Caroline A. Browne

Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants.

Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamines effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse potential of ketamine.

High Fat Diet Produces Brain Insulin Resistance, Synaptodendritic Abnormalities and Altered Behavior in Mice

Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17days or a moderate high fat diet (HFD, 45% kcal by fat) for 8weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS(616)), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.

Differential stress-induced alterations in tryptophan hydroxylase activity and serotonin turnover in two inbred mouse strains

Chronic stress and alterations in the serotonergic system are key predisposing factors to the development of major depression. Tryptophan hydroxylase (TPH) is the key enzyme in the biosynthesis of serotonin (5-HT). The effects of chronic stress on TPH activity remain uncertain. The BALB/c strain is stress-sensitive, highly anxious and possess a single nucleotide polymorphism in their tryptophan hydroxylase (TPH) 2 gene (tph2), resulting in reduced levels of central serotonin compared to C57BL/6J mice, which harbour the wild-type allele. We examined the effects of repeated restraint stress on the serotonergic system and TPH activity in these two inbred strains. TPH activity was assessed by accumulation of 5-hydroxytryptophan, a rapidly decarboxylated intermediate metabolite of tryptophan and precursor of 5-HT, using an enzyme inhibition strategy. Furthermore, the concentrations of 5-HT and its major metabolite 5-hydroxy indole acetic acid were assessed. Interestingly, 5-HT turnover was significantly increased in the majority of the brain regions assessed following acute stress in C57BL/6J. In contrast, BALB/c mice exhibit significant increases in 5-HT turnover in the striatum and hippocampus only following repeated stress. On the other hand, TPH activity was significantly decreased in the brainstem and cortical regions of C57BL/6J mice following both acute and chronic stress. Conversely, no significant stress-induced change in BALB/c TPH activity was observed. Together these data highlight the differential serotonergic response of BALB/c and C57BL/6J mice to acute and chronic restraint stress and may offer insight into the observed differences in their stress-related phenotypes.

Antidepressant-Like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors.

Previous studies have identified potential antidepressant effects of buprenorphine (BPN), a drug with high affinity for mu opioid receptor (MORs) and kappa opioid receptors (KORs) and some affinity at delta opioid receptor (DOR) and opioid receptor-like 1 (ORL-1) receptors. Therefore, these studies examined which opioid receptors were involved in BPN’s effects on animal behavior tests sensitive to antidepressant drugs. The acute effects of BPN were tested in the forced swim test (FST) using mice with genetic deletion of individual opioid receptors or after pharmacological blockade of receptors. For evaluating the effects of BPN on chronic stress, separate groups of mice were exposed to unpredictable chronic mild stress (UCMS) for 3 weeks and treated with BPN for at least 7 days before behavioral assessment and subsequent measurement of Oprk1, Oprm1, and Pdyn mRNA expression in multiple brain regions. BPN did not reduce immobility in mice with KOR deletion or after pretreatment with norbinaltorphimine, even though desipramine remained effective. In contrast, BPN reduced immobility in MOR and DOR knockout mice and in mice pretreated with the ORL-1 antagonist JTC-801. UCMS reduced sucrose preference, decreased time in the light side of the light/dark box, increased immobility in the FST and induced region-specific alterations in Oprk1, Oprm1, and PDYN mRNA expression in the frontal cortex and striatum. All of these changes were normalized following BPN treatment. The KOR was identified as a key player mediating the effects of BPN in tests sensitive to antidepressant drugs in mice. These studies support further development of BPN as a novel antidepressant.

Differential lipopolysaccharide-induced immune alterations in the hippocampus of two mouse strains: effects of stress.

Immunological activation may result in the development of depressive-like symptoms in a large percentage of patients treated with cytokine-based therapies. The mechanisms underlying susceptibility to cytokine-induced depression are currently unknown; however activation of the tryptophan catabolising enzyme indoleamine 2,3-dioxygenase (IDO) is associated with the induction of cytokine-induced depression. Peripheral administration of lipopolysaccharide (LPS) is one of the most commonly used immunological challenges in animal models of cytokine-induced depression. Inbred mouse strains are useful tools in the investigation of the neurobiology of psychiatric illnesses. In this study we hypothesised that two strains which differ in stress susceptibility, namely the BALB/c and C57BL/6J mice, would respond differentially to LPS and swim-stress in cytokine profile, corticosterone concentrations and mRNA expression of genes coding for the tryptophan metabolising enzymes, IDO1, IDO2, Tph1 and Tph2. The stress-sensitive BALB/c strain exhibited increased depressive-like behaviour and enhanced corticosterone concentrations in response to LPS. Furthermore, swim-stress attenuated the LPS-induced corticosterone response in BALB/c mice only. LPS significantly increased plasma interleukin (IL)-1β and tumour necrosis factor α (TNFα) concentrations to a greater extent in BALB/c mice. The LPS-induced increase in IL-1β mRNA expression was significantly attenuated by swim-stress in the hippocampus of C57BL/6J but not in BALB/c mice. TNFα mRNA expression was significantly increased in BALB/c mice only; this increase was attenuated by swim-stress. Tph1 mRNA expression was upregulated in the brainstem of C57BL/6J mice post-LPS and following the combination of swim-stress and LPS in BALB/c mice. In the hippocampus Tph1 and Tph2 mRNA expression was increased in C57BL/6J but not BALB/c mice in response to LPS challenge and swim-stress. Conversely, IDO2 but not IDO1 mRNA expression was significantly altered following swim-stress and LPS, particularly in the hippocampus of BALB/c mice. These data indicate altered central mRNA expression of tryptophan metabolising enzymes and immune activation in BALB/c mice compared to the normo-sensitive C57BL/6J strain.

Antidepressant-like Effects of Buprenorphine in Rats Are Strain Dependent

The prevalence of major depressive disorder and the limited efficacy of conventional drug treatments provide significant impetus to develop novel and more rapidly acting antidepressants for individuals with treatment resistant forms of depression. The primary goal of these studies was to ascertain whether buprenorphine (BPN), a medically available drug with mixed effects at opioid receptors, was effective in behavioral tests using the Wistar Kyoto (WKY) rat strain, a rodent model of exaggerated depressive and anxiety behaviors that demonstrates resistance to certain antidepressants. As WKY rats are maintained by different sources, we assessed the behavioral effects of BPN using the modified rat forced swim test (FST) and the emergence test in WKY rat colonies obtained from different vendors. BPN dose-dependently reduced immobility and increased swimming behavior in the FST and reduced emergence latencies in two WKY lines (Charles River (WKY/NCrl) and Harlan laboratories (WKY/NHsd)) that also showed high baseline immobility in the FST. WKY rats from Taconic (WKY/NTac) did not show high baseline immobility in the FST or anxiety as had been previously reported, suggesting a drift in the phenotype of rats from this supplier. Furthermore, BPN did not reduce immobility in the FST or reduce latencies in the emergence test in WKY rats from Taconic. BPN also failed to produce antidepressant-like effects in Wistar and Sprague-Dawley rats. These results indicate a striking strain-selectivity for the effects of BPN, producing antidepressant and anxiolytic-like responses in WKY/NCrl and WKY/NHsd lines but not in the normosensitive control Wistar and Sprague-Dawley strains.

An effective dietary method for chronic tryptophan depletion in two mouse strains illuminates a role for 5-HT in nesting behaviour

Physiological depletion of tryptophan, the precursor to serotonin has been shown to alter mood and cognition in both humans and rodents. Few studies have investigated the neurochemical and behavioural effects associated with tryptophan depletion in mice. Given that BALB/c and C57BL/6J mice differ in tryptophan hydroxylase (TPH) functionality, serotonin levels and behavioural phenotype, we hypothesised that a differential strain response to chronic dietary tryptophan manipulations would be observed. Therefore, the effects of four chronic dietary tryptophan manipulations were investigated, the diets include a depleted diet (0% tryptophan, TRP(-)), a deficient diet (0.25% tryptophan, TRP(-/+)), an enhanced diet (1.25% tryptophan, TRP(+)) and a control diet (0.7%). Diet-induced alterations in peripheral and central tryptophan levels and brain serotonin turnover were determined by high performance liquid chromatography. In addition, dietary-induced alterations in behaviour were assessed in several commonly used tasks. Peripheral and central tryptophan levels and consequently central serotonergic turnover were significantly decreased by the TRP(-) diet in both strains, however, no effect of tryptophan supplementation was observed on tryptophan or serotonin levels. Dietary tryptophan manipulation induced pronounced behavioural effects, particularly in nesting behaviour where a reduction in nesting was observed following depletion and an increase in nesting behaviour was observed with enhanced tryptophan in both strains. Additionally, depletion produces an anxiolytic-like effect and did not impede locomotion. This study demonstrates significant alterations in the levels of tryptophan, serotonin turnover and behaviour following chronic dietary tryptophan depletion.

A role for the mu opioid receptor in the antidepressant effects of buprenorphine

&NA; Buprenorphine (BPN), a mixed opioid drug with high affinity for mu (MOR) and kappa (KOR) opioid receptors, has been shown to produce behavioral responses in rodents that are similar to those of antidepressant and anxiolytic drugs. Although recent studies have identified KORs as a primary mediator of BPNs effects in rodent models of depressive‐like behavior, the role of MORs in BPNs behavioral effects has not been as well explored. The current studies investigated the role of MORs in mediating conditioned approach behavior in the novelty‐induced hypophagia (NIH) test, a behavioral measure previously shown to be sensitive to chronic treatment with antidepressant drugs. The effects of BPN were evaluated in the NIH test 24 h post‐administration in mice with genetic deletion of the MOR (Oprm1−/−) or KOR (Oprk1−/−), or after pharmacological blockade with the non‐selective opioid receptor antagonist naltrexone and selective MOR antagonist cyprodime. We found that behavioral responses to BPN in the NIH test were blocked in Oprm1−/− mice, but not in Oprk1−/− mice. Both cyprodime and naltrexone significantly reduced approach latency at doses experimentally proven to antagonize the MOR. In contrast the selective MOR agonist morphine and the selective KOR antagonist nor‐BNI were both ineffective. Moreover, antinociceptive studies revealed persistence of the MOR antagonist properties of BPN at 24 h post‐administration, the period of behavioral reactivity. These data support modulation of MOR activity as a key component of BPNs antidepressant‐like effects in the NIH paradigm. HIGHLIGHTSOprm1−/− mice, but not Oprk1−/− mice, showed slower learning to approach palatable food.Oprm1−/− mice, but not Oprk1−/− mice, failed to respond to buprenorphine in the novelty‐induced hypophagia test.Buprenorphine and cyprodime antagonized mu opioid receptors.Buprenorphine and cyprodime reduced approach latency in the novelty induced hypophagia test.

Reversal of Stress-Induced Social Interaction Deficits by Buprenorphine

Abstract Background Patients with post-traumatic stress disorder frequently report persistent problems with social interactions, emerging after a traumatic experience. Chronic social defeat stress is a widely used rodent model of stress that produces robust and sustained social avoidance behavior. The avoidance of other rodents can be reversed by 28 days of treatment with selective serotonin reuptake inhibitors, the only pharmaceutical class approved by the U.S. Food and Drug Administration for treating post-traumatic stress disorder. In this study, the sensitivity of social interaction deficits evoked by 10 days of chronic social defeat stress to prospective treatments for post-traumatic stress disorder was examined. Methods The effects of acute and repeated treatment with a low dose of buprenorphine (0.25 mg/kg/d) on social interaction deficits in male C57BL/6 mice by chronic social defeat stress were studied. Another cohort of mice was used to determine the effects of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg/d), the NMDA antagonist ketamine (10 mg/kg/d), and the selective kappa opioid receptor antagonist CERC-501 (1 mg/kg/d). Changes in mRNA expression of Oprm1 and Oprk1 were assessed in a separate cohort. Results Buprenorphine significantly reversed social interaction deficits produced by chronic social defeat stress following 7 days of administration, but not after acute injection. Treatment with fluoxetine for 7 days, but not 24 hours, also reinstated social interaction behavior in mice that were susceptible to chronic social defeat. In contrast, CERC-501 and ketamine failed to reverse social avoidance. Gene expression analysis found: (1) Oprm1 mRNA expression was reduced in the hippocampus and increased in the frontal cortex of susceptible mice and (2) Oprk1 mRNA expression was reduced in the amygdala and increased in the frontal cortex of susceptible mice compared to non-stressed controls and stress-resilient mice. Conclusions Short-term treatment with buprenorphine and fluoxetine normalized social interaction after chronic social defeat stress. In concert with the changes in opioid receptor expression produced by chronic social defeat stress, we speculate that buprenorphine’s efficacy in this model of post-traumatic stress disorder may be associated with the ability of this compound to engage multiple opioid receptors.

Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism

&NA; Pharmacogenetic studies have identified the non‐synonymous single nucleotide polymorphism (A118G) in the human mu opioid receptor (MOR) gene (OPRM1) as a critical genetic variant capable of altering the efficacy of opioid therapeutics. To date few studies have explored the potential impact of the OPRM1 A118G polymorphism on the pharmacological effects of buprenorphine (BPN), a potent MOR partial agonist and kappa opioid receptor antagonist, which is approved by the FDA for the treatment of opioid addiction and chronic pain. The goal of these studies was to determine whether the MOR‐mediated behavioral effects of BPN were altered in the Oprm1 A112G mouse model of the human OPRM1 A118G SNP. All studies were conducted in female, AA, AG and GG mice. BPNs maximal analgesic effect in the hot plate test was significantly blunted in AG and GG mice compared to wild type AA mice. Similarly, the BPN‐induced reduction of latency to consume food in the novelty induced hypophagia test was blocked entirely in AG and GG mice compared to their AA littermates. In addition, GG mice exhibited marked reductions in psychostimulant hyperlocomotor activity compared to the AA group. In contrast, reduced immobility in the forced swim test, an effect of BPN mediated by kappa opioid receptors, was not affected by genotype. These studies demonstrate the ability of the Oprm1 A112G SNP to attenuate the analgesic, anxiolytic and hyperlocomotor effects of BPN. Overall, these data suggest that the OPRM1 A118G SNP will significantly impact the clinical efficacy of BPN in its therapeutic applications. HighlightsThe Oprm1 A112G SNP (G carriers) blunted buprenorphine‐mediated antinociception.The anxiolytic effects of buprenorphine but not chlorodiazepoxide were blocked in AG and GG mice.The motoric effects of BPN were diminished in mice with the GG genotype.BPNs behavioral effects in the FST were unaffected by Oprm1 A112G polymorphism.