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      A Possible Link between Anxiety and Schizophrenia and a Possible Role of Anhedonia

      review-article
      Schizophrenia Research and Treatment
      Hindawi

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          Abstract

          In the prodromal phase of schizophrenia, severe alterations of the visual appearance of the environment have been found, accompanied by a state of intense anxiety. The present study considers the possibility that these alterations really exist in the appearance of objects, but that healthy people do not see them. The image of the world that we see is continuously deformed and fragmented by foreshortenings, partial overlapping, and so on and must be constantly reassembled and interpreted; otherwise, it could change so much that we would hardly recognize it. Since pleasure has been found to be involved in visual and cognitive information processing, the possibility is considered that anhedonia (the reduction of the ability to feel pleasure) might interfere with the correct reconstruction and interpretation of the image of the environment and alter its appearance. The possibility is also considered that these alterations might make the environment hostile, might at times evoke the sensation of being trapped by a predator, and might be the cause of the anxiety that accompanies them. According to some authors, they might also induce delusional ideas, in an attempt to restore meaning in a world that has become chaotic and frightening.

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          Most cited references85

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          Opioids excite dopamine neurons by hyperpolarization of local interneurons.

          Increased activity of dopamine-containing neurons in the ventral tegmental area is necessary for the reinforcing effects of opioids and other abused drugs. Intracellular recordings from these cells in slices of rat brain in vitro showed that opioids do not affect the principal (dopamine-containing) neurons but hyperpolarize secondary (GABA-containing) interneurons. Experiments with agonists and antagonists selective for opioid receptor subtypes indicated that the hyperpolarization of secondary cells involved the mu-receptor. Most principal cells showed spontaneous bicuculline-sensitive synaptic potentials when the extracellular potassium concentration was increased from 2.5 to 6.5 or 10.5 mM; these were prevented by TTX and assumed to result from action potentials arising in slightly depolarized local interneurons. The frequency of these synaptic potentials, but not their amplitudes, was reduced by opioids selective for mu-receptors. It is concluded that hyperpolarization of the interneurons by opioids reduces the spontaneous GABA-mediated synaptic input to the dopamine cells. In vivo, this would lead to excitation of the dopamine cells by disinhibition, which would be expected to contribute to the positive reinforcement seen with mu-receptor agonists such as morphine and heroin.
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            Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit.

            Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is largely a voluntary behavior, continued drug use can eventually impair neuronal circuits in the brain that are involved in free will, turning drug use into an automatic compulsive behavior. The ability of addictive drugs to co-opt neurotransmitter signals between neurons (including dopamine, glutamate, and GABA) modifies the function of different neuronal circuits, which begin to falter at different stages of an addiction trajectory. Upon exposure to the drug, drug cues or stress this results in unrestrained hyperactivation of the motivation/drive circuit that results in the compulsive drug intake that characterizes addiction.
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              Dynorphin, stress, and depression.

              Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both. Copyright 2009 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Schizophr Res Treatment
                Schizophr Res Treatment
                SCHIZORT
                Schizophrenia Research and Treatment
                Hindawi
                2090-2085
                2090-2093
                2018
                17 January 2018
                : 2018
                : 5917475
                Affiliations
                Via Ragazzi del 99 No. 45, 20010 San Giorgio su Legnano, Milano, Italy
                Author notes

                Academic Editor: Markus Jäger

                Author information
                http://orcid.org/0000-0003-4931-7730
                Article
                10.1155/2018/5917475
                5822762
                af2fba2d-da6c-4e4b-8f52-ee326164ab68
                Copyright © 2018 Luigi Grillo.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 May 2017
                : 24 August 2017
                : 10 December 2017
                Categories
                Review Article

                Neurology
                Neurology

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