Opioid modulation of depression: A focus on imaging studies.

Depression is the leading cause of disability worldwide, with over 300 million people affected. Almost all currently available antidepressant treatments target monoamine neurotransmitter systems and have a delayed onset of action up to several weeks that can be associated with low rates of treatment response. The endogenous opioid system has been identified as a potential target for the development of novel antidepressants due to its high opioid receptor concentrations in central limbic areas that are also implicated in physiological processes including regulation of mood and emotion. Genetic depletion, pharmacological manipulation, and preclinical models have been widely used to characterize the role of opioid transmission in depressive states. Neuroimaging studies have been carried out in clinical populations to investigate opioid transmission in mood and emotion in an attempt to identify those regional anatomical and functional brain changes that are associated with depression. Great insight has been provided into the cerebral structural and functional changes associated with depression but there remains a need to tie the functional theories of depression to anatomical localization and further neuroimaging studies are best placed to do this.

Potential roles for opioid receptors in motivation and major depressive disorder.

Deficits in motivation are at the core of many neuropsychiatric disorders, including major depressive disorder (MDD). Research in MDD has been heavily focused on anhedonia and depression or negative/positive symptoms of depression, with less research attention focused on the dysregulation of motivational processes. Opioid receptors are widely distributed throughout the brain, particularly in areas implicated in motivation, especially the striatum, nucleus accumbens, medial prefrontal cortex, hippocampus, ventral tegmental area, hypothalamus, and amygdala. Mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) and their endogenous ligands play an essential role in the regulation of mood, reward processing, and motivated behavior. This review will highlight the impact of opioids in motivational behavior with a particular focus on depression. An understanding of the neurobiology and neural circuits subserving motivational behavior will facilitate treatment of disorders that comprise reward deficits.

Deficits in temporal order memory induced by interferon-alpha (IFN-α) treatment are rescued by aerobic exercise.

Patients receiving cytokine immunotherapy with IFN-α frequently present with neuropsychiatric consequences and cognitive impairments, including a profound depressive-like symptomatology. While the neurobiological substrates of the dysfunction that leads to adverse events in IFN-α-treated patients remains ill-defined, dysfunctions of the hippocampus and prefrontal cortex (PFC) are strong possibilities. To date, hippocampal deficits have been well-characterised; there does however remain a lack of insight into the nature of prefrontal participation. Here, we used a PFC-supported temporal order memory paradigm to examine if IFN-α treatment induced deficits in performance; additionally, we used an object recognition task to assess the integrity of the perirhinal cortex (PRH). Finally, the utility of exercise as an ameliorative strategy to recover temporal order deficits in rats was also explored. We found that IFN-α-treatment impaired temporal order memory discriminations, whereas recognition memory remained intact, reflecting a possible dissociation between recognition and temporal order memory processing. Further characterisation of temporal order memory impairments using a longitudinal design revealed that deficits persisted for 10 weeks following cessation of IFN-α-treatment. Finally, a 6 week forced exercise regime reversed IFN-α-induced deficits in temporal order memory. These data provide further insight into the circuitry involved in cognitive impairments arising from IFN-α-treatment. Here we suggest that PFC (or the hippocampo-prefrontal pathway) may be compromised whilst the function of the PRH is preserved. Deficits may persist after cessation of IFN-α-treatment which suggests that extended patient monitoring is required. Aerobic exercise may be restorative and could prove beneficial for patients treated with IFN-α.

Antidepressant-like effects of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid receptor modulator, in a rat IFN-α-induced depression model.

Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, which may be reflective of mechanisms underlying inflammation associated depression. We also investigate the potential of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid modulator (antagonist at mu and partial agonist at kappa and delta opioid receptors in vitro), to reverse IFN-α induced changes. In vitro radioligand receptor binding assays and the [35S] GTPγS were performed to determine the affinity of 3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-α treatment increased circulating and central markers of inflammation and hypothalamic-pituitaryadrenal (HPA) axis activity (IL-6, IL-1ß and corticosterone) while increasing immobility in the FST, impairing of object displacement learning in the object exploration task (OET), and decreasing neuronal proliferation and brain-derived neurotrophic factor (BDNF) in the hippocampus. Treatment with 3CS-nalmefene (0.3mg/kg/sc twice per day, 3 times per week for 4weeks) prevented IFN-α-induced immobility in the FST and impaired object displacement learning. In addition, 3CS-nalmefene prevented IFN-α-induced increases in inflammation and hyperactivity of the HPA-axis, the IFN-α-induced reduction in both neuronal proliferation and BDNF expression in the hippocampus. Overall, these preclinical data would support the hypothesis that opioid receptor modulation is a relevant target for treatment of depression.

Exercise prevents IFN-α-induced mood and cognitive dysfunction and increases BDNF expression in the rat.

Aerobic exercise has marked effects on mood and cognition. Here, we used an interferon-alpha (IFN-α) induced depression model to evaluate the potential efficacy of chronic treadmill running on mood and cognition in the rat. IFN-α treatment induces behavioral deficits in the forced swim test (FST), open field test and object exploration task. Male han Wistar rats (n=8 per group, 3month old) were injected 3 times weekly with recombinant human IFN-α or saline (control) for 4weeks. One group was exercised 3 times (1h treadmill running) per week while the other remained sedentary. Animals were tested for anxiety- and depressive-like behavior in the open field test and FST. Spatial and recognition memory were examined by the object exploration task. Hippocampal and prefrontal cortex brain samples were harvested for analysis of brain-derived neurotrophic factor (BDNF). Treadmill running prevented IFN-α-induced decreased central arena exploration in the open field test and decreased immobility in the FST. IFN-α treated rats had impaired spatial memory in the object exploration task compared to saline controls, which was prevented by treadmill running. Further, treadmill running improved recognition memory in both saline and IFN-α treated rats. Treadmill running protected against IFN-α induced decreases in expression of BDNF in the hippocampus and prefrontal cortex. Aerobic exercise protects against IFN-α induced affective and cognitive dysfunction, which is associated with increased BDNF. Results could have implications for future treatments of depression.

Early hippocampal volume loss as a marker of eventual memory deficits caused by repeated stress.

Exposure to severe and prolonged stress has detrimental effects on the hippocampus. However, relatively little is known about the gradual changes in hippocampal structure, and its behavioral consequences, over the course of repeated stress. Behavioral analyses during 10 days of chronic stress pointed to a delayed decline in spatial memory, the full impact of which is evident only after the end of stress. In contrast, concurrent volumetric measurements in the same animals revealed significant reduction in hippocampal volumes in stressed animals relative to their unstressed counterparts, as early as the third day of stress. Notably, animals that were behaviorally the worst affected at the end of chronic stress suffered the most pronounced early loss in hippocampal volume. Together, these findings support the view that not only is smaller hippocampal volume linked to stress-induced memory deficits, but it may also act as an early risk factor for the eventual development of cognitive impairments seen in stress-related psychiatric disorders.

Long-term cognitive dysfunction in the rat following docetaxel treatment is ameliorated by the phosphodiesterase-4 inhibitor, rolipram.

Clinical studies report evidence of long-term cognitive and other deficits following adjunctive chemotherapy treatment, which is often termed "chemobrain" or "chemo-fog". The neurological bases of these impairments are poorly understood. Here, we hypothesize that systemic chemotherapy treatment causes long-term neurobehavioral deficits, and that these deficits are reversed by manipulation of cAMP by the PDE4 inhibitor, rolipram. Male han Wistar rats were treated with docetaxel (an adjunctive chemotherapeutic agent (1mg/kg i.v.)) or control solution (ethanol/Tween 20/0.9% Saline - 5/5/90) once per week for 4 weeks. They were allowed to recover for 4 weeks, administration of rolipram (0.5mg/kg po) or vehicle (maple syrup) then began and continued daily for 4 weeks. At the end of the treatment regime animals were tested for spatial and recognition memory deficits with the object exploration task and for depressive- and anxiety-like behavior in the forced swim test (FST) and open field exploration. We report docetaxel treatment impaired spatial memory but not object recognition memory, compared to control rats. Docetaxel-treated rats also spent significantly more time immobile than controls in the FST. Chronic rolipram treatment attenuated all of these docetaxel-associated changes, recovering spatial memory and reducing immobility. In conclusion, docetaxel-treated rats exhibit alterations in spatial memory and depressive-like behavior, which are reversed following chronic rolipram administration. These results detect long-term cognitive and mood changes following docetaxel treatment and identify PDE4 inhibition as a target treatment of neuropsychological changes associated with "chemobrain".

Neurotrophins play differential roles in short and long-term recognition memory.

The neurotrophin family of proteins are believed to mediate various forms of synaptic plasticity in the adult brain. Here we have assessed the roles of these proteins in object recognition memory in the rat, using icv infusions of function-blocking antibodies or the tyrosine kinase antagonist, tyrphostin AG879, to block Trk receptors. We report that tyrphostin AG879 impairs both short-term and long-term recognition memory, indicating a requirement for Trk receptor activation in both processes. The effect of inhibition of each of the neurotrophins with activity-blocking neutralising antibodies was also tested. Treatment with anti-BDNF, anti-NGF or anti-NT4 had no effect on short-term memory, but blocked long-term recognition memory. Treatment with anti-NT3 had no effect on either process. We also assessed changes in expression of neurotrophins and their respective receptors in the hippocampus, dentate gyrus and perirhinal cortex over a 24 h period following training in the object recognition task. We observed time-dependent changes in expression of the Trk receptors and their ligands in the dentate gyrus and perirhinal cortex. The data are consistent with a pivotal role for neurotrophic factors in the expression of recognition memory.

Age-related declines in delayed non-match-to-sample performance (DNMS) are reversed by the novel 5HT6 receptor antagonist SB742457.

Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system in particular plays an important role in attention, alertness and cognition. Disturbances in serotonergic function have been implicated in differing neurological and neuropsychiatric disorders including depression, psychosis aggression and dementia. The serotonin receptor subtype 5HT6 is distributed within CNS regions relevant to learning and memory, including the striatum, cortex and hippocampus. We examined here the effects of acute and chronic administration of the 5HT6 receptor antagonist SB742457 on performance in a delayed non-matching-to-sample task (DNMS), which was used to identify neurocognitive differences between middle-aged (MA, 13 months) and young adult (YG, 3 months) rats. We found that MA rats have significantly lower performance in the DNMS task compared to YG rats. Acute administration of SB742457 (3 mg/kg/po) significantly improved performance of the MA rats. Chronic administration of SB742457 (3 mg/kg) reversed the age-related deficit of the MA to match their performance to that of YG rats. Furthermore, these improvements were observed for 1 week post-SB742457 treatment cessation. The acute and chronic effects of this treatment suggest that there is both an immediate effect on neurotransmitter action and potentially a longer-term modification of synaptic plasticity. Together these data indicate a role for modulation of the serotonergic system in the development of cognition-enhancing agents.

Differential BDNF signaling in dentate gyrus and perirhinal cortex during consolidation of recognition memory in the rat.

Consolidation of long-term memory is dependent on synthesis of new proteins in the hippocampus and associated cortical regions. The neurotrophin brain-derived neurotrophic factor (BDNF) is tightly regulated by activity-dependent cellular processes and is strongly linked with mechanisms underlying learning and memory. BDNF activation of tyrosine receptor kinase (TrkB) stimulates intracellular signaling cascades implicated in plasticity, including the extracellular-signal related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositide-3-kinase (PI3K)/Akt pathway. Here, we investigate the role of BDNF, ERK/MAPK, and PI3K/AKT signaling cascade in recognition memory in the rat. We report that recognition memory was associated with increased release of BDNF in the dentate gyrus and perirhinal cortex. This was associated with significant increases in p44ERK activation and c-fos expression in the dentate gyrus and PI3K activation and c-fos expression in the perirhinal cortex. Furthermore, both recognition memory and the associated cell signaling events in dentate gyrus and perirhinal cortex were blocked by intraperitoneal injection of the Trk receptor inhibitor tyrphostin AG879. These data are consistent with the hypothesis that BDNF-stimulated intracellular signaling plays a role in consolidation of recognition memory in the rat.

Deficits in LTP and recognition memory in the genetically hypertensive rat are associated with decreased expression of neurotrophic factors and their receptors in the dentate gyrus.

We have previously reported that a genetically hypertensive strain of Wistar rat (GH), is deficient in nerve growth factor (NGF) and Trk receptors in dentate gyrus and that these deficits are accompanied by impaired expression of long-term potentiation (LTP) in perforant path-granule cell synapses. Here we confirm this deficit in LTP and report that this strain of rat also displays impairments in long-term recognition memory when compared with normotensive controls. Further analysis of neurotrophin expression in dentate gyrus confirmed the previously-reported deficit in NGF and revealed a decrease in expression of brain-derived neurotrophic factor (BDNF), but not neurotrophin 3 (NT3) or neurotrophin 4 (NT4), in GH rats. These alterations in ligand expression were accompanied by changes in Trk receptor expression; specifically, a decrease in expression of TrkA and TrkB, but not TrkC, in the dentate gyrus of GH, compared with normotensive, rats. We conclude that the impairments in LTP and learning and memory observed in the GH strain are associated with aberrant expression of specific neurotrophic factors and their receptors in the dentate gyrus, adding weight to the evidence indicating a role for these proteins in several forms of synaptic plasticity.

Blockade of NMDA receptors pre-training, but not post-training, impairs object displacement learning in the rat.

Several forms of hippocampal-dependent learning rely upon activation of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor. Here we have investigated the effects of administration of the NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) on the performance of rats in an object displacement task and the possible role of extracellular signal-regulated kinase (ERK) in this form of learning. The data show that rats injected intraperitoneally with CPP (10 mg/kg) before, but not after, training in the object displacement task displayed impairments in spatial learning when compared with saline-injected controls. The NMDAR may thus be involved in the acquisition, but not the consolidation, of this type of memory. In addition, a significant positive correlation was observed between learning and the expression of activated ERK in the dentate gyrus. No such correlation was apparent in the rest of the hippocampal formation. This study implicates the NMDARs in the acquisition phase of spatial learning and provides evidence for a role for ERK in spatial learning in the dentate gyrus of the rat.