Histamine H3 receptors, the complex interaction with dopamine and its implications for addiction.

Histamine H3 receptors are best known as presynaptic receptors inhibiting the release of histamine, as well as other neurotransmitters including acetylcholine and dopamine. However, in the dorsal and ventral striatum, the vast majority of H3 receptors are actually located postsynaptically on medium sized spiny output neurons. These cells also contain large numbers of dopamine (D1 and D2) receptors and it has been shown that H3 receptors form heterodimers with both D1 and D2 receptors. Thus, the anatomical localization of H3 receptors suggests a complex interaction that could both enhance and inhibit dopaminergic neurotransmission. Dopamine, especially within the striatal complex, plays a crucial role in the development of addiction, both in the initial reinforcing effects of drugs of abuse, as well as in maintenance, relapse and reinstatement of drug taking behaviour. It is, therefore, conceivable that H3 receptors can moderate the development and maintenance of drug addiction. In the present review, we appraise the current literature on the involvement of H3 receptors in drug addiction and try to explain these data within a theoretical framework, as well as provide suggestions for further research.

Effect of apomorphine on cognitive performance and sensorimotor gating in humans.

INTRODUCTION: Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have been performed to assess dopamine receptor functioning, classically using the release of growth hormone (GH) from the hindbrain as primary outcome measure. The objective of the current study was to assess dopamine receptor functioning at the forebrain level. METHODS: Fifteen healthy male volunteers received apomorphine sublingually (2 mg), subcutaneously (0.005 mg/kg), and placebo in a balanced, double-blind, cross-over design. Outcome measures were plasma GH levels, performance on an AX continuous performance test, and prepulse inhibition of the acoustic startle. The relation between central outcome measures and apomorphine levels observed in plasma and calculated in the brain was modeled using a two-compartmental pharmacokinetic-pharmacodynamic analysis. RESULTS: After administration of apomorphine, plasma GH increased and performance on the AX continuous performance test deteriorated, particularly in participants with low baseline performance. Apomorphine disrupted prepulse inhibition (PPI) on high-intensity (85 dB) prepulse trials and improved PPI on low intensity (75 dB) prepulse trials, particularly in participants with low baseline PPI. High cognitive performance at baseline was associated with reduced baseline sensorimotor gating. Neurophysiological measures correlated best with calculated brain apomorphine levels after subcutaneous administration. CONCLUSION: The apomorphine challenge test appears a useful tool to assess dopamine receptor functioning at the forebrain level. Modulation of the effect of apomorphine by baseline performance levels may be explained by an inverted U-shape relation between prefrontal dopamine functioning and cognitive performance, and mesolimbic dopamine functioning and sensorimotor gating. Future apomorphine challenge tests preferentially use multiple outcome measures, after subcutaneous administration of apomorphine.

Serotonin transporter deficiency in rats contributes to impaired object memory.

Serotonin is well known for its role in affection, but less known for its role in cognition. The serotonin transporter (SERT) has an essential role in serotonergic neurotransmission as it determines the magnitude and duration of the serotonin signal in the synaptic cleft. There is evidence to suggest that homozygous SERT knockout rats (SERT(-/-)), as well as humans with the short SERT allele, show stronger cognitive effects than wild-type control rats (SERT(+/+)) and humans with the long SERT allele after acute tryptophan depletion. In rats, SERT genotype is known to affect brain serotonin levels, with SERT(-/-) rats having lower intracellular basal serotonin levels than wild-type rats in several brain areas. In the present study, it was investigated whether SERT genotype affects memory performance in an object recognition task with different inter-trial intervals. SERT(-/-), heterozygous SERT knockout (SERT(+/-)) and SERT(+/+) rats were tested in an object recognition test applying an inter-trial interval of 2, 4 and 8 h. SERT(-/-) and SERT(+/-) rats showed impaired object memory with an 8 h inter-trial interval, whereas SERT(+/+) rats showed intact object memory with this inter-trial interval. Although brain serotonin levels cannot fully explain the SERT genotype effect on object memory in rats, these results do indicate that serotonin is an important player in object memory in rats, and that lower intracellular serotonin levels lead to enhanced memory loss. Given its resemblance with the human SERT-linked polymorphic region and propensity to develop depression-like symptoms, our findings may contribute to further understanding of mechanisms underlying cognitive deficits in depression.

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats.

RATIONALE: Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. OBJECTIVES: As individual differences exist in central serotonin neurotransmission, the impact of ATD may vary accordingly. In this experiment, we investigated the hypothesis that male serotonin transporter knockout (SERT(-/-)), rats marked by a lower SERT function, are more vulnerable to the effects of ATD in an object recognition task than male wildtype (SERT(+/+)) and heterozygous (SERT(+/-)) rats. MATERIALS AND METHODS: Twelve male SERT(+/+), SERT(+/-), and SERT(-/-) rats were treated with standard dose and low-dose ATD using a gelatine-based protein-carbohydrate mixture lacking tryptophan. In the control treatment, L: -tryptophan was added to the mixture. Four hours after treatment, the rats were subjected to the object recognition task. In addition, the effects of ATD on plasma amino acid concentrations were measured, and concentrations of 5-HT and 5-HIAA were measured in the frontal cortex and hippocampus of these rats. RESULTS: Plasma TRP levels and central 5-HT and 5-HIAA levels were decreased in all genotypes after ATD, but effects were stronger in SERT(-/-) rats. The standard dose of ATD impaired object recognition in all genotypes. SERT(-/-) and SERT(+/-) rats were more vulnerable to low dose of ATD in the object recognition task compared to SERT(+/+) rats. CONCLUSIONS: These results indicate a greater sensitivity to ATD in SERT(-/-) and SERT(+/-) rats, which may be related to stronger central depletion effects in these rats.

A study in male and female 5-HT transporter knockout rats: an animal model for anxiety and depression disorders.

Human studies have shown that a reduction of 5-HT transporter (SERT) increases the vulnerability for anxiety and depression. Moreover, women are more vulnerable to develop depression and anxiety disorders than men. For that reason we hypothesized that homozygous 5-HT transporter knockout rat (SERT(-/-)) models, especially female, are valuable and reliable animal models for humans with an increased vulnerability for anxiety- and depression-related disorders. As rats are extensively used in neuroscience research, we used the unique 5-HT transporter knockout rat, that was recently generated using N-ethyl-N-nitrosurea (ENU) -driven mutagenesis, to test this hypothesis. Behavioral testing revealed that male and female SERT(-/-) rats spent less time in the center of the open field and spent less time on the open arm of the elevated plus maze compared with wild-type 5-HT transporter knockout rats (SERT(+/+)). In the novelty suppressed feeding test, only male SERT(-/-) rats showed a higher latency before starting to eat in a bright novel arena compared with SERT(+/+) controls. Both male and female SERT(-/-) rats showed a higher escape latency from their home cage than SERT(+/+) littermates. Moreover, SERT(-/-) rats were less mobile in the forced swim test, and sucrose consumption was reduced in SERT(-/-) rats relative to SERT(+/+) rats. Both effects were sex-independent. Neurochemically, basal extracellular 5-HT levels were elevated to a similar extent in male and female SERT(-/-) rats, which was not influenced by the selective 5-HT reuptake inhibitor citalopram. 5-HT immunostaining revealed no difference between SERT(+/+) and SERT(-/-) rats in the dorsal raphe nuclei, in both males and females. These findings demonstrate that SERT(-/-) rats show anxiety and depression-related behavior, independent of sex. Genetic inactivation of the SERT has apparently such a great impact on behavior, that hardly any differences are found between male and female rats. This knockout rat model may provide a valuable model to study anxiety- and depression-related disorders in male and female rats.

Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system.

Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by N-ethyl-N-nitrosurea (ENU)-driven target-selected mutagenesis. Biochemical characterization revealed that SERT mRNA and functional protein are completely absent in homozygous knockout (SERT-/-) rats, and that there is a gene dose-dependent reduction in the expression and function of the SERT in heterozygous knockout rats. As a result, 5-HT homeostasis was found to be severely affected in SERT-/- rats: 5-HT tissue levels and depolarization-induced 5-HT release were significantly reduced, and basal extracellular 5-HT levels in the hippocampus were ninefold increased. Interestingly, we found no compensatory changes in in vitro activity of tryptophan hydroxylase and monoamine oxidase, the primary enzymes involved in 5-HT synthesis and degradation, respectively. Similarly, no major adaptations in non-serotonergic systems were found, as determined by dopamine and noradrenaline transporter binding, monoamine tissue levels, and depolarization-induced release of dopamine, noradrenaline, glutamate and GABA. In conclusion, neurochemical changes in the SERT knockout rat are primarily limited to the serotonergic system, making this novel rat model potentially very useful for studying the behavioral and neurobiological consequences of disturbed 5-HT homeostasis.

Ontogenic reduction of Aph-1b mRNA and gamma-secretase activity in rats with a complex neurodevelopmental phenotype.

Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about gamma-secretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre- and post-natal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in gamma-secretase cleavage activity towards one of its best-known substrates, the amyloid-beta precursor protein APP. We conclude that the low levels of Aph-1b mRNA and gamma-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.

The effects of stress on alcohol consumption: mild acute and sub-chronic stressors differentially affect apomorphine susceptible and unsusceptible rats.

The aim of this study was to investigate the effects of mild acute and mild sub-chronic challenges on alcohol intake and preference in the genetically selected ratlines of apomorphine susceptible (APO-SUS) and apomorphine unsusceptible (APO-UNSUS) animals. Animals from both lines were subjected to the 24 hr continuous alcohol vs. water paradigm under baseline conditions, after a single stressor and after multiple stressors. The intake of alcohol in ml was measured and converted to two values, namely intake in g/kg/24 hour of, and preference for, alcohol. This study shows that under baseline conditions the APO-UNSUS animals consume/prefer more alcohol than the APO-SUS animals. After an acute challenge the APO-SUS animals show a large increase in consumption, whereas the APO-UNSUS animals display only a small increase. Furthermore, sub-chronic challenges can further increase the consumption of the APO-UNSUS rat, but not that of the APO-SUS rat. The APO-SUS/ APO-UNSUS rats represent a good model to study the interaction between genetic factors and stress on directing alcohol consumption.

The development of various somatic markers is retarded in an animal model for schizophrenia, namely apomorphine-susceptible rats.

UNLABELLED: Although schizophrenia usually sets on after puberty, deviations of normal development exist in pre-schizophrenic children. To investigate the presence of early developmental abnormalities in a valid animal model for schizophrenia, we delineated line-specific developmental differences between apomorphine-susceptible rats (APO-SUS), which share many features with schizophrenic patients, and their counterpart, apomorphine-unsusceptible rats (APO-UNSUS). A battery of somatic developmental markers was assessed in naive animals on postnatal day (PND) 4 and in animals from PND 0 to PND 60. Three comparisons were made: naive APO-SUS and naive APO-UNSUS rats on PND 4; naive and handled APO-SUS and APO-UNSUS rats on PND 4; handled APO-SUS rats and handled APO-UNSUS rats across the initial 60 PND's. Naive APO-SUS rats developed much slower than naive APO-UNSUS rats as far as it concerns digit-separation, anogenital-distance, rooting-reflex, and body-displacement on PND 4, thereby underlining the validity of the APO-SUS rats as model for aspects of schizophrenia. Handling on PND 0-3 retarded the development of both types of rat, implying that early life events have long-lasting effects on pure-somatic markers. Finally, handling from PND 0 to PND 60 had a more pronounced retardation effect in APO-UNSUS rats than in APO-SUS rats. It is suggested that the APO-SUS rats are not affected as much as the APO-UNSUS rats, because they are already overwhelmed by other subliminal stimuli that have no effect on APO-UNSUS rats. IN CONCLUSION: (1) the APO-SUS rat, which is a valid model for schizophrenia, has a retarded development just as pre-schizophrenic children have; (2) early postnatal manipulations have immediate and long-lasting effects on the rodents' morphology; and (3) subchronic, early postnatal handling has a greater effect in APO-UNSUS rats than in APO-SUS rats. The impact of these data for APO-SUS rats as a model for schizophrenia is discussed.

Animal models in the genomic era: possibilities and limitations with special emphasis on schizophrenia.

Although the advances in molecular genetics have revolutionized many areas of the life sciences, they have, so far, been of limited use in the development of animal models for brain diseases. This is due to the fact that the genetics of most neurological and psychiatric diseases are highly complex, presumably involving multiple genes, most of which are still unknown. Moreover, in many brain diseases, non-genetic factors also play an important role. This leads to a general model in which several genetic factors interact with a number of early and late environmental factors, ultimately culminating in the disease. We have tried to illustrate how the existing genetic and environmental models for schizophrenia fit into this general etiological scheme, and how these models can be further improved by focusing specifically on the interaction between genetic and environmental factors.

Removal of short-term isolation stress differentially influences prepulse inhibition in APO-SUS and APO-UNSUS rats.

Epidemiological studies have reported that the risk of developing schizophrenia increases with the number of genes one shares with patients suffering from schizophrenia [Gottesman Schizophrenia Genesis, New York: Freeman; 1991]. In addition, stressful life events are known to increase the risk of developing schizophrenia [Schizophr Res 30 (1998) 251] resulting in the stress hypothesis of schizophrenia. Remarkably, stress increases the release of dopamine and noradrenaline in the nucleus accumbens [Brain Res 554 (1991) 217], which links the stress hypothesis with the known dopamine hypothesis of schizophrenia. Additionally an increased dopamine transmission in the nucleus accumbens (Nacc) is known to disturb prepulse inhibition (ppi) [Pharmacol Biochem Behav 49 (1994) 155], a phenomenon observed in, among others, schizophrenics [Arch Gen Psychiatry 47 (1990) 181]. Some years ago we have genetically selected two rat-lines which are marked by a high (APO-SUS) and by a low (APO-UNSUS) apomorphine susceptibility. Similar to schizophrenics the APO-SUS rat-line shows a reduced ppi [J Neurosci 15 (1995) 7604]. However, these data were obtained after a period of mild stress, namely a 24-h period of social isolation. Mild stress changes the line specific differences of APO-SUS and APO-UNSUS rats. The stress pushes the APO-SUS rat in the direction of an APO-UNSUS and vice versa, especially as far as it concerns the dopamine and noradrenaline activity in the nucleus accumbens [Cools AR, van-den Bos R, Ellenbroek BA, Gaiting function of noradrenaline in the ventral striatum: its role in behavioural responses to environmental and pharmacological challenges. In: Willner P, Scheel-Kruger J, editors. The mesolimbic dopamine system: from motivation to action. New York: Wiley; 1991 [Chapter 6]; Cools AR, Rots NY, De-Kloet ER, Apomorphine-susceptible and apomorphine-unsusceptible Wistar rats: a new tool in the search for the function of striatum in switching behavioural strategies. In: Pea G (Ed.), The basal ganglia IV, New York: Plenum Press; 1994; Brain Res Bull 24 (1990) 49; Behav Neurosci 108 (1994) 1107]. Therefore, in the present paper we investigated the ppi response in non-stressed, i.e. non-isolated APO-SUS and APO-UNSUS rats. In agreement with this hypothesis, we found that removal of the stress led to an increase of ppi in the APO-SUS, but a decrease in the APO-UNSUS. These data clearly shows that the ppi is stress-dependent in APO-SUS and APO-UNSUS rats. It is suggested that the differential stress-induced change in the dopaminergic and the noradrenergic system influences the reaction of APO-SUS and APO-UNSUS rats on ppi.

Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus.

It is well accepted that events that interfere with the normal program of neuronal differentiation and brain maturation may be relevant for the etiology of psychiatric disorders, setting the stage for synaptic disorganization that becomes functional later in life. In order to investigate molecular determinants for these events, we examined the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) and the glutamate NMDA receptor following 24 h maternal separation (MD) on postnatal day 9. We found that in adulthood the expression of BDNF as well as of NR-2A and NR-2B, two NMDA receptor forming subunits, were significantly reduced in the hippocampus of MD rats whereas, among other structures, a slight reduction of NR-2A and 2B was detected only in prefrontal cortex. These changes were not observed acutely, nor in pre-weaning animals. Furthermore we found that in MD rats the modulation of hippocampal BDNF in response to an acute stress was altered, indicating a persistent functional impairment in its regulation, which may subserve a specific role for coping with challenging situations. We propose that adverse events taking place during brain maturation can modulate the expression of molecular players of cellular plasticity within selected brain regions, thus contributing to permanent alterations in brain function, which might ultimately lead to an increased vulnerability for psychiatric diseases.

Early maternal deprivation alters hippocampal levels of neuropeptide Y and calcitonin-gene related peptide in adult rats.

Stressful events early in life are reported to be more prevalent among patients with an adult life psychiatric disorder. Early maternal deprivation is considered an animal model of early life stress. Maternally deprived adult rats display long-term alterations in the neuroendocrine system, brain and behavior that are in many ways analogous to depressive and schizophrenic symptomatology. Neuropeptide Y (NPY) and calcitonin-gene related peptide (CGRP) have been implicated in both disorders and also been suggested to play a role in the neuroadaptational response to stress. Consequently, male Wistar rat-pups were subjected to early maternal deprivation or control handling, on postnatal day (pnd) 9. On pnd 21, pups were weaned and split into two groups that were reared either on a saw-dust floor or on a grid-floor, considered to be a mild stressor. On pnd 67, all animals were subjected to the prepulse inhibition test. One week later, the animals were sacrificed, the brains removed and dissected on ice. Levels of NPY-like immunoreactivity (LI) and CGRP-LI were quantified by radioimmunoassay in brain regional extracts. Maternal deprivation led to a significant reduction in basal startle amplitude and disruption of prepulse inhibition. These findings were paralleled by significantly reduced levels of NPY and CGRP in the hippocampus and occipital cortex. It is hypothesised that these changes may be of relevance to aspects of schizophrenic and affective symptomatology. The present study further shows that brain NPY and, in particular, CGRP are sensitive to long-term mild stress and further implicate the involvement of these peptides in the neuroendocrine stress response.

Dopamine characteristics in rat genotypes with distinct susceptibility to epileptic activity: apomorphine-induced stereotyped gnawing and novelty/amphetamine-induced locomotor stimulation.

Rat genotypes differ in their susceptibility to spontaneously occurring spike-wave discharges and in their dopaminergic properties. In a previous study, it was found that spike-wave discharge incidence decreased in the following order in four rat genotypes during baseline and following injection with the dopamine antagonist haloperidol: apomorphine-susceptible (APO-SUS) > WAG/Rij > apomorphine-unsusceptible (APO-UNSUS) and ACI rats. The question in the present study was to what extent certain dopaminergic properties are pathognomonic for epileptic rats. Therefore, behavioral responses were assessed in order to investigate the dopaminergic properties in the four rat genotypes. Apomorphine-induced gnawing data imply that the dopamine activity of the nigrostriatal system in the WAG/Rij rats is higher than in APO-SUS but lower than in the ACI and APO-UNSUS rats. Furthermore, in previous studies APO-SUS have been shown to have a higher novelty/amphetamine-induced locomotion, indicative of a higher dopamine reactivity of the mesolimbic system as compared to APO-UNSUS rats. Results from the present study showed that WAG/Rij rats have a higher locomotor responsiveness to novelty/amphetamine, indicating a higher dopamine reactivity of the mesolimbic system in comparison to the ACI rats. It is suggested that the functional dopaminergic mesolimbic dominance is an important factor in the susceptibility to show spontaneously occurring spike-wave discharges.

Auditory information processing in rat genotypes with different dopaminergic properties.

RATIONALE: Auditory filtering disturbances, as measured in the sensory gating and prepulse inhibition (PPI) paradigms, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In both paradigms, the response to the second stimulus (S2) is attenuated by an inhibitory effect of the first stimulus (S1). Dopamine (DA) agonists have been found to reduce gating of auditory evoked potentials (AEPs) and PPI in healthy human subjects and in rats. These effects have been linked to DA hyperactivity in the mesolimbic system. A non-invasive approach in studying the role of the DA system in PPI and AEP gating is to compare rat genotypes that are marked by distinct DA systems. OBJECTIVES: Several questions were asked in the present study. Are PPI and AEP gating disturbed in (a) rats that are marked by a relatively high DA reactivity of the mesolimbic system, namely apomorphine-susceptible (APO-SUS) and WAG/Rij rats or in (b) rats that are marked by a relatively high DA activity of the nigrostriatal system, namely apomorphine-unsusceptible (APO-UNSUS) and ACI rats? Moreover, is the particular DA balance (c) between the nigrostriatal and mesolimbic system related to deficits in PPI and AEP gating? METHODS: For this purpose, the above-mentioned four rat genotypes (APO-SUS, APO-UNSUS, ACI and WAG/Rij) that vary in DA balance between both systems, were compared in the AEP gating paradigm. PPI was only measured in the ACI and WAG/Rij rats, since it has already been shown in a previous study that APO-SUS rats show diminished PPI as compared to rats of the APO-UNSUS genotype. RESULTS: AEP gating of the vertex N50 was significantly reduced in WAG/Rij rats as compared to the remaining three rat genotypes (APO-SUS, APO-UNSUS and ACI). No PPI deficits were found in the ACI and WAG/Rij rats, although ACI rats had a significantly higher basal startle amplitude. CONCLUSIONS: The PPI deficit in APO-SUS and not in the other genotypes, suggests that especially a relatively high DA reactivity of the mesolimbic system, together with a relatively low activity of the nigrostriatal system, contributes to this deficit. In contrast, the N50 gating deficit in WAG/Rij rats and not in the other genotypes suggests that a relatively high DA activity of the nigrostriatal system together with a relatively high DA reactivity of the mesolimbic system is necessary for the presence of a N50 gating deficit. On the basis of these results we have concluded that both auditory filtering processes are differently regulated by DA in the nigrostriatal and mesolimbic systems.

The role of medial prefrontal cortical dopamine in spontaneous flexibility in the rat.

In rat studies, both lesions in the medial prefrontal cortex (mPFC) and alterations of the level of mPFC dopamine (DA) have been found to induce disturbances in behavioural flexibility, as measured with switching tasks. It is not clear whether mPFC DA is also involved in spontaneous flexibility. Therefore, the aim of the present study was to investigate the role of mPFC DA in spontaneous flexibility. As a measure for spontaneous flexibility, the diversity in spatial distribution of exploration on a large open field was used. The rats received local injections into the mPFC with a D1 or D2 antagonist, or the dopamimetic, amphetamine. The results showed that both DA antagonists reduced spontaneous flexibility, due to increased stimulus-bound behaviour. Amphetamine had a similar effect to the DA antagonists. It is suggested that this is most likely due to an amphetamine-induced increase in extracellular DA, leading to a suboptimal level of mPFC DA.

Hippocampal and cortical sensory gating in rats: effects of quinpirole microinjections in nucleus accumbens core and shell.

Sensory processing disturbances, as measured in the P50/sensory gating paradigm, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In this paradigm, the response to the second of paired-click stimuli is attenuated by an inhibitory effect of the first stimulus. Sensory gating has been observed in most healthy human subjects and normal laboratory rats. Because mesolimbic dopamine has been implicated in other filtering disturbances such as prepulse inhibition of the acoustic startle response and given the fact that amphetamine and apomorphine have been shown to disrupt gating, this study was performed to investigate the role of mesolimbic dopamine in sensory gating. The dopamine D2 receptor agonist quinpirole (10 microg/0.5 microl) was injected bilaterally in nucleus accumbens core and shell and effects on cortical and hippocampal sensory gating were investigated. Also, effects of the dopamine D2 receptor antagonist haloperidol (0.1 mg/kg, subcutaneously) as pretreatment were studied. First, quinpirole significantly reduced both the amplitude to the first click and gating as measured in the cortex and in the hippocampus. There was a tendency for the quinpirole effects on hippocampal gating to be more pronounced in rats injected in the shell. Secondly, haloperidol did not antagonize effects of quinpirole on hippocampal parameters, whereas haloperidol pretreatment fully antagonized quinpirole effects on cortical parameters. In conclusion, gating can be significantly reduced when a dopamine agonist is specifically targeted at mesolimbic dopamine D2 receptors. However, an important consideration is that the dopaminergic effects in the present study on gating are predominantly mediated by the effects on the amplitude to the first click. This has also been suggested for systemic amphetamine injections in rats and schizophrenic patients. This casts doubt on whether dopamine receptor activation affects the putative inhibitory process between the first and the second stimulus.

Effects of JL13, a pyridobenzoxazepine with potential atypical antipsychotic activity, in animal models for schizophrenia.

JL13 [5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5] benzoxazepine fumarate] is a substance with a close structural resemblance to clozapine. However, it is less sensitive to oxidation and may therefore have less hematological side effects. In the present study, JL13 was compared with clozapine and haloperidol in several animal models for schizophrenia. The paw test represents a screening model for antipsychotic drugs that can discriminate between drugs with extrapyramidal side effects and drugs without. Haloperidol increased both forelimb retraction time and hindlimb retraction time (HRT), whereas both clozapine and JL13 increased only HRT. In the prepulse inhibition paradigm, all three drugs reversed the apomorphine- and the amphetamine-induced disruption of prepulse inhibition. However, whereas haloperidol was equally effective against both dopaminergic drugs, JL13 and clozapine were more effective against amphetamine. Finally, only JL13 was able to increase prepulse inhibition in normal rats, whereas only clozapine reduced basal startle amplitude. Taken together, these data suggest that JL13 may be an effective antipsychotic drug, with a profile similar to clozapine.

Neural correlates of sensory gating in the rat: decreased Fos induction in the lateral septum.

In the P(50) gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. Fos immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. Fos induction was analyzed in selected brain structures. In the auditory pathways, Fos-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. Fos-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of Fos-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of Fos induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia.