Dopamine is implicated in the pathogenesis of both the positive and the negative symptoms of schizophrenia. Clinical efficacy of antipsychotic drugs, without the production of side-effects, may be achieved by a dose–response separation of pharmacological function, regional (i.e., anatomical) selectivity of action, or by the selective targeting of neuroreceptors. The atypical antipsychotics have many different ways of acting on receptors in the brain, but they have in common a decreased likelihood of producing extrapyramidal side-effects. Patients respond well to them by showing improvements of both positive and negative symptoms. The preclinical profile of amisulpride shows specificity for D2/D3 dopamine receptors and selective activity in the limbic system. There is evidence that amisulpride is effective in treating both the negative and positive symptoms of schizophrenia, and that it has a low propensity to induce motor side-effects. Therefore, both positive and negative symptoms can be treated, without inducing these side-effects, by selectively targeting dopamine receptors.

Tiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D2 (IC50 = 110–320 nM) and D3 (IC50 = 180 nM) receptors in vitro but lacks affinity for dopamine D1 and D4 receptors and for non-dopaminergic receptors including H1, α1, α2-adrenergic and serotonergic receptors. Tiapride also shows dose-related inhibition of [3H]-raclopride binding in limbic areas and in the striatum of the rat in vivo (ED50 ∼ 20 mg/kg, ip). In microdialysis experiments, tiapride (over the range 10–30 mg/kg, ip) increased extracellular levels of dopamine in the nucleus accumbens and striatum, a reflection of its blockade of postsynaptic dopamine receptors in these brain areas.

In behavioral experiments in rats, lower doses of tiapride (ED50 = 10 mg/kg, ip) antagonised dopamine agonist-induced hyperactivity while higher doses (ED50 = 60 mg/kg, ip) were required to block stereotyped movements.

In addition, doses of tiapride up to 200 mg/kg, ip failed to induce catalepsy, an effect observed with many other drugs which block dopamine receptors. In tests of conditioned behavior in rats, tiapride was found to give rise to an interoceptive stimulus associated with dopamine receptor blockade at doses (ED50 = 2.2 mg/kg, ip) much lower than those producing motor disturbances or sedation (ED50 = 40 mg/kg, ip), in striking contrast to a range of conventional or atypical neuroleptics that produced interoceptive stimulus and sedation at similar doses. Furthermore, the acquisition by rats of a place-learning task in a water maze was not affected by tiapride (over the range 3–30 mg/kg, ip), whereas haloperidol (MED = 0.25 mg/kg, ip) and risperidone (MED = 0.03 mg/kg, ip) impaired performance.

The preclinical pharmacologic and behavioral profile of tiapride suggests that its clinical activity may be due to a selective blockade of dopamine D2 and D3 receptors in limbic brain regions. The results are also consistent with a lack of motor or cognitive side effects.

Autonome functies en emoties worden beide gestuurd door het limbische systeem; een groep kernen in de voorhersenen die voor het eerst als zodanig beschreven zijn door Papez in 1937. Ondanks jarenlang fundamenteel wetenschappelijk onderzoek rijzen nog steeds vele vragen over de bouw en functies van het limbische systeem, met inline waar het de rol van dit systeem betreft bij emotionele stoornissen zoals angst en depressie. Fundamenteel neurobiologisch onderzoek van cardiovasculaire autonome sturing biedt de mogelijkheid inzicht le verkrijgen in de bouw van limbische neuronale circuits. In deze publicatie wordt een overzicht gegeven van de vorderingen op dit gebied. De bouw van de limbische cardiovasculaire circuits zal worden beschreven aan de hand van resultaten verkregen met verschillende - moderne - neurobiologische technieken. Ook het effect van typische en atypische antipsychotica in deze circuits zal warden gepresenteerd.

In de afgelopen zes jaar is veel onderzoek verficht naar de effecten van antipsychotica op de regionale c-fos-expressie in de hersenen. Deze benadering biedt in een dierexperimentele proefopzet de mogelijkheid op cellulair niveau de effecten van psychofarmaca te bestuderen. Het fos-gen behoort tot de groep ‘immediate early genes’. Dit zijn genen die de transcriptie van andere, vaak onbekende genen reguleren. Een aantal aspecten van dit mechanisme wordt in deze bijdrage beschreven. Het onderzoek naar de effecten van antipsychotica op c-fos-expressie wordt samengevat en de betekenis voor de classificatie van antipsychotica benadrukt. Het blijkt dat deze farmaca effectief zijn in zowel de (meso)limbische gebieden (als nucleus accumbens, septum en amygdala) als ook in de basale ganglia. De relatieve effecten, wat betreft de c-fos-reactie, van de atypische antipsychotica (als clozapine en risperidon) zijn hoger in de limbische structuren, vergeleken met de effecten van de typische (als haloperidol). De potentie van de c-fos-methodiek voor verdere ontwikkelingen in dit gebied wordt aangegeven.

This paper summarizes the possible interrelation between peripheral and/or cerebral inflammation and depression. Often, depression is regarded as a consequence of life events, including disabling diseases. The question addressed here is whether activation of the inflammatory response system (IRS) can cause depression. Epidemiological studies suggest that depression can be precipitated by bacterial or viral infections. In depressed patients, peripheral markers of the IRS are often increased. There is some evidence that some forms of depression are caused by a viral infection of the limbic system. More consistent are the observations that depression in diseases with active cerebral inflammatory processes (e.g. multiple sclerosis, Alzheimer's disease) may concur. Direct evidence of a relation between depression and inflammation was found in post-mortem brain material of patients with a vascular depression. In both inflammatory brain diseases and in depression, a state-dependent increased hypothalamus–pituitary–adrenal axis activity is seen. Animals studies have shown that intact cerebral serotonin systems are required for the activation of the IRS following an endotoxin challenge and that long-term treatment with antidepressants may change such a response. Gender differences between the prevalence of depression and inflammatory diseases are similar, as more females are affected. We hypothesize that cerebral or peripheral activation of the IRS may contribute to the course of some antidepressant treatment-resistant depressions. Clinical trials combining antidepressants and drugs that reduce the activation of the IRS may provide evidence for such proposed depression subtypes.

This Short Review critically evaluates three hypotheses about the effects of emotion on memory: First, emotion usually enhances memory. Second, when emotion does not enhance memory, this can be understood by the magnitude of physiological arousal elicited, with arousal benefiting memory to a point but then having a detrimental influence. Third, when emotion facilitates the processing of information, this also facilitates the retention of that same information. For each of these hypotheses, we summarize the evidence consistent with it, present counter-evidence suggesting boundary conditions for the effect, and discuss the implications for future research. (JINS, 2013, 19, 1–9)

Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the limbic system after myocardial infarction (MI). A PUFA n-3 diet or the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 probiotics, when given before the ischaemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. The present study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depression-like behaviour observed after MI. MI was induced by the occlusion of the left anterior descending coronary artery for 40 min in rats. After the onset of reperfusion, animals were fed with a high- or low-PUFA n-3 diet, combined or not with one billion live bacteria of L. helveticus and B. longum. At 3 d post-MI, caspase-3 enzymatic activities and terminal 2′-deoxyuridine, 5′-triphosphate (dUTP) nick-end labelling (TUNEL)-positive cells were decreased in the CA1, dentate gyrus (DG) and amygdala with the high-PUFA n-3 diet, as compared to the three other diets. Probiotics attenuated caspase-3 activity and TUNEL-positive cells in the DG and the medial amygdala. At 2 weeks post-MI, depression-like behaviour was observed in the low-PUFA n-3 diet without probiotics-group, and this behaviour was attenuated with the high-PUFA n-3 diet or/and probiotics. These results indicate that a high-PUFA n-3 diet or the administration of probiotics, starting after the onset of reperfusion, are beneficial to attenuate apoptosis in the limbic system and post-MI depression in the rat.

A model is proposed for integrating the neural and cognitive aspects of the positive symptoms of acute schizophrenia, using evidence from postmortem neuropathology and neurochemistry, clinical and preclinical studies of dopaminergic neurotransmission, anatomical connections between the limbic system and basal ganglia, attentional and other cognitive abnormalities underlying the positive symptoms of schizophrenia, specific animal models of some of these abnormalities, and previous attempts to model the cognitive functions of the septohippocampal system and the motor functions of the basal ganglia. Anatomically, the model emphasises the projections from the septohippocampal system, via the subiculum, and the amygdala to nucleus accumbens, and their interaction with the ascending dopaminergic projection to the accumbens. Psychologically, the model emphasises a failure in acute schizophrenia to integrate stored memories of past regularities of perceptual input with ongoing motor programs in the control of current perception. A number of recent experiments that offer support for the model are briefly described, including anatomical studies of limbic-striatal connections, studies in the rat of the effects of damage to these connections, and of the effects of amphetamine and neuroleptics, on the partial reinforcement extinction effect, latent inhibition and the Kamin blocking effect; and studies of the latter two phenomena in acute and chronic schizophrenics.