimulus priority interact with phasic NE release to preferentially route such information through large-scale functional brain networks. A surge of NE before, during, or after encoding enhances synaptic plasticity at NE hotspots, triggering local protein synthesis processes that enhance selective memory consolidation. Together, these noradrenergic mechanisms promote selective attention and memory under arousal. GANE not only reconciles apparently contradictory findings in the emotion-cognition literature but also extends previous influential theories of LC neuromodulation by proposing specific mechanisms for how LC-NE activity increases neural gain.

Based on previous studies demonstrating detrimental effects of reduced alertness on attentional orienting our study seeks to examine covert and overt attentional orienting in different arousal states. We hypothesized an attentional asymmetry with increasing reaction times to stimuli presented to the left visual field in a state of maximally reduced arousal. Eleven healthy participants underwent sleep deprivation and were examined repeatedly every 4 hr over 28 hr in total with two tasks measuring covert and overt orienting of attention. Contrary to our hypothesis, a reduction of arousal did not induce any asymmetry of overt orienting. Even in participants with profound and significant attentional asymmetries in covert orienting no substantial reaction time differences between left- and right-sided targets in the overt orienting task could be observed. This result is not in agreement with assumptions of a tight coupling of covert and overt attentional processes. In conclusion, we found differential effects of lowered arousal induced by sleep deprivation on covert and overt orienting of attention. This pattern of results points to a neuronal non-overlap of brain structures subserving these functions and a differential influence of the norepinephrine system on these modes of spatial attention. (JINS, 2015, 21, 545–557)

Neuroendocrine system plays an important role in modulating our body functions and emotions. At the same time, emotions implicate a pivotal role in the regulation of brain function and neuroendocrine system. Negative affective states such as depression and stress are associated with premature mortality and increase the risk of various fatal diseases. It has been suggested that positive affective states are protective and improve our health and productiveness. Several potential mechanisms have been posited to account for these associations including improved health behaviour, direct physiological benefits, enhanced resistance and recovery from stress among individuals with high versus low positive emotional resources. This review summarises information concerning the neuronal and hormonal systems in mood, impact of negative and positive affective states on the level of cortisol, epinephrine, serotonin, dopamine and endorphins. The functional correlation of neuronal and hormonal systems in the development of diseases and their ability to enhance health-relevant biological processes are also evaluated.

Experimental and clinical evidence implicates stress as a major predisposing factor in depression and other severe psychiatric disorders. In this review, evidence is presented to show how the impact of stress on the central sympathetic system leads to changes in the endocrine, immune and neurotransmitter axes which underlie the main clinical symptoms of depression. Thus it can be shown that the noradrenergic system is dysfunctional in depression, a situation which reflects the chronic hypersecretion of glucocorticoids and inflammatory mediators within the brain in addition to an enhanced activity of the locus ceruleus. With regard to the actions of antidepressants in modulating the stress response and alleviating depression it is now evident that, irrespective of the presumed specificity of the antidepressants for the noradrenergic or serotonergic systems, they all normalize noradrenergic function. This action is due partly to the regulation of tyrosine hydroxylase activity in the locus ceruleus but also enhances neuronal sprouting which counteracts the neurodegenerative effects of chronic stress.

In addition to having difficulties with social communications, individuals with an autism spectrum disorder (ASD) often also experience impairment in higher-order, executive skills. The present study examined the effects of pharmacological modulation of the norepinephrine system on the severity of such impairments. A sample of 14 high-functioning adults with ASD and a demographically-matched comparison group of 13 typically developing individuals participated. An AX continuous performance test (AX-CPT) was used to evaluate working memory and inhibitory control. AX-CPT performance was assessed following administration of a single dose of propranolol (a beta adrenergic antagonist) and following placebo (sugar pill) administration. Individuals with ASD performed more poorly than non-ASD individuals in the working memory condition (BX trials). Importantly, administration of propranolol attenuated this impairment, with the ASD group performing significantly better in the propranolol condition than the placebo condition. Working memory performance of the non-ASD group was unaffected by propranolol/placebo administration. No group or medication effects were observed for the inhibition condition (AY trials). The present findings suggest that norepinephrine may play a role in some, but not necessarily all, cognitive impairments associated with ASD. Additional research is needed to fully understand whether this role is primarily causal or compensatory in nature. (JINS, 2012, 18, 556–564)