Björn Steiniger-Brach

Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to D -amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons.

J. Neurochem. (2009) 109, 766–775.

Increased dopaminergic activity in socially isolated rats: An electrophysiological study

The development of animal models mimicking symptoms associated with schizophrenia has been a critical step in understanding the neurobiological mechanisms underlying the disease. Long-term social isolation from weaning in rodents, a model based on the neurodevelopmental hypothesis of schizophrenia, has been suggested to mimic some of the deficits seen in schizophrenic patients. We confirm in the present study that socially isolated rats display an increase in both spontaneous and d-amphetamine-induced locomotor activity, as well as deficits in sensorimotor gating as assessed in a pre-pulse inhibition paradigm. In addition, in vivo electrophysiological studies revealed changes in dopaminergic cell firing activity in the ventral tegmental area of isolated rats when compared to group-housed controls. These alterations include an increase in the number of spontaneously active dopaminergic neurons, and a change of firing activity towards a more irregular and bursting firing pattern. Taken together, our findings suggest that the behavioral phenotype induced by social isolation may be driven by an overactive dopamine system.

Auditory sensory processing deficits in sensory gating and mismatch negativity-like responses in the social isolation rat model of schizophrenia.

Patients with schizophrenia exhibit disturbances in information processing. These disturbances can be investigated with different paradigms of auditory event related potentials (ERP), such as sensory gating in a double click paradigm (P50 suppression) and the mismatch negativity (MMN) component in an auditory oddball paradigm. The aim of the current study was to test if rats subjected to social isolation, which is believed to induce some changes that mimic features of schizophrenia, displays alterations in sensory gating and MMN-like response. Male Lister-Hooded rats were separated into two groups; one group socially isolated (SI) for 8 weeks and one group housed (GH). Both groups were then tested in a double click sensory gating paradigm and an auditory oddball paradigm (MMN-like) paradigm. It was observed that the SI animals showed reduced sensory gating of the cortical N1 amplitude. Furthermore, the SI animals showed significant reduction in cortical MMN-like response compared with the GH animals. No deficits in sensory gating or MMN-like response were observed in the hippocampus (CA3) of the SI animals compared with GH animals. In conclusion, the change in sensory gating of the N1 amplitude supports previous findings in SI rats and the reduced MMN-like response is similar to the deficits of MMN seen in patients with schizophrenia. Since reduced auditory MMN amplitude is believed to be more selectively associated with schizophrenia than other measures of sensory gating deficits, the current study supports the face validity of the SI reared rat model for schizophrenia.

Socially isolated rats exhibit changes in dopamine homeostasis pertinent to schizophrenia.

Post‐weaning social isolation of rats produces an array of behavioral and neurochemical changes indicative of altered dopamine function. It has therefore been suggested that post‐weaning social isolation mimics some aspects of schizophrenia. Here we replicate and extent these findings to include an investigation of prefrontal cortical dopamine dynamics using in vivo microdialysis.

Stereological brain volume changes in post-weaned socially isolated rats.

Rearing rats in isolation after weaning is an environmental manipulation that leads to behavioural and neurochemical alterations that resemble what is seen in schizophrenia. The model is neurodevelopmental in origin and has been used as an animal model of schizophrenia. However, only a few studies have evaluated the neuroanatomical changes in this animal model in comparison to changes seen in schizophrenia. In this study, we applied stereological volume estimates to evaluate the total brain, the ventricular system, and the pyramidal and granular cell layers of the hippocampus in male and female Lister Hooded rats isolated from postnatal day 25 for 15 weeks. We observed the expected gender differences in total brain volume with males having larger brains than females. Further, we found that isolated males had significantly smaller brains than group-housed controls and larger lateral ventricles than controls. However, this was not seen in female rats. Isolated males had a significant smaller hippocampus, dentate gyrus and CA2/3 where isolated females had a significant smaller CA1 compared to controls. Thus, our results indicate that long-term isolation of male rats leads to neuroanatomical changes corresponding to those seen in schizophrenia.

Identification of a new series of non-peptidic NK3 receptor antagonists.

The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK(3) receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK(3) receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils.

Comparing Pharmacological Modulation of Sensory Gating in Healthy Humans and Rats: The Effects of Reboxetine and Haloperidol

Sensory gating is the brain’s ability to filter out irrelevant information before it reaches high levels of conscious processing. In the current study we aimed to investigate the involvement of the noradrenergic and dopaminergic neurotransmitter systems in sensory gating. Furthermore, we investigated cross-species reliability by comparing effects in both healthy humans and rats, while keeping all experimental conditions as similar as possible between the species. The design of the human experiment (n=21) was a double-blind, placebo-controlled, cross-over study where sensory gating was assessed following a dose of either reboxetine (8 mg), haloperidol (2 mg), their combination or placebo at four separate visits. Similarly in the animal experiment sensory gating was assessed in rats, (n=22) following a dose of reboxetine (2 mg/kg), haloperidol (0.08 mg/kg), their combination or placebo. The sensory gating paradigms in both experiments were identical. In humans, we found significantly reduced P50 suppression following separate administration of reboxetine or haloperidol, while their combined administration did not reach statistical significance compared with placebo. In the rats, we found a similar significant reduction of sensory gating (N40) following treatment with haloperidol and the combination of haloperidol and reboxetine, but not with separate reboxetine treatment, compared with placebo. Our study indicates that even when experimental conditions are kept as similar as possible, direct human to rat cross-species translation of pharmacological effects on sensory gating is challenging, which calls for more focussed research in this important translational area.