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The positive association between alcoholism and depression is a common clinical observation. We investigated the relationship between depression and reward mechanisms using a validated animal model for depressive-like behaviour, the olfactory bulbectomy in rats. The effects of bilateral olfactory bulbectomy on reward mechanisms were studied in two different experimental paradigms - the voluntary self-administration of ethanol and the conditioned place preference to alcohol injection and compared to the effects of ethanol on locomotor activity and body core temperature. The voluntary ethanol intake was increased significantly in bulbectomised rats in a drinking experiment and also after a period of abstinence. Conditioned place preference (CPP) was induced in all animals. However, bulbectomised rats needed a higher dose of alcohol to produce CPP. The sedative effect of ethanol on locomotor activity was reduced in bulbectomised animals. Measurement of body temperature revealed a dose-dependent hypothermic effect of ethanol in both groups. These results suggest that the reward mechanisms may be altered in this animal model as a common phenomenon associated with depression. Furthermore, they support the hypothesis that the addictive and/or rewarding properties of some drugs of abuse may be modified in depression., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex., (Copyright © 2014 Elsevier B.V. All rights reserved.)

SKAP-HOM is an adapter protein which regulates the cross-talk between immunoreceptors and integrins and is involved in signal transduction. It is present in murine brain structures such as the hippocampus, frontal cortex, and cerebellum. In the present study we investigated types of hippocampus-dependent learning (fear conditioning, social memory, and the Morris Water Maze) and locomotor sensitization to amphetamine in transgenic SKAP-HOM deficient mice (-/-) in comparison with respective controls (+/+). Animals from both groups showed comparable fear conditioning, and the extinction of conditioned fear was accelerated in -/-. In terms of sociability, there were no differences between the animals, but in -/- mice social memory was impaired. There was no difference between the two groups of mice in spatial learning and memory measured in the Morris Water Maze. Wild-type and deficient animals exhibited similar sensitization to amphetamine. In reaction to amphetamine challenge, the response in +/+ was enhanced. It was hypothesized that SKAP-HOM deficiency does not affect hippocampus-dependent learning in general, but that its effects on cognitive tasks seem to be dependent on the nature of the cognitive task, i.e. spatial vs. non-spatial., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling., (© The Author(s) 2014.)

Objective: Mitragyna speciosa and its extracts are named kratom (dried leaves, extract). It contains several alkaloids and is used in traditional medicine to alleviate musculoskeletal pain, hypertension, coughing, diarrhea, and as an opiate substitute for addicts. Abuse and addiction to kratom is described, and kratom has attracted increasing interest in Western countries. Individual effects of kratom on opioidergic, adrenergic, serotonergic, and dopaminergic receptors are known, but not all of the effects have been explained. Pharmacokinetic and pharmacodynamic data are needed., Methods: The effects of kratom extract on mice behavior were investigated following oral (po), intraperitoneal (ip), and intracerebroventricular (icv) application. Receptor-binding studies were performed., Results: In μ opioid receptor knockout mice (-/-) and wild type (+/+) animals, the extract reduced locomotor activity after ip and low po doses in +/+ animals, but not after icv administration. The ip effect was counteracted by 0.3 mg/kg of apomorphine sc, suggesting dopaminergic presynaptic activity. An analgesic effect was only found in -/- mice after icv application. Norbinaltorphimine abolished the analgesic effect, but not the inhibitory effect, on locomotor activity, indicating that the analgesic effect is mediated via κ opioid receptors. Oral doses, which did not diminish locomotor activity, impaired the acquisition of shuttle box avoidance learning. There was no effect on consolidation. Binding studies showed affinity of kratom to μ, δ, and κ opioid receptors and to dopamine D1 receptors., Conclusions: The results obtained in drug-naïve mice demonstrate weak behavioral effects mediated via μ and κ opioid receptors.

We studied nociceptive behavior and the effects of analgesics in Wistar (Wist) and Sprague Dawley (SPD) rats and in CB1 receptor-deficient mice with neuropathic pain experimentally. Neuropathic pain was induced by loose ligation of the sciatic nerve (chronic constriction injury, CCI). In CCI rats from both strains, cold allodynia and a reduced thermal pain threshold were detected, whereas no effect was found in the hot plate test. Thermal pain threshold was used to study the antinociceptive effects of morphine, gabapentin, and parecoxib 5 days after surgery. Doses of gabapentin and morphine which had no effect on sham-operated animals provoked antinociceptive activity in CCI rats from both strains. An antinociceptive effect of parecoxib was only found in CCI Wist rats. No pharmacokinetic differences were detected between the two strains in parecoxib metabolism. Antinociceptive activity caused by parecoxib was attenuated by the CB1 antagonist rimonabant. To further clarify parecoxib-CB1 interaction, the effect of parecoxib was investigated in CB1-deficient mice and wild-type animals. CCI did not affect thermal pain threshold and mechanical pain threshold was decreased. Parecoxib normalized the altered mechanical pain threshold in CCI wild-type animals, whereas it had only a marginal effect in CB1 receptor deficient mice. Receptor binding experiments showed increased CB1 binding in parecoxib-treated CCI Wist rats. Levels of the CB1 receptor mRNA remained constant in both strains of rats 5 days after surgery. Differences in antinociceptive activity might be due to modification of the cannabinoid system.

Background: Vagus nerve stimulation (VNS) has been introduced as a therapeutic option for treatment-resistant depression. The neural and chemical mechanisms responsible for the effects of VNS are largely unclear., Methods: Bilateral removal of the olfactory bulbs (OBX) is a validated animal model in depression research. We studied the effects of vagus nerve stimulation (VNS) on disturbed one-way active avoidance learning and neurogenesis in the hippocampal dentate gyrus of rats., Results: After a stimulation period of 3 weeks, OBX rats acquired the learning task as controls. In addition, the OBX-related decrease of neuronal differentiated BrdU positive cells in the dentate gyrus was prevented by VNS., Conclusions: This suggests that chronic VNS and changes in hippocampal neurogenesis induced by VNS may also account for the amelioration of behavioral deficits in OBX rats. To the best of our knowledge, this is the first report on the restorative effects of VNS on behavioral function in an animal model of depression that can be compared with the effects of antidepressants., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Morphine is one of the most potent analgesic drugs. However, the utility of morphine in the management of chronic pain is limited by its rapid development of tolerance. Morphine exerts all of its pharmacological effects via the μ-opioid receptor. In many systems, tolerance is associated with phosphorylation and desensitization of G-protein-coupled receptors (GPCRs). In case of the μ-opioid receptor, phosphorylation occurs in an agonist-selective manner. High-efficacy agonists such as [d-Ala(2)-MePhe(4)-Gly-ol]enkephalin (DAMGO), fentanyl, or etonitazene stimulate the phosphorylation of both C-terminal threonine 370 (T370) and serine 375 (S375). In contrast, morphine promotes the phosphorylation of S375 but fails to stimulate T370 phosphorylation. Here, we have assessed the contribution of S375 phosphorylation to the development of antinociceptive tolerance to high- and low-efficacy μ agonists in vivo. We show that S375 phosphorylation of the μ-opioid receptor occurs in intact mouse brain in a dose-dependent manner after administration of morphine, fentanyl, or etonitazene. In knock-in mice expressing the phosphorylation-deficient S375A mutant of the μ-opioid receptor, morphine and fentanyl exhibited greater dose-dependent antinociceptive responses than in wild-type mice. However, acute and chronic tolerance to morphine was retained in S375A mutant mice. In contrast, antinociceptive tolerance after repeated subcutaneous application of etonitazene or repeated intracerebroventricular application of DAMGO was diminished. Thus, tolerance to μ agonists with different efficacies develops through distinct pathways. Whereas tolerance induced by DAMGO or etonitazene requires agonist-driven phosphorylation of S375, the development and maintenance of antinociceptive tolerance to morphine occurs independent of S375 phosphorylation.

Ethnopharmacological Relevance: In traditional medicine, Astragalus mongholicus (AM) has been used for the treatment of general weakness, chronic illness, and to increase overall vitality., Aim of the Study: The present study investigated possible effects of the saponin fraction of AM on the central nervous system. Moreover, its effects on locomotor activity, anxiety, and hippocampal morphology were studied., Material and Methods: AM extract was tested for its effects on locomotor activity using the Moti-Test, for situational anxiety in the elevated plus maze, and for anticonvulsant activity against acute pentylenetetrazole (PTZ)-induced seizures and in the PTZ kindling model., Results: It was shown that AM (50, 100, 200mg/kg) did not interfere with locomotor activity and situational anxiety as measured in the elevated plus maze. In these doses, AM significantly suppressed pentylenetetrazole (PTZ)-induced seizures (p<0.05). Its anticonvulsant efficacy was also evident against repeated PTZ seizures (p<0.05). This suggests potential therapeutic usefulness. After subchronic application, the number of cells in hippocampal CA1 was reduced, whilst the cell number in CA3 and hilus remained unaffected., Conclusions: Doses of AM extract which did not interfere with locomotor activity and situational anxiety appear to be useful in the treatment of convulsive disorders. The mechanisms underlying this effect on hippocampal morphology are not yet understood., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Considering the fact that schizophrenia is a highly complex disorder of the human brain, different models are needed to test specific causative or mechanistic hypotheses. The pathogenesis of schizophrenia is also characterized by abnormal neuronal development. It was found that schizophrenia as well as antipsychotic treatment are accompanied by alterations in neuronal proliferation. Recently we reported on increased neurogenesis and their controllability by neuroleptics in a pharmacological (ketamine) model of schizophrenia. To complete our understanding, here we studied neurogenesis and its sensitivity to the classical neuroleptic haloperidol in a developmental model of schizophrenia (maternal vitamin D deficiency). It was found that maternal vitamin D deficiency resulted in decreased neurogenesis. This effect was ameliorated by subchronic treatment with haloperidol. Thus, the results complete previous findings concerning the ability of haloperidol to ameliorate behavioral abnormalities induced by prenatal vitamin D deficiency and introduce the possibility to explain the curative effects of haloperidol, at least in part, due to re-establishment of disturbed cell proliferation., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Altered neuroplasticity contributes to the pathophysiology of schizophrenia. However, the idea that antipsychotics may act, at least in part, by normalizing neurogenesis has not been consistently supported. Our study seeks to determine whether hippocampal cell proliferation is altered in adult rats pretreated with ketamine, a validated model of schizophrenia, and whether chronic administration with neuroleptic drugs (haloperidol and risperidone) affect changes of cell genesis/survival. Ketamine per se has no effect on cell proliferation. Its withdrawal, however, significantly induced cell proliferation/survival in the hippocampus. Risperidone and haloperidol supported cell genesis/survival as well. During ketamine withdrawal, however, their application did not affect cell proliferation/survival additionally. TUNEL staining indicated a cell-protective potency of both neuroleptics with respect to a ketamine-induced cell death. As RT-PCR and Western blot revealed that the treatment effects of risperidone and haloperidol seemed to be mediated through activation of VEGF and MMP2. The mRNA expression of NGF, BDNF, and NT3 was unaffected. From the respective receptors, only TrkA was enhanced when ketamine withdrawal was combined with risperidone or haloperidol. Risperidone also induced BCL-2. Ketamine withdrawal has no effect on the expression of VEGF, MMP2, or BCL-2. It activated the expression of BDNF. This effect was normalized by risperidone or haloperidol. The findings indicate a promoting effect of risperidone and haloperidol on survival of young neurons in the hippocampus by enhancing the expression of the anti-apoptotic protein BCL-2 and by activation of VEGF/MMP2, whereby an interference with ketamine and thus a priority role of the NMDA system was not evident.

Transient prenatal vitamin D deficiency is considered a neurodevelopmental animal model in schizophrenia research. Vitamin D deficiency in female rats causes morphological, cellular and molecular changes in the brain and alters behaviour and nerve growth factors expression in their offspring. Prenatal depleted animals showed a significant impairment of latent inhibition, a feature often associated with schizophrenia and of hole board habituation. Interestingly, memory consolidation of brightness discrimination was improved. Possible functional effects of altered brain development that results from prenatal vitamin D deficiency were characterized by investigation of potentiation phenomena in the hippocampus in freely moving rats. Transient prenatal vitamin D deficiency induced an enhancement of long-term potentiation (LTP) using either weak tetanic or strong tetanic stimulation, whereas the response to test stimuli was not changed. The classic neuroleptic drug haloperidol (Hal) and the atypical neuroleptic risperidone (Ris) in doses, which normalized behavioural disturbances in prenatal vitamin D-deficient animals without any side effects on the normal behaviour decreased the enhanced LTP in the experimental group to control level. Interestingly, the effect of the substances was different in experimental and control rats. The LTP was enhanced in control animals by the low doses of the drugs effective in our behavioural experiments. It can be suggested, that changes in brain development induced by prenatal vitamin D deficiency lead to specific functional alterations in hippocampal synaptic plasticity. LTP is considered a cellular correlate of learning and memory. The better retention performance in brightness discrimination seems in accordance with enhanced potentiation level.

The potential neuroleptic-like effect of ampullosporin A, a new peptaibol, isolated from the fungus Sepedonium ampullosporum HKI-0053, was characterized using specific behavioural models and methods. Ampullosporin A (amp) disrupted the retrieval of a well-trained conditioned reaction and normalized the behavioural effects of subchronic ketamine treatment in the social interaction test in a dose which showed only inconsiderable side effects. The experiments demonstrated that the substance did not antagonize the apomorphine (apo) induced hyperactivity. On the other hand, the locomotor stimulation induced by the NMDA receptor antagonist MK-801 was nearly completely suppressed by ampullosporin A, supposing interactions with the glutamatergic system. Binding studies demonstrated no interaction with dopaminergic D(1) and D(2) receptors. However, amp can alter the activity of glutamate receptors. The results resemble characteristics of an atypical neuroleptic drug. But further experiments are necessary to validate the suggested neuroleptic-like activity.

Rationale: The ketamine (ket) model reflects features of schizophrenia as well as secondary symptoms such as altered pain sensitivity., Objectives: In the present study, we investigated the effect of subchronic oral treatment with haloperidol (hal, 0.075 mg/kg) and risperidone (ris, 0.2 mg/kg) on altered pain perception and locomotor activity in this model., Results: In reaction to 5 mg/kg morphine, ket pretreated animals showed a diminished analgesic response. Hal had no analgesic effect per se, but the compound normalised the analgesic reaction to morphine in the ket pretreated animals. The effect of ris was complex. First, there was no analgesic effect per se, and control animals showed a dose-dependent increase in the analgesic index after morphine injection. In the ket group treated with ris, the analgesic response to 5 mg/kg morphine was attenuated and in response to 10 mg/kg analgesia was comparable with that measured in controls. The reduced analgesic effect was not due to pharmacokinetic differences in morphine metabolism. After administration via drinking water in saline-injected control animals, the hal blood serum concentration was 2.6 +/- 0.45 ng/ml. In ket-injected animals, the mean serum concentration of hal amounted to 1.2 +/- 0.44 ng/ml. In the experiment using ris, animals in the control group had higher ris serum concentrations compared with ket-injected animals. In control animals, morphine dose dependently decreased locomotor activity. This effect was significantly stronger in the ket pretreated groups., Conclusions: Hal and ris had different effects on altered pain sensitivity. It was hypothesised that these results are connected with alterations in dopamine D2 and mu opioid receptor binding.

Background: Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-like symptoms in mice., Methodology/principal Findings: We found that while endogenous Abeta concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Abeta deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Abeta degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice., Conclusions/significance: Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases.

The effects of inducible heat shock protein 70 (HSP70) on emotional and learning behaviour as well as hippocampal long-term potentiation was investigated in transgenic HSP70 overexpressing mice. In active two-way avoidance learning (shuttle box) as well as spatial 8-arm radial maze learning, the HSP70 overexpressing mice showed diminished learning performance. In several tests there was no indication of differences in anxiety behaviour between transgenic mice and wild-type mice. This suggests that impairment in learning behaviour is unrelated to the learning task and motivational aspects of behaviour. To investigate the neurophysiological correlate of learning, long-term potentiation experiments were performed. In transversal hippocampal slices, an enhanced amplitude of the population spike was found in HSP70 overexpressing mice. It was hypothesised that enhanced potentiation in conjunction with potentiation effects due to learning led to learning impairment.

Mental retardation is the most frequent cause of serious handicap in children and young adults. Mutations in the human angiotensin II type 2 receptor (AT2) have been implicated in X-linked forms of mental retardation. We here demonstrate that mice lacking the AT2 receptor gene are significantly impaired in their performance in a spatial memory task and in a one-way active avoidance task. As no difference was observed between the genotypes in fear conditioning, the detected deficit in spatial memory may not relate to fear. Notably, receptor knockout mice showed increased motility in an activity meter and elevated plus maze. Importantly, these mice are characterized by abnormal dendritic spine morphology and length, both features also found to be associated with some cases of mental retardation. These findings suggest a crucial role of AT2 in normal brain function and that dysfunction of the receptor has impact on brain development and ultrastructural morphology with distinct consequences on learning and memory.

The neurotrophic factors play an important role in the maintenance of neurone viability and neuronal communication which are considered to be altered in schizophrenia. Subchronic application of ketamine (Ket) was found to be a useful model in schizophrenia research. To further validate this model the mRNA levels of neurotrophic factors NGF, NT-3, and BDNF and their receptors TrkA, TrkB, and TrkC, respectively, were measured in different brain areas in Ket-pretreated rats subchronically dosed with the atypical antipsychotic drug risperidone (Ris). With the exception of NGF in the frontal cortex, Ket pretreatment did change NGF, NT-3, and BDNF mRNA levels in the frontal cortex, the hippocampus, the striatum, the thalamus/hypothalamus region, and in the cerebellum. These changes correspond with changes at their tyrosine kinase receptors. Ris treatment normalised altered NT-3 levels in the hippocampus and balanced BDNF levels in the same structure. It was concluded that the Ket model might reflect distinct alterations in neurotrophic factor activity as found in schizophrenic patients and, moreover, that Ris treatment rebalances disturbed neurotrophic factor activity.

The beacon gene is involved in the regulation of energy metabolism, food intake, and obesity. We localized its gene product, beacon-/ubiquitin 5-like immunoreactivity in brains of normal-weight, non-psychotic individuals, adipose (BMI over 32), non-psychotic individuals, and haloperidol-treated schizophrenics. The protein was found to be highly expressed in many neurons of the paraventricular and supraoptic hypothalamic nuclei. Besides, it was detected in neurons of other hypothalamic areas (suprachiasmatic, arcuate, and ventromedial nuclei) as well as outside the hypothalamus (Nuc. basalis Meynert, thalamus, hippocampus, and some neocortical areas). A morphometric analysis of beacon-immunoreactive hypothalamic and neocortical neurons revealed that compared to normal-weight controls in haloperidol-treated schizophrenics, there was a significant increase of protein-expressing supraoptic, paraventricular, and orbitofrontal neurons. However, a significant increase in beacon-expressing supraoptic neurons was also seen in adipose, non-psychotic individuals in comparison with normal-weight controls. Haloperidol at different doses has no effect on beacon expression in SHSY5Y neuroblastoma cells, which makes the assumption unlikely that haloperidol per se is responsible for the increased neuronal expression of the peptide in schizophrenics. In rats with a neonatal lesion of the ventral hippocampus (a widely used animal model of schizophrenia), we found an increased neuronal expression of beacon in the paraventricular and supraoptic nuclei. We suppose that elevated hypothalamic expression of beacon-like protein in non-obese schizophrenics is not primarily related to metabolic alterations, but to a certain role in schizophrenia, which is possibly unrelated to aspects of weight gain and obesity. The latter assumption finds some support by data obtained in rats with ventral hippocampus lesion.

It was suggested that phosphodiesterase (PDE) inhibitors may be potential neuroleptic drugs with a low risk of extrapyramidal symptoms. In the study presented, we compared the effects of the neuroleptics, haloperidol, and risperidone and the PDE10A inhibitor papaverine as well as the PDE4 inhibitor rolipram on retrieval of conditioned avoidance responding in the pole-jumping task and on locomotor activity. After acute administration, the substances used reduced locomotor activity dose-dependently. Both PDE inhibitors interfered with conditioned avoidance responding, suggesting neuroleptic-like effects. Risperidone showed a favourable profile of action. In all the doses tested, no signs of unspecific impairments in the performance of the instrumental task occurred. The profile of rolipram was similar. In the doses tested, only minor impairments in the performance of the instrumental task were found. Rolipram showed a similar effect to risperidone, suggesting therapeutic usefulness as an atypical neuroleptic. However, the use of this substance is limited by its emetic effects in therapeutically relevant doses.

The present experiments were designed to study fear conditioning as an emotional learning task with disrupted visceral feedback. For that purpose we used the peripherally acting beta1-adrenoceptor blocker atenolol and studied its effects on the behavior of male C57BL/6JOlaHsd mice in an exploration-related test and during fear-conditioning. In the first experiment, we treated mice with saline or different doses of the beta1-adrenergic blocker atenolol (5mg/kg and 20mg/kg body weight i.p.) 30 min before behavioral testing in a motility box. Only the high but not the low dose of atenolol led to a reduction of locomotor activity (p<0.02). Factors known to be related to emotionality (rearing, area preference) were unaffected. In a second experiment, saline- and atenolol-treated mice (same dosages and mode of application) were trained for auditory fear conditioning, and 24h later they were retested in the same environment. We found differences between the effects of atenolol upon contextual- and cue-fear conditioning. Animals treated with 20mg/kg BW doses of atenolol showed significantly decreased background contextual fear compared to saline-treated control animals. In contrast, no differences were found during CS presentation in the conditioning context between atenolol-treated animals and saline-treated controls, independent from a paired or an unpaired conditioning paradigm. Thus, the blockade of peripheral beta1-adrenoceptors by atenolol may have disrupted the positive feedback to the central nervous system via visceral afferents resulting in a decreased locomotor activity and background contextual fear.

Kindling induced by the convulsant pentylenetetrazol (PTZ) is an accepted model of primary generalized epilepsy. Because seizures represent a strong distressing stimulus, stress-induced proteins such as heat shock proteins might counteract the pathology of increased neuronal excitation. Therefore, the aim of the present study was to determine whether PTZ kindling outcome parameters are influenced by heat shock protein 70 (Hsp70) overexpression in Hsp70 transgenic mice as compared to the respective wild-type mice. Kindling was performed by nine intraperitoneal injections of PTZ (ED(16) for induction of clonic-tonic seizures, every 48 h); control animals received saline instead of PTZ. Seven days after the final injection, all mice received a PTZ challenge dose. Outcome parameters included evaluation of seizure stages and overall survival rates. In addition, histopathological findings such as cell number in hippocampal subfields CA1 and CA3 were determined. The onset of the highest convulsion stage was delayed in Hsp70 transgenic mice as compared to wild-type mice, and overall survival during kindling was improved in Hsp70 transgenic mice as compared to wild-type mice. In addition, a challenge dose after termination of kindling produced less severe seizures in Hsp70 transgenic mice than in wild-type mice. PTZ kindling did not result in significant subsequent neuronal cell loss in CA1 or CA3 neither in wild-type mice nor in the Hsp70 transgenic mice. The results of the present experiments clearly demonstrate that overexpression of Hsp70 exerts protective effects regarding seizure severity and overall survival during PTZ kindling. In addition, the decreased seizure severity in Hsp70 transgenic mice after a challenge dose suggests an interference of Hsp70 with the developmental component of kindling.

Purpose: The aim of the study was to define sleep disturbances in pentylenetetrazole (PTZ)-kindled rats and to explore the effects of the nootropic drug piracetam (Pir; 100 mg/kg) and the noncompetitive N-methyl-D-aspartate (NMDA)-antagonist MK-801 (0.3 mg/kg), which normalized learning performance in PTZ-kindled rats, on altered sleep parameters., Methods: This is the first report showing a significant reduction in paradoxical sleep (PS) as a consequence of PTZ kindling. A correlation analysis revealed a significant correlation between seizure severity and PS deficit., Results: Pir did not interfere with seizure severity, and the substance did not ameliorate the PS deficit. However, the substance disconnected the correlation between seizure severity and PS deficit. MK-801, which reduced the severity of kindled seizures, counteracted the PS deficit efficaciously., Conclusions: The results suggest that seizure severity and alterations in sleep architecture are two factors in the comprehensive network underlying learning impairments associated with epilepsy. Considering the results obtained in the experiments with Pir, reduction of seizure severity does not guarantee the reduction of impairments in the domain of learning.

Rationale: Clinical observations have shown that pain sensitivity is altered in some schizophrenic patients., Objectives: To study alterations in pain sensitivity, the ketamine model in schizophrenia research was employed., Materials and Methods: Rats were subchronically injected with the dissociative anaesthetic ketamine (Ket, ten injections of 30 mg/kg, one injection per day over a period of 10 days). Two weeks after treatment completion, the animals' pain sensitivity was assayed in the hot plate test and they were subjected to electrical stimulation of the tail root. In addition, the effect of morphine was studied., Results: In group-housed animals, there was no difference between Ket-injected animals and control rats as measured in both nociceptive tests. In singly housed Ket-injected rats, pain threshold was increased in the electrical stimulation test. This suggests that stress due to single housing might be essential for modifications of pain sensitivity. Moreover, the antinociceptive effect of morphine was modified after single housing. Interestingly, the effect of morphine on locomotor activity was similar in both groups. In group-housed rats, mu receptor binding was unchanged in the frontal cortex, whereas Ket-injected animals had decreased levels in the hippocampus. In singly housed animals, mu receptor binding in Ket-injected rats increased in the frontal cortex and decreased in the hippocampus. (35)S-GTPgamma-S binding increased in the frontal cortex in both singly housed groups, but remained unchanged in the hippocampus., Conclusions: The data suggest that the ketamine model might be useful for studying altered pain sensitivity in schizophrenia. Moreover, the data suggest that modifications in mu opioid receptor binding contribute to this phenomenon.

Growing evidence indicates that alterations of neuroplasticity may contribute to the pathophysiology of depression. In contrast, various antidepressants increase adult hippocampal neurogenesis and block the effects of stress. These findings result in the 'neurogenesis hypothesis of depression'. The present study seeks to determine out whether cell proliferation is altered in the hippocampus, subventricular zone (SVZ), and basolateral amygdala of adult rats exposed to bilateral olfactory bulbectomy, another established model of depression and, if so, how imipramine effects bulbectomy-induced changes of cell genesis. Bulbectomy results in a significant reduction of cell proliferation in the hippocampus and SVZ, an effect that is normalized by subchronic doses of imipramine. Moreover, an increase in cell genesis in the basolateral amygdala, which is not affected by imipramine, is demonstrated. TUNEL staining indicates an enhanced apoptosis after bulbectomy in the SVZ that cannot be reduced by imipramine. Cell death rates in the hippocampus and amygdala are not affected by bulbectomy. The opposing effects of bulbectomy and imipramine treatment in the hippocampus and amygdala demonstrate that these structures of the limbic system, both integrated in emotional processing, react quite differently with regard to neuroplasticity. Further to this, we discuss a possible link between the pathogenesis of depression and changed neuronal plasticity in the SVZ.

Rationale: Despite numerous investigations, the mechanisms underlying the development of opioid tolerance are far from clear. However, several in vitro studies implicated a protective role of agonist-induced micro-opioid receptor endocytosis in the development of opioid tolerance. Moreover, we have recently demonstrated that the high-efficacy agonist etonitazene promotes rapid endocytosis of micro-opioid receptors, whereas the agonist morphine and the low-efficacy agonist buprenorphine fail to promote detectable receptor endocytosis in micro-opioid receptor expressing HEK293 cells., Objectives: The present study explored the effects of these opioids on the development of tolerance and sensitization in rats in vivo., Methods: The opioid effects were quantified using the hot plate, electric tail root stimulation, and the locomotor activity chamber in male Wistar rats. Dose-response curves were generated for each test drug. To induce tolerance, equieffective doses of etonitazene, morphine, and buprenorphine were administered daily for 29 days., Results: We found that chronic treatment with the non-internalizing drugs buprenorphine and morphine resulted in a greater development of tolerance than etonitazene. In addition, the sensitization to the locomotor stimulant effect was high after buprenorphine and morphine, but was lacking after chronic etonitazene application., Conclusion: The results support a role for the endocytotic potency of agonists in the development of tolerance and addiction during long-term opioid treatment.

Psychotic disorders affecting up to 1% of the human population represent pathological changes to the metabolic homeostasis of the brain. Increasing evidence in the literature suggests complex biochemical and/or transcriptional alterations accompanying schizophrenia-like phenomena. Sub-chronic treatment with sub-anaesthetic doses of ketamine induces schizophrenia-related psychotic alterations that can be used as an animal model in the study of this disorder. Ampullosporin A belongs to a specific group of pore-forming fungal peptides, peptaibols. We focused on the analysis of molecular events occurring in the brain of ketamine-pre-treated rats after administration of Ampullosporin A with neuroleptic-like activity. The complex experimental approach allowed us to correlate the use of low molecular weight substances with a transcriptome fingerprint in the prefrontal cortex. We found 63 genes to be up-regulated and 22 genes suppressed, with transthyretin, syndecan-1 and NeuroD1 showing the highest degree of up-regulation. Our results suggest the possibility that Ampullosporin A belongs to the group of neuroleptic-like compounds, inducing massive changes in neurotransmitter receptor composition, calcium signalling cascades and second messenger systems, and leading to the plastic reorganization of brain tissue, metabolic pathways and synapses.

Neurocognitive impairment has consistently been considered a central and stable feature of schizophrenia. There is much controversy about the effects of neuroleptics on neurocognitive deficits. Thus, further investigations are needed to clarify the pathological substrate of cognitive deficits in schizophrenia as well as to identify pharmacological tools for treatment. Transient prenatal Vitamin D deficiency is considered a developmental model in schizophrenia research. Recently, it was reported that prenatal Vitamin D-depleted rats showed a habituation deficit in the hole board. Here, we tested the effect on hole board habituation of haloperidol (Hal, 0.075 mg/kg, i.p.), risperidone (Ris, 0.2 mg/kg, i.p.) and the mGluR5 agonist CHPG (0.1 mg, i.c.v.) after subchronic treatment. Hal was found to impair habituation in control animals, Ris restored hole board habituation, whereas Hal and CHPG normalised hole board habituation in the deplete animals completely. The results of the study demonstrate that (i) the Vitamin D model might be a valuable tool in the study of neurodevelopmental aspects of schizophrenia, (ii) the model is sensitive in detecting the effect of antipsychotic drugs and (iii) the model appears to be sensitive in differentiating between typical and atypical antipsychotic drug.

Brailowsky and Garcia (1999) proposed the existence of a relationship between epilepsy and addiction. To prove this hypothesis, pentylenetetrazol kindled rats were tested in the conditioned place preference (CPP) paradigm for their reaction to various addictive drugs with different modes of action (morphine, cocaine and ethanol). In separate experiments, locomotor activity and body temperature after application of the same drugs were tested in kindled and non-kindled rats. In the CPP experiment there were significant differences between both groups of rats. Non-kindled animals showed place preference to morphine (5.0 mg/kg) or cocaine (20.0 mg/kg). This reaction was abolished in the kindled rats. Moreover, control rats demonstrated aversion to 2.0 g/kg ethanol. However, ethanol aversion was not detectable in kindled rats. Moreover, there was no difference between non-kindled and kindled rats in locomotor activity and body temperature after morphine (1.0 and 5.0 mg/kg), cocaine (10.0 and 20.0 mg/kg), or ethanol (0.5 and 2.0 g/kg) application. This suggests alterations in reward systems as a consequence of kindling. It is hypothesised that GABAergic neurones in the ventral tegmental area might play a major role in the alterations found.

Based on clues from epidemiology, low prenatal vitamin D has been proposed as a candidate risk factor for schizophrenia. Recent animal experiments have demonstrated that transient prenatal vitamin D deficiency is associated with persistent alterations in brain morphology and neurotrophin expression. In order to explore the utility of the vitamin D animal model of schizophrenia, we examined different types of learning and memory in adult rats exposed to transient prenatal vitamin D deficiency. Compared to control animals, the prenatally deplete animals had a significant impairment of latent inhibition, a feature often associated with schizophrenia. In addition, the deplete group was (a) significantly impaired on hole board habituation and (b) significantly better at maintaining previously learnt rules of brightness discrimination in a Y-chamber. In contrast, the prenatally deplete animals showed no impairment on the spatial learning task in the radial maze, nor on two-way active avoidance learning in the shuttle-box. The results indicate that transient prenatal vitamin D depletion in the rat is associated with subtle and discrete alterations in learning and memory. The behavioural phenotype associated with this animal model may provide insights into the neurobiological correlates of the cognitive impairments of schizophrenia.

In contrast to endogenous opioids, the highly addictive drug morphine activates the mu-opioid receptor without causing its rapid endocytosis. It has recently been reported that coapplication of low concentrations of [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) facilitates the ability of morphine to stimulate mu-opioid receptor endocytosis and prevents the development of morphine tolerance in rats. To investigate the clinical relevance of this finding for analgesic therapy, the endocytotic efficacies of a series of clinically used opioids were determined, and the effect of a combination of these drugs with morphine on the mu-opioid receptor endocytosis in receptor-expressing human embryonic kidney (HEK) 293 cells was quantified. The combination of morphine and opioid drugs with high endocytotic efficacies (e.g., DAMGO, etonitazene, sufentanil, beta-endorphin, piritramide, or methadone) did not result in a facilitation of morphine-mediated endocytosis but rather in a decrease of the receptor endocytosis mediated by the tested opioid drugs. These findings demonstrate a partial agonistic effect of morphine on the agonist-induced receptor endocytosis. Moreover, we demonstrated that the endocytotic potencies of opioid drugs are negatively correlated with their ability to cause receptor desensitization and opioid tolerance in HEK 293 cells. These results strongly support the hypothesis that mu-opioid receptor endocytosis counteracts receptor desensitization and opioid tolerance by inducing fast receptor reactivation and recycling. In addition, it is shown that agonist-induced receptor endocytosis facilitates the compensatory up-regulation of the cAMP pathway, a cellular hallmark of opioid withdrawal. Our findings suggest that opioids with high endocytotic efficacies might cause reduced opioid tolerance but can facilitate compensatory mechanisms, resulting in an enhanced opioid dependence.