Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability.

The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KO mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD.

Identification of a novel, fast-acting GABAergic antidepressant.

Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl-gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response-binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression.

Identifying fast-onset antidepressants using rodent models.

Depression is a leading cause of disability worldwide and a major contributor to the burden of suicide. A major limitation of classical antidepressants is that 2-4 weeks of continuous treatment is required to elicit therapeutic effects, prolonging the period of depression, disability and suicide risk. Therefore, the development of fast-onset antidepressants is crucial. Preclinical identification of fast-onset antidepressants requires animal models that can accurately predict the delay to therapeutic onset. Although several well-validated assay models exist that predict antidepressant potential, few thoroughly tested animal models exist that can detect therapeutic onset. In this review, we discuss and assess the validity of seven rodent models currently used to assess antidepressant onset: olfactory bulbectomy, chronic mild stress, chronic forced swim test, novelty-induced hypophagia (NIH), novelty-suppressed feeding (NSF), social defeat stress, and learned helplessness. We review the effects of classical antidepressants in these models, as well as six treatments that possess fast-onset antidepressant effects in the clinic: electroconvulsive shock therapy, sleep deprivation, ketamine, scopolamine, GLYX-13 and pindolol used in conjunction with classical antidepressants. We also discuss the effects of several compounds that have yet to be tested in humans but have fast-onset antidepressant-like effects in one or more of these antidepressant onset sensitive models. These compounds include selective serotonin (5-HT)2C receptor antagonists, a 5-HT4 receptor agonist, a 5-HT7 receptor antagonist, NMDA receptor antagonists, a TREK-1 receptor antagonist, mGluR antagonists and (2R,6R)-HNK. Finally, we provide recommendations for identifying fast-onset antidepressants using rodent behavioral models and molecular approaches.

Dopamine D2/3 receptor antagonism reduces activity-based anorexia.

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted.

Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.

Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling.

Expression of the G72/G30 gene in transgenic mice induces behavioral changes.

The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially expressed in transgenic mice compared with wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders.

Gestational environment programs adult depression-like behavior through methylation of the calcitonin gene-related peptide gene.

Early life exposure to specific environmental factors can increase risk for developing psychopathology including major depression in adulthood. However, the molecular pathways and epigenetic mechanisms that mediate the effects of early environments on adult mood remain poorly understood. We examined the effects of different gestational and rearing conditions on adult anxiety- and depression-like behavior using a combined reciprocal outcrossing and cross-fostering design in Balb/cJ (cJ) and C57BL/6J (B6) mouse strains. First filial (F1) hybrid offspring, which were gestated by B6 or cJ dams and then reared by either strain, were evaluated for behavior and whole-genome hippocampal gene expression during adulthood. Adult hybrid mice gestated by B6 dams showed increased depression-like behavior in the forced swim and sucrose preference tests, increased hippocampal expression of alpha calcitonin gene-related peptide (αCGRP) transcripts, and decreased methylation of the αCGRP promoter compared with those gestated by cJ dams. Differential expression of αCGRP in adulthood did not result from genomic imprinting, and differences between B6 and cJ mitochondrial DNA were not responsible for behavioral phenotypes observed. Finally, central administration of αCGRP to adult hybrid mice increased depression-like behavior, whereas the CGRP1 receptor antagonist CGRP8-37 reduced depression-like behavior in the forced swim test. Our findings suggest that gestational factors influence adult depression-like behavior through methylation of the αCGRP gene.

Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors.

The glutamate hypothesis of schizophrenia derived from evidence that phencyclidine, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, produces schizophrenia-like symptoms in healthy humans. Sensorimotor gating, measured by prepulse inhibition (PPI), is a fundamental form of information processing that is deficient in schizophrenia patients and rodents treated with NMDA antagonists. Hence, PPI is widely used to study the neurobiology of schizophrenia. As the use of PPI as a model of gating deficits in schizophrenia has become more widespread, it has become increasingly important to assess such deficits accurately. Here we identify a possible role of mGluR5 in PPI by using wild type (WT) and mGluR5 knockout (KO) mice of two different background strains, 129SvPasIco and C57BL/6. In both strains, PPI was disrupted dramatically in the mGluR5 KO mice throughout a range of interstimulus intervals and sensory modalities. The present findings further support the glutamate hypothesis of schizophrenia and identify a functional role for mGluR5 in sensorimotor gating.

Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice.

Neural sensorimotor gating mechanisms prevent the interruption of ongoing information processing routines by ensuing stimuli to permit mental integration and adaptive behavior. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is now being investigated using murine models to exploit transgenic and "knockout" technology. The present studies were undertaken to evaluate potential murine strain differences in the effects of serotonergic drugs on PPI and habituation. Two strains used most often as a genetic background for transgenic or knockout manipulations, C57BL/6 and 129Sv, and the outbred ICR strain were used. We assessed the effects of the 5-HT(1A/1B) agonist 5-methoxy-3(1,2,3,6)tetrahydropyridin-4-yl-1H-indole (RU24969), the 5-HT(1A) agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT(2A/2C) agonist (+/-)2,5-dimethoxy-4-methylamphetamine (DOM), and the serotonin releaser (+)3, 4-methylenedioxy-N-methylamphetamine (MDMA) on PPI and habituation of acoustic startle in the three strains. C57BL/6 mice exhibited lower baseline PPI levels than 129Sv and ICR mice, and 129Sv mice habituated less than C57BL/6 and ICR mice. MDMA decreased PPI in C57BL/6 and ICR, but not 129Sv mice, and RU24969 disrupted habituation in C57BL/6 and 129Sv, but not ICR mice. Lastly, RU24969 decreased and 8-OH-DPAT increased PPI across all strains, although qualitative differences were observed. Thus, both baseline and serotonergic drug-induced effects on murine PPI and habituation are strain-dependent.

Prepulse startle deficit in the Brown Norway rat: a potential genetic model.

Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients. PPI was compared among 4 strains of rats: Sprague-Dawley, Spontaneously Hypertensive, Wistar Kyoto (WKY), and Brown Norway (BN). PPI was dramatically lower in BN versus the other strains, especially WKY, for both acoustic and airpuff startle stimuli, whereas startle amplitude was similar between BN and WKY. Female BN also had lower PPI than did female WKY. Response to increasing prepulse intensities showed a right shift in the BN relative to the WKY. Visual prepulses also showed deficiencies in BN versus WKY. The absence of background noise did not negate strain differences. Auditory brainstem response to clicks and tone pips revealed no differences in auditory threshold between the 2 strains. These results are the first to demonstrate that BN have impaired sensorimotor gating compared with WKY, without impaired acoustic acuity.

Serotonin releasers increase prepulse inhibition in serotonin 1B knockout mice.

RATIONALE: Prepulse inhibition (PPI) is the normal reduction of the startle response which occurs when an abrupt startling stimulus is preceded by a weak pre-stimulus and is decreased in several neuropsychiatric disorders. OBJECTIVE: The role of the serotonin 1B (5-HT(1B)) receptor in modulating PPI was investigated using 5-HT-releasing agents in wild-type (WT) and 5-HT1B knockout (1BKO) mice. Whether the differential effects of 5-HT-releasing agents on PPI in WT and 1BKO mice resulted from lack of the 5-HT1B receptor or altered development was also assessed. METHODS: PPI was assessed in WT and 1BKO mice treated with the 5-HT-releasing agents (+)3,4-methylenedioxy-N-methylamphetamine (MDMA: 0, 10 mg/kg) or (+/-)N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB: 0, 10 mg/kg). Additionally, intact 129 Sv mice received pre-treatments of the 5-HT1B/1D antagonist GR 127935 (0, 0.75, 1.5, 3.0 mg/kg) and treatments of MDMA (10 mg/kg). RESULTS: MDMA and MBDB increased PPI in 1BKO mice, but did not alter PPI in WT mice. Intact 129 Sv mice receiving 3.0 mg/kg GR 127935 and 10 mg/kg MDMA exhibited increases in PPI. CONCLUSIONS: The ability of GR 127935 to increase PPI in intact MDMA-treated mice suggests that lack of the 5-HT1B receptor, and not altered development, is responsible for the PPI-increasing effects of 5-HT releasers in 1BKO mice. 5-HT release activates multiple 5-HT receptor subtypes, which individually may increase or decrease PPI and together have a combined effect on PPI. Our finding that MDMA and MBDB increase PPI in 1BKO, but not WT mice, indicates that the activation of 5-HT1B receptors by 5-HT disrupts PPI.

Knockout mice reveal opposite roles for serotonin 1A and 1B receptors in prepulse inhibition.

The serotonergic system is involved in the modulation of prepulse inhibition (PPI) and habituation of startle, which are deficient in schizophrenia patients. PPI is the reduction in startle amplitude that occurs when a weak "prepulse" precedes a startling stimulus by 30-500 msec. The roles of 5-HT(1A) and 5-HT(1B) receptors in modulating PPI and habituation were examined using wild-type (WT), 5-HT(1A) knockout (1AKO), and 5-HT(1B) knockout (1BKO) mice. The 5-HT(1A/1B) agonist RU24969 reduced PPI and habituation in WT and 1AKO, but not 1BKO mice, whereas the 5-HT(1A) agonist 8-OH-DPAT increased PPI in WT and 1BKO, but not in 1AKO mice. Similarly, the selective 5-HT(1B) agonist anpirtoline reduced PPI in WT, but not in 1BKO mice. In experiments using intact 129Sv mice, the 5-HT(1A) agonist flesinoxan increased PPI while anpirtoline decreased PPI and habituation. Findings suggest that 5-HT(1B) receptor activation decreases PPI and habituation, and 5-HT(1A) receptor activation increases PPI in mice.

Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli.

The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by reports that reward is related to increased dopamine activity, that dopamine modulates exploratory behavior in animals, and that Parkinson's disease patients report diminished responses to novelty. Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called "novelty-seeking". To explore a potential role for the D4R in behavioral responses to novelty, we evaluated D4R-knock-out (D4R-/-) and wild-type (D4R+/+) mice in three approach-avoidance paradigms: the open field, emergence, and novel object tests. These three paradigms differ in the degree to which they elicit approach, or exploratory behavior, and avoidance, or anxiety-related behavior. Thus, we used these three tests to determine whether the D4R primarily influences the exploratory or the anxious component of responses to approach-avoidance conflicts. D4R-/- mice were significantly less behaviorally responsive to novelty than D4R+/+ mice in all three tests. The largest phenotypic differences were observed in the novel object test, which maximizes approach behavior, and the smallest phenotypic differences were found in the open field test, which maximizes avoidance behavior. Hence, D4R-/- mice exhibit reductions in behavioral responses to novelty, reflecting a decrease in novelty-related exploration.

Behavioral organization is independent of locomotor activity in 129 and C57 mouse strains.

Assessing locomotor behavior is a standard methodology to characterize the behavioral phenotype of a genetic manipulation. Typically, levels of locomotor activity are measured using various methods that are based on the frequency of photobeam breaks or distance traveled as assessed by video-tracking systems. Locomotor behavior, however, is multi-dimensional and reflects the combined influences of multiple processes. Here, we examine the number of independent dimensions of locomotor behavior in mice based on measures derived from a video-tracking system. In addition, we test the hypothesis that locomotor behavior varies substantially across mouse strains. 84 mice were tested for 30 min in a 41 x 41 cm enclosure. Based on previous investigations in rats, we also assessed the spatial and dynamical aspects of locomotor behavior using the spatial scaling exponent, d, and the dynamical entropy, h. A principal component analysis and a one-way repeated measure ANOVA were conducted. C57 mouse strains differ substantially from 129 mouse strains on almost all measures of locomotor behavior. The principal component analysis revealed that two independent factors influence this set of measures. The first factor reflects the amount or level of locomotor activity, the second factor quantifies the degree of spatial and dynamical organization of behavior. These strain differences and the existence of at least two independent dimensions when measuring locomotor behavior may help to parse the effects of gene manipulations relative to strain differences in mutant mice.

Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor.

In order to determine the distribution and function of the 5-HT5A serotonin receptor subtype, we generated knockout mice lacking the 5-HT5A gene. Comparative autoradiography studies of brains of wild-type (wt) and 5-HT5A knockout (5A-KO) mice revealed the existence of binding sites with high affinity for [125I]LSD that correspond to 5-HT5A receptors and that are concentrated in the olfactory bulb, neocortex, and medial habenula. When exposed to novel environments, the 5A-KO mice displayed increased exploratory activity but no change in anxiety-related behaviors. In addition, the stimulatory effect of LSD on exploratory activity was attenuated in 5A-KO mice. These results suggest that 5-HT5A receptors modulate the activity of neural circuits involved specifically in exploratory behavior and suggest that some of the psychotropic effects of LSD may be mediated by 5-HT5A receptors.

5-HT1B receptor modulation of prepulse inhibition: recent findings in wild-type and 5-HT1B knockout mice.

Sensorimotor gating of the startle reflex occurs when the presentation of a weak "prepulse" 30-500 msec prior to a startling stimulus inhibits the reflex, and is called prepulse inhibition (PPI). The study of PPI has recently been extended to mice to take advantage of recent advances in molecular genetics, because several neuropsychiatric disorders including schizophrenia, obsessive compulsive disorder, and schizotypal personality disorder are characterized by PPI deficits. Studies in wild-type and 5-HT1B knockout mice suggest that activation of 5-HT1B receptors decreases PPI. The direct 5-HT1A/1B agonist RU24969 decreases PPI in wild-type but not 5-HT1B knockout mice. Likewise, the serotonin releasing compounds MDMA(+), MBDB(+/-), and alpha-ethyltryptamine (AET) have no effect on PPI in wild-type mice, but increase PPI in 5-HT1B knockout mice. As the direct 5-HT1A agonist 8-OH-DPAT increases PPI in mice, the unmasking of these effects may also contribute to the PPI-increasing effects of 5-HT releasers in 5-HT1B knockout mice.

Serotonin1B receptor modulation of startle reactivity, habituation, and prepulse inhibition in wild-type and serotonin1B knockout mice.

Two operational measures of central information processing mechanisms are habituation and prepulse inhibition (PPI) of the startle response. Both measures can be assessed reliably in humans and other animals, and have been shown to be deficient in patients with schizophrenia. The three present experiments assessed the involvement of the serotonin1B (5-HT1B) receptor in modulating startle reactivity, habituation, and PPI by comparing 5-HT1B receptor gene knockout (5-HT1B knockout) with wild-type 129/Sv mice. In experiment I, female mice received saline, 2.0 mg/kg 5-methoxy-3(1,2,3,6)tetrahydropyridin-4-yl-1H-indole (RU24969), a 5-HT1A/1B agonist, and 1.0 mg/kg 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist. Female mice received saline, 10.0 mg/kg RU24969, and 5.0 mg/kg 8-OH-DPAT in experiment 2, and male mice received saline, 10.0 mg/kg RU24969, and 5.0 mg/kg 8-OH-DPAT in experiment 3. All three studies used identical within-subjects designs. Two phenotypic differences were observed following saline treatment: 5-HT1B knockout mice consistently exhibited a small increase in PPI that achieved significance in experiment 1; and 5-HT1B knockout male mice exhibited robust decreases in startle reactivity. Habituation was disrupted consistently by RU24969 in wild-type but not in 5-HT1B knockout mice, while 8-OH-DPAT had no effect on habituation. Consistent with the phenotypic difference in PPI, the high dose of RU24969 significantly and consistently reduced PPI in wild-type but not in 5-HT1B knockout mice. 8-OH-DPAT increased PPI in both wild-type and 5-HT1B knockout mice in every experiment. These findings suggest that 5-HT1B receptors modulate startle reactivity, habituation, and PPI in mice. Additionally, a potential species difference may exist in the behavioral effects of 5-HT1A receptor activation on PPI.

The effects of intra-accumbens neurotensin on sensorimotor gating.

Neurotensin is a neuropeptide which coexists with mesolimbic dopamine. Previous studies have shown that centrally administered neurotensin can modulate the activity of mesolimbic dopamine with a profile similar to neuroleptics. For example, infusions of neurotensin into the nucleus accumbens inhibit amphetamine-induced hyperlocomotion. Prepulse inhibition (PPI) occurs when a weak prestimulus ('prepulse') inhibits the amplitude of the startle response to an intense stimulus ('pulse'). PPI is an operational measure of sensorimotor gating which is strongly regulated by mesolimbic dopamine. This study examined the effects of various doses of neurotensin infused into the nucleus accumbens of rats on the prepulse inhibition (PPI) of their acoustic startle reflex. Neurotensin (0.25-5.0 microg) was infused into the nucleus accumbens of rats. Animals then received subcutaneous injections of amphetamine (2 mg/kg) or saline and were placed in startle chambers where measures of startle amplitude and PPI were obtained. Neurotensin increased baseline PPI and blocked amphetamine-induced disruption of PPI in a dose-dependent fashion. The lowest dose of neurotensin tested (0.25 microg) significantly increased baseline PPI and both 0.25 and 1.0 microg neurotensin blocked amphetamine-induced decreases in PPI. The 5.0 microg dose of neurotensin had no significant effect on prepulse inhibition. Neurotensin had no effect on the amplitude of the acoustic startle reflex in amphetamine- or saline-treated rats. The results suggest that intra-accumbens neurotensin has a significant, dose-dependent effect on sensorimotor gating in which lower doses (0.25-1.0 microg) exhibit a neuroleptic-like action.

Psychopharmacology of prepulse inhibition in mice.

The attenuation of the startle response termed "prepulse inhibition" (PPI) occurs when an abrupt startling stimulus is preceded 30-500 msec by a barely detectable prestimulus or "prepulse". PPI provides a measure of sensorimotor gating, which is a short time-constant central processing mechanism that is disrupted in patients with schizophrenia, and a number of other neuropsychiatric disorders. The present experiments examined normal PPI in the mouse, and assessed the effects of apomorphine, d-amphetamine, PCP, and MDMA on mouse PPI. As predicted, mice demonstrated robust and reliable PPI, and each compound tested disrupted PPI. As with rats, 2.0 mg/kg apomorphine, 10.0 mg/kg PCP, and 10.0 mg/kg MDMA disrupted PPI significantly, while 5.0 mg/kg d-amphetamine produced a large reduction of PPI that approached significance. Our findings suggest that the mouse may provide another model system for the study of sensorimotor gating mechanisms.

Cholecystokinin and estradiol synergistically potentiate satiety in rats.

The ability of octapeptide cholecystokinin (CCK), in interaction with ovarian steroid conditions, to decrease 1-h feeding was studied in 5-h food-deprived Sprague-Dawley rats. In Experiment 1, intact, unilaterally ovariectomized, and bilaterally ovariectomized females and intact males were given IP injections of 0, 0.25, 0.50, and 1.0 microgram/kg b.wt. CCK and were assessed for food ingestion at 1, 3, and 19 h. Food intake at 1 h was suppressed in animals receiving CCK compared to saline (0 dose); the threshold dosage was 1 microgram/kg b.wt. (p < 0.01) in this paradigm. No significant sex difference was observed between the four groups; however, animals with decreased ovarian steroids (intact males and bilaterally ovariectomized females) suppressed ingestion less than animals with greater ovarian steroid levels (intact and unilaterally ovariectomized females) at both the 0.25 and 1.0 microgram/kg b.wt. dosages (p < 0.01). Therefore, in a second experiment, sensitivity to CCK was compared in females in early metestrus, when estrogen levels are decreased, and during late diestrus, when estrogen levels are high, using dosages of 0, 0.25, 1, and 2.5 micrograms/kg b.wt. A statistically significant difference was found between sensitivity at early metestrus and late diestrus at the 2.5 micrograms/kg b.wt. dose only, with food ingestion more reliably depressed during periods of increased estrogen (p < 0.05). These results suggest that estradiol and CCK can have a synergistic effect on satiety.