State-dependent effects of the D2 partial agonist aripiprazole on dopamine neuron activity in the MAM neurodevelopmental model of schizophrenia.

Aripiprazole is an antipsychotic drug characterized by partial agonist activity at D2 receptors to normalize both hyperdopaminergic and hypodopaminergic states. Traditional D2 antagonist antipsychotic drugs have been shown previously to reduce dopamine neuron activity through action on D2 autoreceptors to produce an overexcitation-induced cessation of cell firing, referred to as depolarization block. It is unclear whether aripiprazole reduces dopamine neuron activity via inhibition or, as seen following D2 antagonist administration, depolarization block. The impact of acute and repeated aripiprazole treatment was examined in the methylazoxymethanol acetate (MAM) rodent model to observe its effects on a hyperdopaminergic system, compared to normal rats. We found that administration of aripiprazole acutely or after 1 or 7 days of withdrawal from 21-day repeated treatment led to a decrease in the number of spontaneously active dopamine neurons in MAM rats but not in controls. This reduction was not reversed by apomorphine (100-200 µg/kg i.p. or 20 µg/kg i.v.) administration, suggesting that it was not due to depolarization block. In contrast, 1 h after induction of depolarization block of dopamine neurons by acute haloperidol treatment (0.6 mg/kg i.p.), aripiprazole (1 mg/kg, i.p.) reversed the depolarization block state. Therefore, aripiprazole rapidly reduced the hyperdopaminergic activity selectively in MAM rats. The reduction is unlikely due to depolarization block and persists following 7-day withdrawal from repeated treatment. Aripiprazole also removes haloperidol-induced depolarization block in MAM rats, which may underlie the acute psychotic state often observed with switching to this treatment.

Reduced frontal slow wave density during sleep in first-episode psychosis.

BACKGROUND: Sleep disturbances are commonly reported in psychotic patients and often contribute to the manifestation and severity of their symptoms. Slow waves characterize the deepest stage of NREM sleep, and their occurrence is critical for restorative sleep. Slow wave abnormalities have been reported in patient with schizophrenia, especially when experiencing an exacerbation of psychosis. However, their presence and delineation, with an emphasis on topography, in first-episode psychosis patients (FEP) have not yet been characterized. METHODS: We performed sleep high density (hd)-EEG recordings in twenty FEP patients and twenty healthy control subjects (HC). Slow wave activity (SWA) and several other slow wave parameters, e.g. density, amplitude, up- and down-slopes, were calculated at each electrode location and compared across groups. Additionally, the association between slow wave characteristics and clinical symptoms was assessed. RESULTS: FEP patients showed a reduction selectively in slow-wave density relative to HC, and this reduction was significant in a large frontal area, including channels overlying the prefrontal cortex. Furthermore, slow wave density was inversely correlated with the severity of FEP positive symptoms. CONCLUSIONS: Abnormalities in slow waves are present at the beginning of psychosis, occur in frontal-prefrontal regions that are highly dysfunctional in psychotic patients, and are associated with their positive symptom severity. Building on these findings, future work will help establish the direction of these associations (i.e., if clinical symptoms precede, coincide, or follow SW deficits), which will determine whether ameliorating slow wave sleep deficits is a viable treatment target in early psychosis.

Impaired contextual fear-conditioning in MAM rodent model of schizophrenia.

The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model. Male offspring of dams treated with MAM (20mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0-10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning. Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block. These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning.

Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model.

Alteration in normal hippocampal (HPC) function attributed to reduced parvalbumin (PV) expression has been consistently reported in schizophrenia patients and in animal models of schizophrenia. However, it is unclear whether there is an overall loss of interneurons as opposed to a reduction in activity-dependent PV content. Co-expression of PV and the constitutively expressed substance P (SP)-receptor protein has been utilized in other models to ascertain the degree of cell survival, as opposed to reduction in activity-dependent PV content, in the HPC. The present study measured the co-expression of PV and SP-receptors in the dentate and dorsal and ventral CA3 subregions of the HPC in the methylazoymethanol acetate (MAM) rat neurodevelopmental model of schizophrenia. In addition, these changes were compared at the post-natal day 27 (PND27) and post-natal day 240 (PND > 240) time points. Brains from PND27 and PND > 240 MAM (n = 8) and saline (SAL, n = 8) treated offspring were immunohistochemically processed for the co-expression of PV and SP-receptors. The dorsal dentate, dorsal CA3 and ventral CA3 subregions of PND27 and PND > 240 MAM rats demonstrated significant reductions in PV but not SP-receptor expression, signifying a loss of PV-content. In contrast, in the ventral dentate the co-expression of PV and SP-receptors was significantly reduced only in PND > 240 MAM animals, suggesting a reduction in cell number. While MAM-induced reduction of PV content occurs in CA3 of dorsal and ventral HPC, the most substantial loss of interneuron number is localized to the ventral dentate of PND > 240 animals. The disparate loss of PV in HPC subregions likely impacts intra-HPC network activity in MAM rats.

Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia.

Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel α5 gamma-aminobutyric acid (GABA(A)) receptor positive allosteric modulator (α5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6 mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both α5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to α5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective.

The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia.

Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABAA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity.

Differential effects of acute and repeated stress on hippocampus and amygdala inputs to the nucleus accumbens shell.

The basolateral amygdala (BLA) and ventral subiculum (vSub) of the hippocampus convey emotion and context information, respectively, to the nucleus accumbens (NAc). Using in vivo extracellular recordings from NAc neurons, we examined how acute and repeated restraint stress alters the plasticity of the vSub and BLA afferent pathways. High-frequency (HFS) and low-frequency (LFS) stimulation was applied to the vSub to assess the impact on NAc responses to vSub and BLA inputs. In addition, iontophoretic application of the dopamine D2-antagonist sulpiride was used to explore the role of dopamine in the NAc in mediating the effects of stress on plasticity. Acute and repeated restraint caused disparate effects on BLA- and vSub-evoked responses in the NAc. Following repeated restraint, but not after acute restraint, HFS of the vSub failed to potentiate the vSub­NAc pathway while instead promoting a long-lasting reduction of the BLA­NAc pathway and these effects were independent of D2-receptor activity. In contrast, LFS to the vSub pathway after acute restraint resulted in potentiation in the vSub­NAc pathway while BLA-evoked responses were unchanged. When sulpiride was applied prior to LFS of the vSub after acute stress, there was a pronounced decrease in vSub-evoked responses similar to control animals. This work provides new insight into the impact of acute and repeated stress on the integration of context and emotion inputs in the NAc. These data support a model of stress whereby the hippocampus is inappropriately activated and dominates the information processing within this circuit via a dopaminergic mechanism after acute bouts of stress.

Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure.

Stressors can exert a wide variety of responses, ranging from adaptive responses to pathological changes; moreover, recent studies suggest that mild stressors can attenuate the response of a system to major stressful events. We have previously shown that 2-week exposure to cold, a comparatively mild inescapable stressor, induced a pronounced reduction in ventral tegmental area (VTA) dopamine (DA) neuron activity, whereas restraint stress increases DA neuron activity. However, it is not known if these stressors differentially impact the VTA in a region-specific manner, if they differentially impact behavioral responses, or whether the effects of such different stressors are additive or antagonistic with regard to their impact on DA neuron firing. To address these questions, single-unit extracellular recordings were performed in anesthetized control rats and rats exposed to chronic cold, and tested after delivery of a 2-h restraint session. Chronic cold stress strongly attenuated the number of DA neurons firing in the VTA, and this effect occurred primarily in the medial and central VTA regions that preferentially project to reward-related ventral striatal regions. Chronic cold exposure also prevented the pronounced increase in DA neuron population activity without affecting the behavioral sensitization to amphetamine produced by restraint stress. Taken together, these data show that a prolonged inescapable mild stressor can induce plastic changes that attenuate the DA system response to acute stress.

Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia.

Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia [methyl-azoxymethanol acetate (20 mg/kg, i.p.) injected into G17 pregnant female rats, with offspring tested as adults], the extant hyperdopaminergic state combines with the excitatory actions of a first- (haloperidol; 0.6 mg/kg, i.p.) and a second- (sertindole; 2.5 mg/kg, i.p.) generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1, 3, 7, 15, and 21 d continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia.

A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia.

We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline- (SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the α5 subunit of the GABA(A) receptor, SH-053-2'F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2'F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the α5GABA(A)R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following α5GABA(A)R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following α5GABA(A)R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.

Heterogeneous processing of amygdala and hippocampal inputs in the rostral and caudal subregions of the nucleus accumbens.

The nucleus accumbens (NAc) receives converging input from a number of structures proposed to play a role in affective disorders. In particular, the basolateral amygdala (BLA) provides an affective input that overlaps with context-related information derived from the ventral subiculum of the hippocampus (vSub). We examined how stimulation of the BLA is modulated by, and in turn affects, vSub inputs to this region. In-vivo extracellular recordings were performed in the NAc of anaesthetized rats. The effect of high-frequency (theta-burst) stimulation (HFS) of the BLA on both BLA and vSub-evoked responses was tested. In addition, the involvement of dopamine D2 receptors in BLA-induced plasticity in the NAc was examined by pre-treatment with sulpiride (5 mg/kg i.v.). Finally, tetrodotoxin (TTX) was used to inactivate the vSub and the effect on BLA-evoked responses was assessed. We found that HFS of the BLA causes hetereogeneous patterns of plasticity, depression and potentiation, respectively, in the rostral and caudal subregions of the NAc that are disrupted following D2 receptor antagonist treatment. In addition, inactivating the vSub with TTX attenuates the ability of the BLA to drive spike firing in the NAc. Thus, the vSub is required for activation of the NAc by the BLA. These data support a model whereby the amygdala can coordinate reward-seeking and fear-related behaviours via its differential regulation of NAc output. In addition, the hippocampus inappropriately dominates information processing within this circuit, potentially contributing to the overwhelming focus on internal emotional states in disorders such as depression.

Immediate early gene activation in hippocampus and dorsal striatum: effects of explicit place and response training.

Evidence from lesion, electrophysiological, and neuroimaging studies support the hypothesis that the hippocampus and dorsal striatum process afferent inputs in such a way that each structure regulates expression of different behaviors in learning and memory. The present study sought to determine whether rats explicitly trained to perform one of two different learning strategies, spatial or response, would display disparate immediate early gene activation in hippocampus and striatum. c-Fos and Zif268 immunoreactivity (IR) was measured in both hippocampus and striatum 30 or 90 min following criterial performance on a standard plus-maze task (place learners) or a modified T-maze task (response learners). Place and response learning differentially affected c-Fos-IR in striatum but not hippocampus. Specifically, explicit response learning induced greater c-Fos-IR activation in two subregions of the dorsal striatum. This increased c-Fos-IR was dependent upon the number of trials performed prior to reaching behavioral criterion and accuracy of performance during post-testing probe trials. Quantification of Zif268-IR in both hippocampus and striatum failed to distinguish between place and response learners. The changes in c-Fos-IR occurred 30 min, but not 90 min, post-testing. The synthesis of c-Fos early in testing could reflect the recruitment of key structures in learning. Consequently, animals that were able to learn the response task efficiently displayed greater amounts of c-Fos-IR in dorsal striatum.

Context-dependent modulation by D(1) receptors: differential effects in hippocampus and striatum.

Place-specific firing by hippocampal and striatal neurons was recorded simultaneously following injection of a D(1) receptor antagonist (SCH23390) and during spatial working memory task performance. SCH23390-induced changes in unit responses were observed during light and dark test conditions. Although hippocampal place field locations were altered by the contextual change, the reliability and specificity of place fields was disrupted only by combining D(1) antagonism and a change in context. Striatal place field locations were reorganized after either contextual change or D(1) antagonism, without altering place field reliability and specificity. Disrupted velocity encoding by place cells in both regions was induced by darkness, whereas greater stability in acceleration encoding followed removal of D(1) receptor activity. Dopamine may differentially regulate hippocampal context learning and striatum-based predictive codes.

Parallel processing across neural systems: implications for a multiple memory system hypothesis.

A common conceptualization of the organization of memory systems in brain is that different types of memory are mediated by distinct neural systems. Strong support for this view comes from studies that show double (or triple) dissociations between spatial, response, and emotional memories following selective lesions of hippocampus, striatum, and the amygdala. Here, we examine the extent to which hippocampal and striatal neural activity patterns support the multiple memory systems view. A comparison is made between hippocampal and striatal neural correlates with behavior during asymptotic performance of spatial and response maze tasks. Location- (or place), movement, and reward-specific firing patterns were found in both structures regardless of the task demands. Many, but not all, place fields of hippocampal and striatal neurons were similarly affected by changes in the visual and reward context regardless of the cognitive demands. Also, many, but not all, hippocampal and striatal movement-sensitive neurons showed significant changes in their behavioral correlates after a change in visual context, irrespective of cognitive strategy. Similar partial reorganization was observed following manipulations of the reward condition for cells recorded from both structures, again regardless of task. Assuming that representations that persist across context changes reflect learned information, we make the following conclusions. First, the consistent pattern of partial reorganization supports a view that the analysis of spatial, response, and reinforcement information is accomplished via an error-driven, or match-mismatch, algorithm across neural systems. Second, task-relevant processing occurs continuously within hippocampus and striatum regardless of the cognitive demands of the task. Third, given the high degree of parallel processing across allegedly different memory systems, we propose that different neural systems may effectively compete for control of a behavioral expression system. The strength of the influence of any one neural system on behavioral output is likely modulated by factors such as motivation, experience, or hormone status.