Current Pharmaceutical Design - Volume 16, Issue 18, 2010

With the development of neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), it has become possible to directly monitor the effects of pharmacological agents on brain functioning. This is especially important for the research in the area of psychiatry and psychology. With fMRI it has become possible to see which brain functions are affected by the agent and how this change in functioning is related to symptoms of the disease. With PET it has become possible to monitor more basic processes like receptor binding and metabolic functions of different types of brain cells. Both techniques have become increasingly important in establishing the role of neurotransmitter systems in psychiatric diseases and monitoring the effects of different pharmacological treatments. One of the dominant hypotheses with respect to major depression is that disrupted serotonin function plays a key role. Various studies have found evidence for lowered serotonin function and increasing central serotonin levels by means of administration of selective serotonin reuptake inhibitors (SSRI) is the dominant treatment. However, very few studies have established a direct link. With recent developments in PET it has become possible to directly map serotonin metabolism in vivo and establish such a direct link. The paper of Veltman et al. [1] nicely reviews the recent PET findings with respect to the role of serotonin in major depression and other psychiatric disorders. By using fMRI is has become possible to directly look at effects of treatment with an SSRI on brain function. The paper of Murphy [2] reviews the literature in this area and focuses on emotion-related processing. Finally, fMRI has also made it possible to examine the effects of changes in central serotonin levels in healthy controls, which provides the opportunity to acquire more basic knowledge regarding the role of serotonin in various aspects of normal information processing. The paper Evers et al. [3] reviews the literature in this area and focuses on the effect of acute tryptophan depletion, a well-established method to transiently lower central serotonin levels. The dominant hypothesis with respect to schizophrenia is that dopamine function is disrupted. Various forms of the dopamine hypothesis have been put forward and a recent version of the hypothesis states that in schizophrenic patients dopamine activity is lowered in prefrontal brain areas leading to negative symptoms and to stronger dopamine activity in mesolimbic areas which might be the cause of the positive symptoms. First generation antipsychotics have explicitly targeted the dopamine system but second generation antipsychotics also aim at influencing other neurotransmitter systems. The paper of Roder et al. [4] reviews the literature with respect to the effects of both first and second generation antipsychotics on brain function of schizophrenic patients, as can be measured with fMRI. The fMRI technique has also been used to further elucidate the role of dopamine in information processing in healthy controls. Literature in this area is reviewed by Schouwenburg et al. [5] who especially focus on the role of dopamine in cognitive control. This special issue reviews the role of dopamine and serotonin in information processing in healthy and sick brains as can be established by the new and exciting neuroimaging techniques of PET and fMRI. The included reviews will present a broad and informative perspective of this new and rapidly developing field of research.

Mono-aminergic neurotransmitters, in particular serotonin (5-HT), are involved in regulating a large number of psychological and physiological functions, and abnormal 5-HT transmission has been implicated in a wide variety of neuropsychiatric disorders. Positron emission tomography (PET) is a non-invasive nuclear imaging technique with exquisite sensitivity and specificity, allowing delineation of neurotransmitter function in vivo. Over the last two decades, PET has been used to investigate 5-HT function in several neuropsychiatric disorders, in particular mood and anxiety disorders, schizophrenia, Alzheimer's disease, and impulse control disorders. In the present review, an overview of recent findings is provided, and possibilities for further research are discussed.

Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression and a range of anxiety disorders [1,2]. Preclinical models have been relatively successful at elucidating the key neurochemical effects of these serotonergic agents; however, a lack of understanding exists of the functional mechanisms by which these drugs exert their effects on mood and anxiety. Elucidating the link between the neurochemical effects of these drugs and their therapeutic action is an essential step in further understanding some of the current limitations of SSRIs, and in developing novel agents that are more selectively designed to target the symptoms they treat. An increasingly popular experimental method within psychopharmacological research is the use of functional neuroimaging techniques to investigate the pharmacological modulation of task-induced brain activity by psychoactive drugs. Such an approach offers an exciting opportunity to investigate the mechanisms of drug action and, in this way, bridge the gap between preclinical and clinical studies. Applying this approach to the study of SSRIs has highlighted that direct modulation of activity in neural areas involved in emotional processing may represent a key functional mechanism through which these agents exert their antidepressant clinical effects. This review summarises the cognitive and neuroimaging evidence suggesting the critical role that disruptions in emotion-related processing play in depression and anxiety disorders. It then examines the functional neuroimaging evidence, from both patient and healthy volunteer studies, to suggest that the amelioration of such disruptions is a key mechanism through which SSRIs exert their therapeutic effects.

Acute tryptophan depletion (ATD), a method to temporarily lower central serotonin levels, has been used to study the functioning of the serotonergic system. Relatively recent studies that examined the effects of ATD on brain activation associated with cognitive and emotional processing in healthy volunteers are reviewed. An overview of the findings in healthy volunteers is important for the interpretation of the effect of ATD on brain activation in patients with an affective disorder, such as major depression. These studies show that during response control and negative feedback processing ATD modulates the BOLD response in the inferior/orbitofrontal cortex, the anterior cingulate cortex and the dorsomedial prefrontal cortex. During emotional processing, it is consistently found that ATD modulates the BOLD response in the amygdala. These brain regions also show abnormal activation in depressed patients. However, at the moment it remains unclear if the changes induced by ATD are related to decreased basal serotonin (5-HT) release or the result of other biochemical changes that are mediated by ATD. Future studies should implement methodological improvements, explore the possibilities of new promising imaging techniques and expand investigations into the effects of ATD on basal 5-HT release and other biochemical mechanisms that might be modulated by ATD.

In the last decade, functional Magnetic Resonance Imaging (FMRI) has been increasingly used to investigate the neurobiology of schizophrenia. This technique relies on changes in the blood-oxygen-level-dependent (BOLD) - signal, which changes in response to neural activity. Many FMRI studies on schizophrenia have examined medicated patients, but little is known about the effects of antipsychotic medication on the BOLD-signal. In this review we investigated to what extent studies in patients with schizophrenia (SC), who were treated with different antipsychotics, could give insight in the effects of antipsychotics on the BOLD-signal. A PubMed search was performed using the search items “schizophrenia”, “FMRI”, “antipsychotics” and “schizophrenia”, “BOLD”, “antipsychotics”. Only articles in which there were at least two groups of patients with different treatments or in which patients were scanned twice with different treatments were selected. 18 articles, published between 1999 and 2009, fulfilled these criteria. Paradigms and results of these studies were compared regarding differences induced by the administered antipsychotics. This analysis showed no general effect of antipsychotics on the BOLD-signal. However, there is some evidence that the extent of blockade of the dopamine (DA) D2 receptor does influence the BOLD-signal. Higher affinity to the dopamine D2 receptor, as expressed by a higher/lower inhibition constant (Ki) seems to cause a decrease in BOLD-signal.

Evidence from psychopharmacological functional neuroimaging begins to elucidate the neurochemical mechanisms of cognitive control. Here the role of dopamine in two subcomponent processes of cognitive control is discussed: the active maintenance and the flexible updating of goal-relevant representations. A range of studies have highlighted a role for the prefrontal cortex (pFC) and its modulation by dopamine in the active maintenance of distractor-resistant goal-relevant representations. This work suggests that dopamine might modulate top-down signals from the pFC, thereby increasing the activity of posterior cortical regions that process goalrelevant representations and rendering them distractor-resistant. Conversely, other studies highlight a role for dopamine in the basal ganglia in cognitive switching, which might reflect a modulation of the selective gating of cortical cognitive and motor programs. We present a working hypothesis that integrates these two disparate literatures and states that the flexible adaptation of current goal-relevant representations is mediated by modulatory influences of activity in the dopamine-sensitive basal ganglia on connectivity between the prefrontal cortex and posterior cortex.

Phenolic group in therapeutic drugs can be used for a prodrug modification to overcome various undesirable drug properties that may become pharmacological, pharmaceutical or pharmacokinetic barriers for application. Several strategies have been used in order to overcome the limited bioavailability of phenolic drugs. Classical design represents a nonspecific chemical approach to mask undesirable drug properties, limited bioavailability or chemical instability. Targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrug to specific enzyme or specific membrane transporter has potential as selective drug delivery system mainly in cancer therapy. The article brings examples of ester, sulphate, carbamate, carbonate, phosphate and ether prodrugs as well as the limitations of these prodrug strategies. Some specific enzyme targets are also presented.

Amyotrophic lateral sclerosis (ALS) is a debilitating and ultimately fatal indication that is the most prevalent adult-onset motoneuron disorder. ALS imparts tremendous suffering upon patients and caregivers alike. Exciting new insight has been obtained as to the etiology and initiation of the disease during the past decade, particularly affecting the larger, sporadic patient population. An important new discovery is the involvement of the TAR DNA binding protein (TDP-43) based upon genetic evidence and the presence of the cytosolic ubiquitinylated TDP-43 aggregates found during post-mortem analysis of damaged motoneuron in the spinal cord of ALS patients. Superoxide dismutase (SOD1) continues to be of interest for the ∼20% of the familial ALS patients who have the inherited form of the disease (∼15% of the total), but SOD1 does not appear to be as relevant as was once imagined for the sporadic patient population. We can now target specific biochemical pathways and deficits via traditional drug discovery efforts and may thus be able to achieve more effective therapeutic relief for patients who suffer from this disease. In this review we present a comprehensive discussion of current molecular targets and pathways that are of interest to small molecule drug discovery efforts for the treatment of ALS.