Prepulse Inhibition Deficits In Rats Research Articles

DSP-6745, a novel 5-hydroxytryptamine modulator with rapid antidepressant, anxiolytic, antipsychotic and procognitive effects.

Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention. The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms. In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8mg/kg, p.o.) enhanced cognition. These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression.

7-Methoxyderivative of tacrine is a ‘foot-in-the-door’ open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory neurotransmission in the mammalian central nervous system (CNS), and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials (including memantine) and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine (tacrine; THA) was the first approved drug for Alzheimer's disease (AD) treatment. 7-methoxyderivative of THA (7-MEOTA) is less toxic and showed promising results in patients with tardive dyskinesia. We employed electrophysiological recordings in HEK293 cells and rat neurones to examine the mechanism of action of THA and 7-MEOTA at the NMDAR. We showed that both THA and 7-MEOTA are “foot-in-the-door” open-channel blockers of GluN1/GluN2 receptors and that 7-MEOTA is a more potent but slower blocker than THA. We found that the IC50 values for THA and 7-MEOTA exhibited the GluN1/GluN2A < GluN1/GluN2B < GluN1/GluN2C = GluN1/GluN2D relationship and that 7-MEOTA effectively inhibits human GluN1/GluN2A-M817V receptors that carry a pathogenic mutation. We also showed that 7-MEOTA is a “foot-in-the-door” open-channel blocker of GluN1/GluN3 receptors, although these receptors were not inhibited by memantine. In addition, the inhibitory potency of 7-MEOTA at synaptic and extrasynaptic hippocampal NMDARs was similar, and 7-MEOTA exhibited better neuroprotective activity when compared with THA and memantine in rats with NMDA-induced lesions of the hippocampus. Finally, intraperitoneal administration of 7-MEOTA attenuated MK-801-induced hyperlocomotion and pre-pulse inhibition deficit in rats. We conclude that 7-MEOTA may be considered for the treatment of diseases associated with the dysfunction of NMDARs.

Cortical electroconvulsive stimulation alleviates breeding-induced prepulse inhibition deficit in rats

In patients with medical-refractory schizophrenia electroconvulsive therapy (ECT), i.e., the induction of therapeutic seizures via cortical surface electrodes, is effectively used. Electroconvulsive stimulation (ECS) in rodents simulates ECT in humans and is applied to investigate the mechanisms underlying this treatment. Experimentally-induced reduced prepulse inhibition (PPI) of the acoustic startle response (ASR), i.e., the reduction of the startle response to an intense acoustic stimulus when this stimulus is shortly preceded by a weaker not-startling stimulus, serves as an endophenotype for neuropsychiatric disorders that are accompanied by disturbed sensorimotor gating, such as schizophrenia. Here we used rats selectively bred for high and low PPI to evaluate whether bifrontal cortical ECS would affect PPI.For this purpose, cortical screw electrodes were stereotactically implanted above the frontal cortex. After recovery ECS was applied for five consecutive days with stimuli of 1ms pulse-width, 100 pulses/s, 1s duration, ranging from 5.5mA to 10mA. PPI of ASR was measured one day before ECS, and on days 1, 7, and 14 after the last ECS.In rats with breeding-induced low PPI ECS increased PPI one week after stimulation. In contrast, ECS decreased PPI in rats with high PPI on the first day after stimulation. The reaction to the startle impulse was reduced by ECS without difference between groups. This work provides evidence that rats with breeding-induced high or low PPI could be used to further investigate the underlying mechanisms of ECT in neuropsychiatric disorders with disturbed sensorimotor gating like schizophrenia.

Sleep Deprivation Disrupts Prepulse Inhibition and Induces Psychosis-Like Symptoms in Healthy Humans

Translational biomarkers, such as prepulse inhibition (PPI) of the acoustic startle response, are playing an increasingly important role in the development of antipsychotic drugs for schizophrenia and related conditions. However, attempts to reliably induce a PPI deficit by psychotomimetic drugs have not been successful, leaving an unmet need for a cross-species psychosis model sensitive to this widely studied surrogate treatment target. Sleep deprivation (SD) might be such a model as it has previously been shown to induce PPI deficits in rats, which could be selectively prevented with antipsychotic but not anxiolytic or antidepressant compounds. Here, in a first proof-of-concept study we tested whether SD induces a deficit in PPI and an increase in psychosis-like symptoms in healthy humans. In two counterbalanced sessions, acoustic PPI and self-reported psychosis-like symptoms (Psychotomimetic States Inventory) were measured in 24 healthy human volunteers after a normal night's sleep and after a night of total SD. SD decreased PPI (p = 0.001) without affecting the magnitude or habituation of the startle response (all p > 0.13). SD also induced perceptual distortions, cognitive disorganization, and anhedonia (all p < 0.02). Thus, extending previous rodent work, we conclude that SD, in combination with the PPI biomarker, might be a promising translational surrogate model for psychosis as this method represents a possibility to partially and reversibly mimic the pathogenesis of psychotic states.

Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats

Lamotrigine (LTG) is sometimes co-administered with antipsychotic drugs for the treatment of schizophrenia. Nevertheless, the pharmacological basis of LTG use for schizophrenia has not been reported. Our group recently proposed a new psychostimulant animal model that might reflect the progressive pathophysiology of schizophrenia. Results obtained using that model show that LTG blocks the initiation and expression of repeated high-dosage methamphetamine-induced prepulse inhibition deficit in rats (Nakato et al., 2010, Neurosci. Lett. [25]). Using the model, the effect of LTG (30mg/kg) on methamphetamine (METH, 2.5mg/kg)-induced increases in extracellular glutamate levels in the medial prefrontal cortex (mPFC) was examined in this study. Then the effect of repeated co-administration of LTG (30mg/kg) on repeated METH (2.5mg/kg)-induced apoptosis in this region of rats was investigated. Results show that LTG (30mg/kg) blocked the METH (2.5mg/kg)-induced glutamate increase in the mPFC. Repeated co-administration of LTG (30mg/kg) blocked the development of apoptosis induced by repeated administration of METH (2.5mg/kg) in the mPFC. The LTG blocks histological abnormalities induced by repeated administration of METH, which suggests a mechanism of LTG that protects against progressive pathophysiology in schizophrenia.

Lamotrigine blocks the initiation and expression of repeated high-dose methamphetamine-induced prepulse inhibition deficit in rats

Our group developed a new psychostimulant animal model reflecting some clinical aspects of schizophrenia better than the conventional model does. In this model, long-lasting prepulse inhibition (PPI) deficit at the basement state is induced via repeated administration of methamphetamine (METH, 2.5 mg/kg) without challenge injection of this psychostimulant. This study elucidates the effects of lamotrigine (LTG, 30 mg/kg) on the initiation and expression of a steady-state PPI deficit induced by the repeated METH administration. We assessed the effect of coadministration of LTG and METH on the initiation of PPI deficit. The LTG was injected 120 min after each METH injection for 5 times on every alternate day and for an additional 5 times every day, amounting to a total of 10 times. After 11–13 days of the withdrawal period, we measured PPI using the SR-LAB system. Using other animals after 20 min of LTG injection, we subsequently examined the effect of a single injection of LTG on the expression of PPI deficit caused by the repeated METH administration. The LTG blocked the initiation of PPI deficit induced by the repeated METH administration at 68 dB of prepulse intensity, but had no effect on the startle amplitude. The LTG prevented the initiation and expression of neuroplastic PPI deficit detected at the baseline state without any METH challenge injection, which was induced by the repeated administration of this psychostimulant. Results suggest that LTG is useful for blocking progressive deterioration of neurocognitive function and recovering the neurocognitive deficit in schizophrenia.

Evaluation of the Selective A2A Receptor Antagonist, SCH 412348, and the D2/D3 Receptor Agonist Pramipexole in Rat Models of Psychotic and Obsessive Behavior

Dopamine D2/D3 receptor agonists, used to treat Parkinson's Disease (PD), have serious side effects, including hallucinations and obsessive behavior. Adenosine A2A receptor antagonists have been proposed as a PD treatment, but little has been done to evaluate potential psychiatric side‐effects. We tested the D2/D3 receptor agonist pramipexole, and the selective A2A receptor antagonist SCH 412348 in rodent prepulse inhibition (PPI). Pramipexole (0.3–3 mg/kg) induced a significant PPI deficit in rats and mice. PPI is used to preclinically model psychotic‐like behavior. Ropinirole (1–30 mg/kg) and SCH 412348 (0.3–3 mg/kg) had no effect. Currently there is no preclinical model of the obsessive behavior side effect associated with D2/D3 receptor agonists. To address this, we trained water‐deprived rats that licking a water spout would result in a mild footshock. We hypothesized that pramipexole‐treated animals would favor the rewarding stimulus over the punishing stimulus manifested as increased licking relative to vehicle‐treated animals. The resembles the clinical phenomenon in which individuals treated with a D2/D3 agonist appear to become hypersensitive to the rewarding effects of behaviors, but discount the negative consequences. Pramipexole (3 mg/kg) significantly increased licking; neither SCH 412348 nor ropinerole did. This represents a novel animal model of pramipexole‐induced obsessive behaviors. Taken together, these data indicate that treatment with an A2A receptor antagonist will not have the psychotic or obsessive side effects associated with pramipexole.

Selective breeding for deficient sensorimotor gating is accompanied by increased perseveration in rats

Prepulse inhibition (PPI) of the acoustic startle response is a measure of sensorimotor gating that is deficient in some neuropsychiatric disorders, such as schizophrenia and Tourette’s syndrome. Experimentally induced PPI deficits in rats are regarded as endophenotype to study the biological mechanisms and therapeutic strategies of these disorders. We have recently shown that selectively breeding rats for high and low PPI levels, respectively, leads to groups with different PPI performance that remains stable from the second generation on. We here tested whether the low PPI is accompanied by other behavioral deficits. Different spatial and operant learning paradigms were used to assess rats’ learning and memory abilities as well as their behavioral flexibility. In the delayed alternation T-maze task the two groups did not differ in task acquisition and working memory. Rats with low PPI showed enhanced perseveration during switching between an egocentric and allocentric radial maze task. Enhanced perseveration was also found in an operant behavioral task, where different demands, i.e. a different number of lever presses for a pellet-reward, were assigned to and switched between two levers of a Skinner box. Rats with low PPI stayed longer at the ineffective lever before switching, thus being less able to adjust their behavior to changing reward values. Additionally, PPI low rats had a higher breakpoint value during a progressive ratio-schedule of reinforcement. Rats selectively bred for low PPI showed some cognitive deficits that are apparent in a number of psychiatric disorders with deficient information processing. Specifically in both, spatial and operant behavioral paradigms, PPI low rats are deteriorated in their ability to modulate behavior based upon new changing information. They may thus provide a non-pharmacological model that can be used to evaluate new therapeutic strategies ranging from pharmacological treatment to functional neurosurgery.

(±) Ketamine-induced prepulse inhibition deficits of an acoustic startle response in rats are not reversed by antipsychotics

Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (the prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in psychiatric disorders such as schizophrenia. Ketamine, a non-competitive N-methyl-D-aspartate antagonist has been shown to induce schizophrenia-like behavioural changes in humans and PPI deficits in rats, which can be reversed by antipsychotics. Thus, ketamine-induced PPI deficits in rats may provide a translational model of schizophrenia. The aim of this study was to investigate the effects of antipsychotic drugs and drugs known to alter the glutamate system upon ketamine-induced PPI deficits in rats. Rats were habituated to the PPI procedure [randomized trials of either pulse alone (110 dB/50 ms) or prepulse + pulse (80 dB/10 ms)]. Animals were assigned to pre-treatments based on the level of PPI on the last habituation test and balanced across startle chambers. Ketamine (1-10 mg/kg s.c; 15 min ptt) increased startle amplitude and induced PPI deficits at 6 and 10 mg/kg. PPI deficits induced by ketamine at 6 mg/kg were not attenuated by clozapine (2.5-10 mg/kg s.c.; 60 min ptt), risperidone (0.1-1 mg/kg i.p.; 60 min ptt), haloperidol (0.1-1 mg/kg i.p.; 60 min ptt), lamotrigine (3-30 mg/kg p.o.; 60 min ptt), or SB-271046-A (5-20 mg/kg p.o.; 2 hour ptt) nor potentiated by 2-methyl-6-(phenylethynyl)-pyridine (3-10 mg/kg i.p.; 30 min ptt). These results suggest that under these test conditions ketamine-induced PPI deficits in rats is relatively insensitive and does not represent a translational model for drug discovery in schizophrenia.

High glycine levels are associated with prepulse inhibition deficits in chronic schizophrenia patients

Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is decreased in schizophrenia. The validity of a glutamatergic, N-methyl- d-aspartate receptor (NMDAR)-mediated model of PPI disruption is presently equivocal. The NMDAR antagonist ketamine disrupts PPI in rodents, but may increase PPI in healthy volunteers. Glycine (GLY), which acts as an obligatory co-agonist at the NMDAR-GLY site, induces PPI deficits in rats although, consistent with the hypo-NMDAR hypothesis, improves negative and cognitive symptoms in schizophrenia patients. We assessed the hypothesis that GLY serum levels may affect PPI parameters in schizophrenia. Forty-five chronically ill medicated schizophrenia patients and 37 matched healthy comparison subjects were tested for PPI of the eyeblink component of the startle reflex measured by electromyogram recording. Patients' demographic variables, symptom severity scores and GLY, serine and glutamate serum levels were obtained. Patients showed deficient PPI in blocks two and three of the PPI session and differed from controls in terms of change of degree of PPI as a function of the prepulse to eliciting stimulus interval. GLY levels correlated negatively with PPI parameters, such that patients with the highest GLY levels showed decreased PPI ( rs = − 0.4, p = 0.03). These preliminary findings indirectly support previous observations on ketamine effects upon PPI in humans and suggest a dissociation of symptomatology and PPI changes as function of NMDAR modulation in schizophrenia.

Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats: an update

Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders. We have previously reported that ten cohorts of Lister Hooded rats reared in isolation showed robust and reliable PPI deficits. Our methodology differed from those used by others (Weiss and Feldon in Psychopharmacology 156(2-3):305-326, 2001), most notably in the weaning of pups at postnatal day (PND) 28 compared with PND20-22. Since our initial report, we have studied 18 more cohorts weaned at PND28 and one cohort weaned at PND21. At weaning, male Lister Hooded pups were singly (isolates) or group (n=5) housed (grouped). Eight weeks later, startle and PPI responses of isolates and grouped rats were investigated using conditions of fixed inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse (PP)=75-80 dB/30 ms; ISI=100 ms). Isolates from 14 of the subsequent 18 cohorts demonstrated PPI deficits, giving an overall success rate of 86% for all 28 cohorts. %PPI ranged from 12 to 26% in the isolates and from 26 to 47% in the grouped for the successful cohorts, compared to 16-30% (isolates) and 19-35% (grouped) for those that failed. Only five out of the 19 subsequent cohorts demonstrated startle hyperreactivity, which was unrelated to PPI response. The isolates from the cohort weaned at PND21 did not show a significant deficit in PPI, suggesting, in our hands at least, a requirement for weaning at PND28. The data presented here reinforce our original findings that isolation-rearing of Lister Hooded rats provides a viable, non-pharmacological model of impaired PPI.

Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal–lesioned rats: reversal by glycine and a glycine transporter inhibitor

Background Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N-methyl- d-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion–induced PPI deficits in rats. Methods Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood. Results Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively. Conclusions These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.

Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.

Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.

Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats

Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders. However, recent studies have questioned the robustness of this paradigm. The existence of a substantial dataset generated over 4 years in our laboratory has allowed the investigation of the robustness and reliability of the procedure under a variety of environmental conditions. The effects of atypical antipsychotics (clozapine, olanzapine and risperidone) under different experimental conditions are also reported. At weaning, Hooded Lister pups were singly (isolates) or group (n=5) housed (grouped). Eight weeks later, the startle and PPI response of isolates and grouped rats was investigated using conditions of fixed inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse=80 dB/30 ms; ISI=100 ms) or variable

Circadian Time Does Not Modify the Prepulse Inhibition Response or Its Attenuation by Apomorphine

The present study investigated the influence of circadian time (experimental testing during the light or dark phase of the light:dark cycle) on the acoustic startle response (ASR), prepulse inhibition (PPI), and apomorphine-induced PPI deficits in Wistar rats housed under a reversed light:dark cycle (lights off at 0700 h and on at 1900 h). There was no significant difference in the startle response amplitude or PPI response of animals tested during the light phase compared with those tested during the dark phase. Similarly, the response to apomorphine (0.01–0.05 mg/kg subcutaneously) was not modulated by circadian time. Thus, under the conditions adopted in the present study, ASR, PPI, and apomorphine-induced PPI deficits remained stable across the circadian cycle. Such findings may be of importance for other investigators using the PPI paradigm to study brain plasticity mechanisms and pharmacological manipulations of apomorphine-induced PPI deficits in rats housed under normal or reversed light:dark cycle conditions.

Role of the strychnine-insensitive glycine binding site in the nucleus accumbens and anterodorsal striatum in sensorimotor gating: a behavioral and microdialysis study.

This study examined the role of the strychnine-insensitive glycine binding site of the NMDA receptor in prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. PPI is an operational measure of gating processes which normally lead to a diminished ASR when a startling stimulus is preceded by a weak prepulse. PPI is impaired in schizophrenics and, therefore, experimentally induced PPI deficits in rats can be regarded as a model for gating deficits in schizophrenia. Local administration of 7-chlorokynurenate (7-CLKYN), an antagonist of the strychnine-insensitive glycine site of the NMDA receptor, into the nucleus accumbens reduced PPI. This sensorimotor gating deficit was antagonized by systemic pretreatment of the rats with the glycine site agonist D-cycloserine, indicating that the effect of 7-CLKYN was due to a blockade of the NMDA receptor associated glycine binding site. A similar deficit in PPI was observed after intra-accumbal administration of the competitive NMDA receptor antagonist AP-5. PPI was normal after injecting these drugs into the anterodorsal striatum. The hypothesis that the PPI deficit is accompanied by a change in dopamine release was tested by a neurochemical analysis of the effects of local injection of 7-CLKYN. Microdialysis data showed no increase of accumbal and striatal dopamine release after blockade of the glycine site with 7-CLKYN. Our data demonstrate that the glycine/NMDA receptor in the nucleus accumbens plays a important role in sensorimotor information processing that depends not on a hyperactive dopamine system.

GABAergic projection from nucleus accumbers to ventral pallidum mediates dopamine-induced sensorimotor gating deficits of acoustic startle in rats

Previous studies have demonstrated that increased mesolimbic dopamine (DA) activity disrupts sesorimotor gating as measured by prepulse inhibition (PPI)_of the acoustic startle response (ASR) in rats. Other behavioral changes following mesolimbic DA activation are mediated through GABAergic efferent projections from the nucleus accumbens (NAC) to the pallidum (VP). In this experiment, we examined whether PPI deficits in rats following mesolimbic DA activation mediated through these GABAergic subtances. PPI was significantly disrupted in the rats following infusion of DA (40 μg) into the NAC, and this effect was reversed by infusion of a low dose (10 ng) of the GABA agonist muscimol into the VP. In a second experiment, we tested the hypothesis and the loss of PPi following intra-NAC DA infusion results from a disruption of GABAergic activity within the VP. Consistent with this hypotheasis, infusion of the GABA antagonist picrotoxin (0–0.2 μg) into the VP caused a significant loss of PPI. These findings strongly suggest that the accumbens-ventralk pallidal GABAergic circiutry is a subtance for the decrease in sensorimotor gating induced by mesolimbic DA overativity.