dynorphins and Mental-Disorders

Negative affective states are prevalent symptoms in a plethora of neuropsychiatric disorders, including depression and drug addiction. Dysfunction of mesocorticolimbic dopamine systems has been implicated in negative affective states in neuropsychiatric disorders. The dynorphin/kappa-opioid receptor system is a powerful effector of stress-related behavior and is highly enriched within the mesocorticolimbic dopamine system. Dysfunction of dynorphin/KOR signaling within the mesocorticolimbic dopamine system is implicated in promoting symptoms in neuropsychiatric disorders. As such, the kappa-opioid receptor system provides an important therapeutic target to treat negative affective states associated with psychiatric disorders. In this review, we provide a comprehensive overview of the dynorphin/kappa-opioid receptor system and its role in regulating the mesocorticolimbic dopamine system, motivation, and emotional behavior. Furthermore, we highlight unresolved issues in the field and offer some insights for future research.

Topics: Affect; Animals; Dopamine; Dynorphins; Emotions; Humans; Mental Disorders; Psychotic Disorders; Receptors, Opioid, kappa; Signal Transduction

Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.

Topics: Animals; Behavior, Animal; Brain; Cholinergic Fibers; Cognition; Cognition Disorders; Dynorphins; Humans; Memory; Mental Disorders; Neuronal Plasticity; Nootropic Agents; Signal Transduction; Synaptic Transmission

It is known that stress changes state and reactivity of humoral systems of stress, particularly the hypothalamic-pituitary-adrenal system (HPA) and the dynorphin-K-opioid system (DKOS) in any age periods, including ones of early postnatal development. Supposedly these changes are underlying some disorders. Difference in state and reactivity of the HPA system is well established. But the role of DKOS is not clear. Further study of this requires summarizing of the literature data on physiology of DKOS activation and ethological features of the activation in different periods of postnatal development. It is possible to conclude that the mode of reaction to stimulation of the DKOS differs in the early development in contrast to adult animals. The mode of reaction can be changed in relation to the periods of development of the system of stress-reactivity and can depend on prior activation of the stress system in a particular period.

Topics: Analgesics, Opioid; Animals; Dynorphins; Embryonic Development; Humans; Hypothalamo-Hypophyseal System; Mental Disorders; Pituitary-Adrenal System; Receptors, Opioid, kappa; Stress, Psychological

The dynorphin/κ-opioid receptor system has been implicated in the pathogenesis and pathophysiology of several psychiatric disorders. In the present review, we present evidence indicating a key role for this system in modulating neurotransmission in brain circuits that subserve mood, motivation, and cognitive function. We overview the pharmacology, signaling, post-translational, post-transcriptional, transcriptional, epigenetic and cis regulation of the dynorphin/κ-opioid receptor system, and critically review functional neuroanatomical, neurochemical, and pharmacological evidence, suggesting that alterations in this system may contribute to affective disorders, drug addiction, and schizophrenia. We also overview the dynorphin/κ-opioid receptor system in the genetics of psychiatric disorders and discuss implications of the reviewed material for therapeutics development.

Topics: Brain; Central Nervous System Stimulants; Cyclic AMP Response Element-Binding Protein; Dynorphins; Enkephalins; Epigenesis, Genetic; Gene Expression Regulation; Humans; Mental Disorders; Models, Animal; Protein Precursors; Receptors, Opioid, kappa; Self Stimulation; Signal Transduction

Since the first description of their opioid properties three decades ago, dynorphins have increasingly been thought to play a regulatory role in numerous functional pathways of the brain. Dynorphins are members of the opioid peptide family and preferentially bind to kappa opioid receptors. In line with their localization in the hippocampus, amygdala, hypothalamus, striatum and spinal cord, their functions are related to learning and memory, emotional control, stress response and pain. Pathophysiological mechanisms that may involve dynorphins/kappa opioid receptors include epilepsy, addiction, depression and schizophrenia. Most of these functions were proposed in the 1980s and 1990s following histochemical, pharmacological and electrophysiological experiments using kappa receptor-specific or general opioid receptor agonists and antagonists in animal models. However, at that time, we had little information on the functional relevance of endogenous dynorphins. This was mainly due to the complexity of the opioid system. Besides actions of peptides from all three classical opioid precursors (proenkephalin, prodynorphin, proopiomelanocortin) on the three classical opioid receptors (delta, mu and kappa), dynorphins were also shown to exert non-opioid effects mainly through direct effects on NMDA receptors. Moreover, discrepancies between the distribution of opioid receptor binding sites and dynorphin immunoreactivity contributed to the difficulties in interpretation. In recent years, the generation of prodynorphin- and opioid receptor-deficient mice has provided the tools to investigate open questions on network effects of endogenous dynorphins. This article examines the physiological, pathophysiological and pharmacological implications of dynorphins in the light of new insights in part obtained from genetically modified animals.

Topics: Animals; Brain Diseases; Disease Models, Animal; Dynorphins; History, 20th Century; Humans; Mental Disorders; Mice; Substance-Related Disorders

Limited neurobiological data have implicated central arginine vasopressin in the pathobiology of obsessive-compulsive disorder (OCD). Based on twin, family genetic, and pharmacological studies, some forms of OCD are etiologically related to Tourette's syndrome. The role of arginine vasopressin and related compounds such as oxytocin in Tourette's syndrome has not been previously explored.. To compare cerebrospinal fluid (CSF) levels of arginine vasopressin and oxytocin, we collected CSF at midday in a standardized fashion from a total of 83 individuals (29 patients with OCD, 23 patients with Tourette's syndrome, and 31 normal controls). We also collected family study data on each subject to determine which subjects had a family history positive for Tourette's syndrome, OCD, or related syndromes.. In contrast to previous reports, we report similar concentrations of arginine vasopressin for all three groups but increased oxytocin levels in patients with OCD. Remarkably, this increase was observed only in a subset of patients with OCD (n = 22) independently identified as being without a personal or family history of tic disorders (P = .0003). In this subgroup of patients, the CSF oxytocin level was correlated with current severity of OCD (n = 19, r = .47, P < .05).. A possible role for oxytocin in the neurobiology of a subtype of OCD is suggested by the elevated CSF levels of oxytocin and by the correlation between CSF oxytocin levels and OCD severity. These findings reinforce the value of family genetic data in identifying biologically homogeneous (and perhaps more etiologically homogeneous) groups of patients with OCD. Together with emerging pharmacological data showing differential responsiveness to treatment of tic-related OCD vs non-tic-related OCD, these data also argue strongly for the incorporation of tic-relatedness as a variable in biological and behavioral studies of patients with OCD.

Topics: Adolescent; Adult; Age of Onset; Arginine Vasopressin; Biogenic Amines; Comorbidity; Dynorphins; Family; Female; Humans; Hydroxyindoleacetic Acid; Male; Mental Disorders; Middle Aged; Obsessive-Compulsive Disorder; Oxytocin; Psychiatric Status Rating Scales; Severity of Illness Index; Tourette Syndrome; Tryptophan