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Effects of kainate or 6-hydroxidopamine (6-OHDA) lesions in the ventromedial prefrontal cortex (vmPFC) on taste-related learning and memory processes were examined. Neurotoxins were applied by iontophoretic method to minimize the extent of lesion and the side effects. Acquisition and retention of conditioned taste avoidance (CTA) was tested to different taste stimuli (0.05 M NaCl, 0.01 M saccharin, 0.01 M citrate and 0.00025 M quinine). In the first experiment, palatability index of taste solutions with these concentrations has been determined as strongly palatable (NaCl, saccharin), weakly palatable (citrate) and weakly unpalatable (quinine) taste stimuli. In two other experiments vmPFC lesions were performed before CTA (acquisition) or after CTA (retrieval). Our results showed that both kainate and 6-OHDA microlesions of vmPFC resulted in deficit of CTA acquisition (to NaCl, saccharin and citrate) and retrieval (to NaCl and saccharin). Deficits were specific to palatable tastants, particularly those that are strongly palatable, and did not occur for unpalatable stimulus. The present data provide evidence for the important role of vmPFC neurons and catecholaminergic innervation of the vmPFC in taste related learning and memory processes.

Tridecapeptide Neurotensin (NT) is widely distributed in the central nervous system where it acts as a neurotransmitter and neuromodulator. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. Our previous data showed that NT microinjected into the CeA has positive reinforcing properties. We supposed that these effects might be due to modulations of the mesolimbic dopamine system. The aim of our study was to examine in the CeA the possible effects of NT and dopamine interaction on reinforcement by conditioned place preference test. Male Wistar rats were microinjected bilaterally with 100 ng NT or 2 μg D1 dopamine receptor antagonist alone, or D1 dopamine antagonist 15 min before 100 ng NT treatment or vehicle solution into the CeA. Other animals received 4 μg D2 dopamine receptor antagonist Sulpiride alone, or administration of D2 dopamine receptor antagonist 15 min before 100 ng NT treatment or vehicle solution into the CeA. Rats that received 100 ng NT spent significantly more time in the treatment quadrant during the test session. Pre-treatment with the D1 dopamine antagonist, blocked the effects of NT. D2 dopamine receptor antagonist pretreatment could prevent the positive reinforcing effects of NT as well. Antagonists themselves did not influence the place preference. Our results show that the rewarding effect of NT can be due to the modulation of DA system, since its effects could be blocked by either D1 dopamine or D2 dopamine antagonist preteatment.

Effects of destroyed noradrenergic (NE) innervation in the medial prefrontal cortex (mPFC) were examined on dopamine (DA) content and metabolism. Six-hydroxy-DOPA (6-OHDOPA) or 6-hydroxy-dopamine (6-OHDA) in combination with a potent DA reuptake inhibitor GBR 12935 or 6-OHDA were injected bilaterally into the mPFC in separate groups of animals. In addition, GBR 12935 or vehicle was injected into the mPFC in two other groups of animals as control experiments. NE and DA concentrations from postmortem tissue of the mPFC were measured using HPLC with electrochemical detection. In addition, extracellular NE, DA and DOPAC levels were determined using in vivo microdialysis after the 6-OHDA lesion in combination with GBR 12935 pretreatment in the mPFC. Using reverse microdialysis of alpha-2-adrenoreceptor antagonist yohimbine, we tested the remaining activity of NE innervation and the extracellular concentration of DA and DOPAC. NE and DA concentrations from postmortem tissue of the mPFC showed that 6-OHDOPA lesion reduced NE concentration to 76%, which was a non-significant alteration, however it enhanced significantly DA concentration to 186% compared to vehicle. After 6-OHDA lesion with GBR 12935 pretreatment, concentration of NE significantly decreased to 51% and DA level increased to 180%. 6-OHDA lesion without GBR 12635 pretreatment decreased NE concentration to 23% and DA concentration to 67%. In the microdialysis experiment, after 6-OHDA lesion with GBR 12935 pretreatment, extracellular NE levels were not detectable, whereas extracellular DA levels were increased and DOPAC levels were decreased compared to controls. Reverse microdialysis of yohimbine demonstrated that the residual NE innervation was able to increase NE level and DA levels, but DOPAC concentration remained low after lesion of the NE terminals. These findings suggest that the damage of NE innervation in the mPFC may alter extracellular DA level due to a reduced DA clearance.

Substance P (SP) and neurotensin (NT) are neuropeptides isolated in the periphery and in the central nervous system. They are involved in various regulatory processes in the gastrointestinal tract, in the circulatory and respiratory systems, kidney and endocrine system. In addition to the peripheral effects, SP and NT act as neurotransmitters and neuromodulators in the central nervous system, regulating various behavioural actions, such as general and motor activity, pain, food and water intake, anxiety, reward/reinforcement and memory consolidation. In the limbic system SPergic and NTergic pathways, terminals and related receptors have been identified. According to several data of literature and to our recently published results, SP and NT have rewarding/reinforcing effects and facilitate memory consolidation in various limbic regions. In this report evidences are provided about the interaction of these neuropeptides with dopaminergic and acetylcholinergic systems. A hypothesis is presented that rewarding/reinforcing effects of SP and NT develop by modulating the mesencephalic dopaminergic system, while their mnemonic effects are mediated via the mesencephalic dopaminergic and the basal forebrain cholinergic systems.

In our present experiments, the role of D2 dopamine (DA) receptors of the ventral pallidum (VP) was investigated in one trial step-through inhibitory avoidance paradigm. Animals were shocked 3 times in the conditioning trial, with 0.5 mA current for 1 s. Subsequently bilateral microinjection of the D2 DA receptor agonist quinpirole was administered into the VP in three doses (0.1 μg, 1.0 μg or 5.0 μg in 0.4 μl saline). We also applied the D2 DA receptor antagonist sulpiride (0.4 μg in 0.4 μl saline) alone or 15 min prior to the agonist treatment to elucidate whether the agonist effect was specific for the D2 DA receptors. Control animals received saline. In a supplementary experiment, it was also investigated whether application of the same conditioning method leads to the formation of short-term memory in the experimental animals. In the experiment with the D2 DA receptor agonist, only the 0.1 μg quinpirole increased significantly the step-through latency during the test trials: retention was significant compared to the controls even 2 weeks after conditioning. The D2 DA receptor antagonist sulpiride pretreatment proved that the effect was due to the agonist induced activation of the D2 DA receptors of the VP. The supplementary experiment demonstrated that short-term memory is formed after conditioning in the experimental animals, supporting that the agonist enhanced memory consolidation in the first two experiments. Our results show that the activation of the D2 DA receptors in the VP facilitates memory consolidation as well as memory-retention in inhibitory avoidance paradigm.

Cognitive disturbances are among the most important features of schizophrenia, and have a significant role in the outcome of the disease. However, the treatment of cognitive symptoms is poorly effective. In order to develop new therapeutic opportunities, the MAM-E17 rat model of schizophrenia can be an appropriate implement. In the present study we investigated several cognitive capabilities of MAM-treated rats using radial arm maze (RAM) task, which corresponds to the recent research directives. Because of the diachronic appearance of schizophrenia symptoms and the early appearance of cognitive deficiencies, we carried out our experiments in three different age-periods of rats, i.e. in prepuberty, late puberty and adulthood. The performance of MAM-E17 rats was similar to control rats in the acquisition phase of RAM task, except for puberty. However, after rearrangement of reward positions (in the reverse paradigm) the number of errors of MAM-treated rats was higher in each age-period. In the reverse paradigm MAM-treated groups visited more frequently those non-rewarding arms, which were previously rewarding. Our results suggest that working memory of MAM-E17 rats is impaired. This deficit depends on the difficulty of the task and on the age-period. MAM-E17 rats seem to be more sensitive in puberty in comparison to controls. Diminished behavioral flexibility was shown as well. These behavioral results observed in MAM-E17 rats were similar to those of cognitive deficiencies in schizophrenia patients. Therefore, MAM-E17 model can be a useful implement for further research aiming to improve cognition in schizophrenia.

The ventromedial prefrontal cortex (vmPFC) of rats has reciprocal connections with the gustatory and the hedonic impact coding structures. The main goal of the present study was to investigate the involvement of local neurons of vmPFC and their catecholaminergic innervations in taste preference and taste reactivity test. Therefore, kainate or 6-hydroxydopamine (6-OHDA) lesions were performed in the vmPFC by iontophoretic method. In the first experiment, taste preference was tested to 250 mM and 500 mM glucose solutions over water in two-bottle choice test. In the second experiment, taste reactivity was examined to 4 concentrations of glucose solutions (250 mM, 500 mM, 750 mM and 1000 mM) and 4 concentrations of quinine solutions (0.125 mM, 0.25 mM, 1.25 mM and 2.5 mM). Our results showed, that kainate microlesion of vmPFC did not modify the preference of 250 mM and 500 mM glucose solutions in two-bottle choice test. In contrast, 6-OHDA microlesion of vmPFC resulted in increased preference to the higher concentration of glucose (500 mM) solution over water. Results of taste reactivity test showed that kainate lesion resulted in more ingestive and less rejective responses to 750 mM glucose solution and elevated rejectivity to the higher concentrations (1.25 mM and 2.5 mM) of quinine solutions. 6-OHDA lesion of vmPFC increased the number of ingestive responses to highly concentrated (500 mM, 750 mM and 1000 mM) glucose solutions and decreased the number of ingestive responses to the lower concentration (0.125 mM) of quinine solution. The present data provide evidence for the important role of vmPFC neurons and catecholaminergic innervation of the vmPFC in the regulation of hedonic evaluation of tastes and in the hedonic consummatory behavior.

Dopamine D2 receptors (D2Rs) of the ventral pallidum (VP) play important role in motivational and learning processes, however, their potential role in triggering schizophrenic symptoms has not been investigated, yet. In the present experiments the effects of locally administered D2R agonist quinpirole were investigated on behavioral parameters related to sensorimotor gating, motor activity and food-motivated labyrinth learning. Two weeks after bilateral implantation of microcannulae into the VP, the acute (30 min) and delayed (3, 21 and 24 h) effects of quinpirole microinjection (1 μg/0.4 μL at both sides) were investigated in Wistar and schizophrenia model (Wisket substrain) rats in prepulse inhibition (PPI) and the reward-based Ambitus tests. Quinpirole administration did not modify the impaired sensorimotor gating in Wisket rats, but it led to significant deficit in Wistar animals. Regarding the locomotor activity in the Ambitus test, no effects of quinpirole were detected in either groups at the investigated time points. In contrast, quinpirole resulted in decreased exploratory and food-collecting activities in Wistar rats with 21 and 24 h delay. Though, impaired food-related motivation could be observed in Wisket rats, but quinpirole treatment did not result in further deterioration. In summary, our results showed that the VP D2R activation in Wistar rats induces symptoms similar to those observed in schizophrenia model Wisket rats. These data suggest that Wisket rats might have significant alterations in the functional activity of VP, which might be due to its enhanced dopaminergic activity.

The role of dopamine (DA) receptors in spatial memory consolidation has been demonstrated in numerous brain regions, among others in the nucleus accumbens which innervates the ventral pallidum (VP). The VP contains both D1 and D2 DA receptors. We have recently shown that the VP D1 DA receptor activation facilitates consolidation of spatial memory in Morris water maze test. In the present study, the role of VP D2 DA receptors was investigated in the same paradigm. In the first experiment, the D2 DA receptor agonist quinpirole was administered into the VP of male Wistar rats in three doses (0.1, 1.0 or 5.0μg, respectively in 0.4μl physiological saline). In the second experiment, the D2 DA receptor antagonist sulpiride was applied to elucidate whether it can antagonise the effects of quinpirole. The antagonist (4.0μg, dissolved in 0.4μl physiological saline) was microinjected into the VP either by itself or prior to 1.0μg agonist treatment. Control animals received saline in both experiments. The two higher doses (1.0 and 5.0μg) of the agonist accelerated memory consolidation relative to controls and increased the stability of the consolidated memory against extinction. Sulpiride pretreatment antagonised the effects of quinpirole. In addition, the antagonist microinjected into the VP immediately after the second conditioning trial impaired learning functions. The present data provide evidences for the important role of VP D2 DA receptors in the consolidation and stabilization of spatial memory.

Neuropeptide oxytocin (OT) is involved in the regulation of social and non-social behaviour. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. CeA has been shown to be rich in OT receptors in rodents. Our previous findings indicated that OT in the rat CeA has a dose dependent rewarding and anxiolytic effect. The aim of our present study was to examine in the CeA the possible interaction of OT and D2 dopamine (DA) receptor antagonist Sulpiride on reinforcement in place preference test and on anxiety in elevated plus maze test. Wistar rats were microinjected bilaterally with 10 ng OT. In different group of animals 4 μg D2 DA receptor antagonist was applied. Other animals received D2 DA receptor antagonist 15 min before 10 ng OT treatment or vehicle solution into the CeA. Rats receiving 10 ng OT spent significantly longer time in the treatment quadrant during the test session in conditioned place preference test. Prior treatment with D2 DA receptor antagonist blocked the rewarding effects of OT. Antagonist in itself did not influence the time rats spent in the treatment quadrant. In elevated plus maze test, rats receiving 10 ng OT spent significantly longer time on the open arms. Prior treatment with D2 DA receptor antagonist blocked the effects of OT. Our results show that DA system plays a role in positive reinforcing and anxiolytic effects of OT because D2 DA receptor antagonist can block these actions.

Neurotensin (NT) acts as a neurotransmitter and neuromodulator in the central nervous system. NT is involved in reward and memory processes, drug addiction and also in the regulation of anxiety. The ventral pallidum (VP) receives neurotensinergic innervation from the ventral striatopallidal pathway originating from the nucleus accumbens. Positive reinforcing effects of NT in the VP had been shown recently, however the possible effects of NT on anxiety have not been examined yet. In our present experiments, the effects of NT on anxiety were investigated in the VP. In male Wistar rats bilateral microinjections of 100 ng or 250 ng NT were delivered in the volume of 0.4 μl into the VP, and elevated plus maze (EPM) test was performed. In another groups of animals, 35 ng NT-receptor 1 (NTR1) antagonist SR 48,692 was applied by itself, or microinjected 15 min before 100 ng NT treatment. Open field test (OPF) was also conducted. The 100 ng dose of NT had anxiolytic effect, but the 250 ng NT did not influence anxiety. The antagonist pretreatment inhibited the effect of NT, while the antagonist itself had no effect. In the OPF test there was no difference among the groups. Our present results show that microinjection of NT into the VP induces anxiolytic effect, which is specific to the NTR1 receptors because it can be eliminated by a specific NTR1 antagonist. It is also substantiated that neither the NT, nor the NTR1 antagonist in the VP influences locomotor activity.

The MAM-E17 model is one of the most accepted schizophrenia rat models, which follows the neurodevelopmental theory of the disease. While symptoms of MAM-E17 rats were studied extensively, their examinations were usually restricted to adulthood and in a few cases to prepuberty. It is well known, however, that schizophrenia symptoms often start at puberty or early adulthood. Therefore the purpose of this study was to investigate the behavioral characteristics of MAM-E17 rats in various tests throughout three different age-periods, namely in prepuberty, late puberty and adulthood. In open field test, MAM-E17 rats displayed increased locomotor activity, elevated sniffing frequency and, as tendency, enhanced rearing activity. The elevated activity turned up in late puberty and remained there in adulthood, too. There was also a deficient prepulse inhibition (PPI) of startle response in late puberty and adulthood, but not before puberty. In rotarod task, MAM-treated rats performed better than control rats. The enhanced performance on rotarod was only present in late puberty and adulthood. In elevated plus maze test MAM-treated rats displayed diminished anxiety mostly in prepuberty. Histological analysis revealed reduced volume and cell disarray in the dorsal hippocampus. This is the first comprehensive study about symptoms of MAM-E17 rats manifested in behavioral tests carried out in prepuberty, late puberty and adulthood. Results display the age-dependent appearance of schizophrenia symptoms in the same rats. The present findings provide basic information to accomplish the schizophrenia related animal research, as well as can also confer further data to develop preventive treatment for human patients.

Even though several of RFamide peptides have been shown to modify memory and learning processes in different species, almost nothing is known regarding cognitive effects of recently discovered neuropeptide QRFP. Considering multiple physiological functions of QRFP, localization of QRFP-synthesizing neurons in the hypothalamus and its' widely spread binding sites within the CNS, the present study was designed to investigate the possible role of QRFP in the consolidation of spatial memory. As target area for microinjection, the medial hypothalamic area, including dorsomedial (DMN) and ventromedial (VMN) nuclei, has been chosen. At first, the effects of two doses (200 ng and 400 ng) of QRFP were investigated in Morris water maze. After that receptor antagonist BIBP3226 (equimolar amount to the effective dose of neuropeptide) was applied to elucidate whether it can prevent effects of QRFP. To reveal possible changes in anxiety level, animals were tested in Elevated plus maze. The higher dose of QRFP (400 ng) improved short-term memory consolidation in Morris water maze. Pretreatment with antagonist BIBP3226 abolished cognitive effects of QRFP. The neuropeptide did not affect anxiety level of rats. This study provides unique evidence regarding the role of QRFP in the consolidation of memory and gives the basis for further investigations of neuropeptide's cognitive effects.

The medial prefrontal cortex (mPFC) is thought to be an essential brain region for sensorimotor gating. The exact neuronal mechanisms, however, have not been extensively investigated yet by delicate single unit recording methods Prepulse inhibition (PPI) of the startle response is a broadly used important tool to investigate the inhibitory processes of sensorimotor gating. The present study was designed to examine the neuronal mechanisms of sensorimotor gating in the mPFC in freely moving rats. In these experiments, the animals were subjected to both pulse alone and prepulse+pulse stimulations. Head acceleration and the neuronal activity of the mPFC were simultaneously recorded. To adequately measure the startle reflex, a new headstage with 3D-accelerometer was created. The duration of head acceleration was longer in pulse alone trials than in prepulse+pulse trial conditions, and the amplitude of head movements was significantly larger during the pulse alone than during the prepulse+pulse situations. Single unit activities in the mPFC were recorded by means of chronically implanted tetrodes during acoustic stimulation evoked startle response and PPI. High proportion of medial prefrontal cortical neurons responded to these stimulations by characteristic firing patterns: short duration equal and unequal excitatory, medium duration excitatory, and long duration excitatory and inhibitory responses were recorded. The present findings, first time in the literature, demonstrated the startle and PPI elicited neuronal activity changes of the mPFC, and thus, provided evidence for a key role of this limbic forebrain area in sensorimotor gating process.

Schizophrenia is a serious neuropsychiatric disorder. Several brain structures, neurotransmitter systems, genetic and environmental risk factors are suspected in the background. Because of its complexity the mechanism of the disorder is not known exactly, so the treatment of patients is unsolved. In the research of schizophrenia application of the rodent models is widespread. In this study one of these models based on the effect of methylazoxymethanol- acetate (MAM) is described, which is a neurodevelopmental, validated rat model. This antimitotic agent is able to evoke a number of schizophrenic symptomes temporarily disrupting the prenatal neurogenesis. The model reproduces numerous histological and neurophysiological changes of the human disorder, moreover it also represents several behavioral and cognitive phenomena resembling those in schizophrenia. A salient advantage of the model is the demonstration of the diachronic feature of the disorder, that is, postpubertal appearance of the positive symptoms. This model provides widespread opportunities for manipulations of the symptoms, so that using it in the future investigations can lead to a better understanding of this disorder.

Although mast cells are immune cells of hematopoietic origin, they can be found in parts of the central nervous system of many mammalian species. In the rat brain they are located in the thalamic region. Their function is not defined yet, although they are mostly known to secrete several chemicals, which may influence the surrounding neurons. There are no in vivo electrophysiological data available on the possible effects of brain mast cells on neurons. In this study, we used a combined method of microiontophoresis and extracellular single unit recording to simultaneously activate mast cells and record neuronal action potentials. Four-barrelled micropipettes were used for recording neuronal activity and for microiontophoretic application of mast cell degranulator Compound 48/80 (C48/80). Spike sorting routines were performed on-line and off-line to ensure that data were always recorded from a single neuron. C48/80 did not modify the firing rate of cortical neurons (no mast cells are found there), however, it caused excitation ( n = 16/37, 43%), or inhibition ( n = 9/37, 24%) in thalamic neurons possibly due to mast cell activation. Further investigations will clarify the biochemical nature of changes in neural excitability due to mast cell degranulation in the mammalian brain.