Opioid antagonism mitigates antipsychotic-associated weight gain: focus on olanzapine.

BACKGROUND: The endogenous opioid system affects metabolism, including weight regulation. Evidence from preclinical and clinical studies provides a rationale for targeting this system to mitigate weight-related side effects of antipsychotics. This review describes the role of the opioid system in regulating weight and metabolism, examines the effects of opioid receptor antagonism on those functions, and explores the use of opioid antagonists to mitigate antipsychotic-associated weight gain and/or metabolic effects. METHODS: A PubMed literature search was conducted to identify representative opioid antagonists and associated preclinical and clinical studies examining their potential for the regulation of weight and metabolism. RESULTS: The mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) types have overlapping but distinct patterns of central and peripheral expression, and each contributes to the regulation of body weight and metabolism. Three representative opioid antagonists (eg, naltrexone, samidorphan, and LY255582) were identified for illustration. These opioid antagonists differed in their receptor binding and pharmacokinetic profiles, including oral bioavailability, systemic clearance, and half-life, and were associated with varying effects on food intake, energy utilization, and metabolic dysregulation. CONCLUSIONS: Preclinical and clinical data suggest that antagonism of the endogenous opioid system is a mechanism to address antipsychotic-associated weight gain and metabolic dysregulation. However, evidence suggests that the differing roles of MOR, DOR, and KOR in metabolism, together with the differences in receptor binding, pharmacokinetic, and functional activity profiles of the opioid receptor antagonists discussed in this review, likely contribute to their differential pharmacodynamic effects and clinical outcomes observed regarding antipsychotic-associated weight gain.

In vivo Characterization of the Opioid Receptor-Binding Profiles of Samidorphan and Naltrexone in Rats: Comparisons at Clinically Relevant Concentrations.

Introduction: The atypical antipsychotic olanzapine is approved for the treatment of schizophrenia and bipolar I disorder; however, weight gain and metabolic dysregulation associated with olanzapine therapy have limited its clinical utility. In clinical studies, treatment with the combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain while providing antipsychotic efficacy similar to that of olanzapine. Although samidorphan is structurally similar to the opioid receptor antagonist naltrexone, the two differ in their pharmacokinetics and in vitro binding affinities to mu, delta, and kappa opioid receptors (MOR, DOR, and KOR, respectively). The objective of this series of nonclinical studies was to compare the in vivo binding profiles of samidorphan and naltrexone and their receptor occupancies at MOR, DOR, and KOR in rat brains. Methods: Male rats were injected with samidorphan or naltrexone to obtain total and unbound plasma and brain concentrations representing levels observed in humans at clinically relevant oral doses. Subsequently, samidorphan and naltrexone brain receptor occupancy at MOR, DOR, and KOR was measured using ultra-performance liquid chromatography and high-resolution accurate-mass mass spectrometry. Results: A dose-dependent increase in samidorphan occupancy was observed at MOR, DOR, and KOR (EC50: 5.1, 54.7, and 42.9 nM, respectively). Occupancy of naltrexone at MOR (EC50: 15.5 nM) and KOR was dose dependent; minimal DOR occupancy was detected. At the clinically relevant unbound brain concentration of 23.1 nM, samidorphan bound to MOR, DOR, and KOR with 93.2%, 36.1%, and 41.9% occupancy, respectively. At 33.5 nM, naltrexone bound to MOR and KOR with 79.4% and 9.4% occupancy, respectively, with no binding at DOR. Discussion: At clinically relevant concentrations, samidorphan occupied MOR, DOR, and KOR, whereas naltrexone occupied only MOR and KOR. The binding profile of samidorphan differs from that of naltrexone, with potential clinical implications.

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis.

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

Distribution of corticotropin-releasing factor (CRF) receptor binding in the mouse brain using a new, high-affinity radioligand, [125 I]-PD-Sauvagine.

The corticotropin-releasing factor (CRF) family of peptides includes CRF and three urocortins, which signal through two distinct G-protein coupled receptors, CRF1 and CRF2 . Although the cellular distribution of CRF receptor expression has been well characterized at the mRNA level, the localization of receptor protein, and, by inference, of functional receptors, has been limited by a lack of reliable immunohistochemical evidence. Recently, a CRF-related peptide, termed PD-sauvagine, was isolated from the skin of the frog, Pachymedusa dacnicolor, and validated as a high-affinity ligand for CRF receptor studies. A radiolabeled analog, [125 I]-PD-sauvagine, with high signal-to-noise ratio, was used in autoradiographic studies to map the distribution of CRF receptor binding sites in the mouse brain. Through the use of receptor-deficient mice and subtype-specific antagonists, CRF1 and CRF2 binding sites were isolated, and found to be readily reconcilable with regional patterns of mRNA expression. Binding site distributions within a given structure sometimes differed from mRNA patterns, however, particularly in laminated structures of the isocortex, hippocampus, and cerebellum, presumably reflecting the trafficking of receptors to their operational homes on neuronal (mostly dendritic) processes. Binding patterns of [125 I]-PD-sauvagine provided independent assessments of controversial receptor localizations, failing to provide support for CRF1 expression in central autonomic components of the limbic forebrain, the locus coeruleus and cerebellar Purkinje cells, or for CRF2 in any aspect of the cerebellar cortex. Though lacking in ideal resolution, in vitro binding of the PD-sauvagine radioligand currently provides the most sensitive and accurate available tool for localizing CRF receptors in rodent brain.

Characterization of a Pachymedusa dacnicolor-Sauvagine analog as a new high-affinity radioligand for corticotropin-releasing factor receptor studies.

The corticotropin-releasing factor (CRF) peptide family comprises the mammalian peptides CRF and the urocortins as well as frog skin sauvagine and fish urophyseal urotensin. Advances in understanding the roles of the CRF ligand family and associated receptors have often relied on radioreceptor assays using labeled CRF ligands. These assays depend on stable, high-affinity CRF analogs that can be labeled, purified, and chemically characterized. Analogs of several of the native peptides have been used in this context, most prominently including sauvagine from the frog Phyllomedusa sauvageii (PS-Svg). Because each of these affords both advantages and disadvantages, new analogs with superior properties would be welcome. We find that a sauvagine-like peptide recently isolated from a different frog species, Pachymedusa dacnicolor (PD-Svg), is a high-affinity agonist whose radioiodinated analog, [(125)ITyr(0)-Glu(1), Nle(17)]-PD-Svg, exhibits improved biochemical properties over those of earlier iodinated agonists. Specifically, the PD-Svg radioligand binds both CRF receptors with comparably high affinity as its PS-Svg counterpart, but detects a greater number of sites on both type 1 and type 2 receptors. PD-Svg is also ∼10 times more potent at stimulating cAMP accumulation in cells expressing the native receptors. Autoradiographic localization using the PD-Svg radioligand shows robust specific binding to rodent brain and peripheral tissues that identifies consensus CRF receptor-expressing sites in a greater number and/or with greater sensitivity than its PS-Svg counterpart. We suggest that labeled analogs of PD-Svg may be useful tools for biochemical, structural, pharmacological, and anatomic studies of CRF receptors.

VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation.

Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal.

Modulation of neuroplastic changes and corticotropin-releasing factor-associated behavior by a phylogenetically ancient and conserved peptide family.

The co-evolution of peptides and early cells some 3.7 billion years ago provided bioactive peptides with a long history for the proliferation and refinement of peptide hormones. Central to the adaptation and evolution of cell types in metazoans is the development of peptide signaling systems that regulate stress mechanisms. The corticotropin-releasing factor (CRF) family of peptides represents the canonical family of peptides that are pivotal to the regulation of stress in vertebrates. However, these peptides appear to have evolved at least 2 billion years after the formation of the first postulated bioactive peptides, suggesting that before this, other peptide systems played a role in stress and energy metabolism. The teneurin C-terminal associated peptides (TCAPs) are a recently discovered family of highly conserved peptides that are processed from the teneurin transmembrane proteins. This peptide/protein system is ubiquitous in multicellular organisms and evolved before the CRF family. TCAP-1 is a potent regulator of CRF-associated physiology and behavior and may play a significant role in the regulation of cell-to-cell communication and neuroplasticity in neurons.

Teneurin C-terminal associated peptide (TCAP)-1 modulates dendritic morphology in hippocampal neurons and decreases anxiety-like behaviors in rats.

Teneurin C-terminal associated peptide (TCAP)-1 is a member of a novel family of neuropeptides that has been highly conserved throughout evolution. TCAP-1 is expressed in the limbic system in areas such as the hippocampus and amygdala. In vitro, TCAP-1 increases cytoskeletal proteins in immortalized neurons and modulates neurite outgrowth in cultured primary hippocampal neurons. In vivo, TCAP-1 blocks stress-induced c-Fos in the hippocampus and amygdala, and modulates stress-induced anxiety-like behaviors. This suggests that TCAP-1 plays a role in the remodeling of limbic system networks to alter stress behaviors. Dendritic spines on the apical and basilar shafts of hippocampal neurons are sensitive to stress and many receive incoming excitatory synaptic connections. In this study, repeated daily injection of TCAP-1 for 10 days increased spine density in the CA1 and CA3 regions of the hippocampus without affecting spine density in the amygdala. Further investigation of the CA3 region indicated that TCAP-1 did not affect the morphology of apical dendrites, but decreased branching in the basilar dendrites 90-130 µm away from the soma. Moreover, TCAP-1 treatment increased open arm time and decreased closed arm entries on the elevated plus maze, a test of anxiety-like behavior. These results suggest that TCAP-1 may be associated with anxiety-like behavior via regulation of dendritic morphology in the hippocampus, independent of amygdalar modification.

Behavioral effects of neuropeptides in rodent models of depression and anxiety.

In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment.

Teneurin C-terminal associated peptide (TCAP)-1 attenuates corticotropin-releasing factor (CRF)-induced c-Fos expression in the limbic system and modulates anxiety behavior in male Wistar rats.

The teneurin C-terminal associated peptides (TCAPs) are a novel family of four endogenous peptides that have previously shown bioactive properties both in vitro and in vivo. Previously we have shown that repeated intracerebral injections of synthetic TCAP-1 modulate anxiety-like behaviors in three tests of anxiety, although the neural substrates responsible for these effects were previously unknown. In the current study, we examined both c-Fos induction and behavioral responses in the elevated plus maze and open field tests after a single intracerebroventricular dose of TCAP-1 followed by an intracerebroventricular injection of CRF in male Wistar rats. The results indicate that TCAP-1 injection attenuated the CRF-induced increase in c-Fos expression in the limbic system and many of the areas associated with the behavioral responses to stress, including the hippocampus, central and basolateral nuclei of the amygdala, medial prefrontal cortex, and dorsal raphe nucleus. Other areas, such as the paraventricular nucleus of the hypothalamus, bed nucleus of the stria terminalis, medial nucleus of the amygdala, and locus coeruleus, displayed CRF-induced c-Fos levels that were unaffected by TCAP-1. Furthermore, TCAP-1 administration increased stretched-attend postures, a type of risk-assessment behavior, on the elevated plus maze. These results indicate that TCAP-1 may play a potential role in the regulation of stress by blocking CRF-mediated activity in specific stress-sensitive areas of the brain.

Repeated intracerebral teneurin C-terminal associated peptide (TCAP)-1 injections produce enduring changes in behavioral responses to corticotropin-releasing factor (CRF) in rat models of anxiety.

The teneurin C-terminal associated peptides (TCAP) are a recently discovered family of peptides encoded by a bioactive neuropeptide-like gene sequence found at the carboxy terminus of the teneurin transmembrane proteins. TCAP is structurally related to the corticotropin-releasing factor (CRF) family of peptides. Synthetic TCAP-3 and TCAP-1 are active in vitro in stimulating cAMP and proliferation in neuronal lines. TCAP-1 mRNA is expressed in limbic brain regions and modulates acoustic startle behavior in rats when injected into the basolateral amygdala. In the current study, TCAP-1 was administered into the cerebral ventricles once per day for 5 days to rats. At 1-3 weeks after the last TCAP-1 treatment, the rats were tested in the elevated plus maze, open field test, or the acoustic startle test, with or without an acute CRF injection 30 min prior to the test. The results show a difference in behavioral response between TCAP-treated and saline-treated rats, but only when an acute CRF challenge is delivered prior to testing. In the plus maze and open field tests, acute CRF effects were enhanced by prior TCAP-1 treatment, whereas in the acoustic startle test, the acute CRF effects were diminished by prior TCAP-1 administration.