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There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity.

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Corticotropin-releasing hormone (CRH) coordinates multiple aspects of the stress response. Recently, CRH mRNA has been identified in two regions of the thalamus: the posterior nuclear group (Po), and a region located at the interface of the central medial and ventral posteromedial nucleus (parvicellular part) (CM-VPMpc). Previous studies demonstrated that in both regions CRH mRNA increases following 1 h of restraint stress, suggesting involvement of thalamic CRH in processing somatosensory and visceral information related to stress. The current study was proposed to further understand the effects of repeated and acute restraint stress on levels of thalamic CRH mRNA. Adult male rats were assigned to one of four groups in a 2 (repeated stress, no repeated) x2 (acute, no acute) design. Brain sections were processed for CRH mRNA in situ hybridization. ANOVA revealed no main effects of acute or repeated stress in either thalamic region. However, significant interactions between acute and repeated stress for levels of CRH mRNA were found for both regions of the thalamus. Compared to the no stress condition, acute restraint significantly increased CRH mRNA in the Po (39%) and the CM-VPMpc (32%). Repeated restraint did not alter baseline CRH mRNA levels, but blocked the acute restraint-induced effects. Thus, while acute stress increases levels of thalamic CRH mRNA, repeated exposure to the same stressor is without effect and prevents the acute response. These findings add to data establishing a role for thalamic CRH in the stress response and suggest a mechanism that may underlie habituation to repeated stress exposure.

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Corticotropin-releasing hormone plays a critical role in mediating the stress response. Brain circuits hypothesized to mediate stress include the thalamus, which plays a pivotal role in distributing sensory information to cortical and subcortical structures. In situ hybridization revealed neurons containing corticotropin-releasing hormone messenger RNA in the posterior thalamic nuclear group and the central medial nucleus of the thalamus, which interfaces with the ventral posteromedial nucleus (parvicellular part). These regions are of interest because they process somatosensory and visceral information. In the first experiment, the effect of acute stress on thalamic corticotropin-releasing hormone messenger RNA levels was assessed. Rats restrained for 1 h and killed 1 h later were found to have increased corticotropin-releasing hormone messenger RNA in the posterior thalamic nuclear group. The time course of these changes was examined in a second experiment in which rats were killed immediately or 3 h after restraint. While no changes occurred in the thalamus immediately after restraint, 3 h after restraint, increases in corticotropin-releasing hormone messenger RNA occurred in both the posterior thalamic nuclear group and the central medial-ventral posteromedial nucleus (parvicellular part) of the thalamus. A different pattern of activation was observed in the paraventricular nucleus of the hypothalamus with increased corticotropin-releasing hormone messenger RNA immediately after restraint, but not 1 or 3 h later. In addition to the stress-induced changes, a prominent decrease in baseline thalamic corticotropin-releasing hormone messenger RNA was observed from 1000 to 1300 h. These results show that the thalamus contains corticotropin-releasing hormone messenger RNA that increases after restraint stress, indicating a role for thalamic corticotropin-releasing hormone systems in the stress response. Stress-induced changes in thalamic corticotropin-releasing hormone messenger RNA expression appears to be regulated differently than that in the paraventricular nucleus of the hypothalamus, and may be influenced by diurnal mechanisms.

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Corticotropin-releasing hormone (CRH) mediates endocrine, behavioral, and autonomic responses to stress. In addition to binding to two receptor subtypes, CRH binds to a CRH-binding protein (CRH-BP). While CRH-BP is hypothesized to play a role in regulating levels of free CRH and modulating the stress response, the effects of stressors on brain CRH-BP are relatively unexplored. The present study determined effects of acute and repeated restraint on CRH-BP mRNA in basolateral amygdala (BLA) and dorsal hippocampus (DH), brain regions involved in fear and motivation. Using in situ hybridization, we found that a single acute period of restraint significantly increased CRH-BP mRNA in BLA by 20% but had no effect in DH. Repeated restraint had no effect on basal levels of CRH-BP mRNA in BLA or DH. Importantly, repeated restraint blocked the effects of acute restraint in the BLA. These results demonstrate differential effects of acute and repeated restraint on CRH-BP mRNA.

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It has previously been demonstrated that stimulation of opiate receptors within the nucleus accumbens results in marked hyperphagia, perhaps reflecting enhancement of taste palatability. Rats that have received multiple morphine treatments also increase feeding in response to environmental stimuli that have been associated with the morphine injections. The present investigation further examined this phenomenon. In Experiment 1, it was shown that induction of conditioned feeding was dose-dependent; significant conditioned feeding was obtained with repeated (n = 5) intra-accumbens injections of 5 or 10 microg/microl morphine but not with saline or 1 microg. The conditioned feeding response was blocked by systemic naltrexone (5 mg/kg). In the second experiment, co-treatment with either a D-1 (SCH 23390, 0.1 mg/kg) or D-2 (haloperidol, 0.25 mg/kg) antagonist did not block the development of conditioned feeding, nor did these drugs block morphine-induced feeding. In Experiment 3, it was found that systemic naltrexone blocked the expression of conditioned feeding (confirming Experiment 1), as did SCH-23390, whereas haloperidol did not affect expression of conditioned feeding. In the fourth experiment, we observed that significant conditioned feeding was induced with repeated treatment with the selective mu agonist D-Ala2, NMe-phe4, Glyol5-enkephalin (DAMGO, 2.5 microg), but not with the delta agonist D-Pen2,5-enkephalin (DPEN, 3.1 microg). The final experiment tested the diurnal variability of the expression of conditioned feeding, and it was found that the magnitude of the effect depended on time of day. In summary, the development of opioid-induced conditioned feeding depends on mu opiate receptor stimulation, but not dopamine receptor stimulation. Its expression, however, involves both opiate and D-1 receptor activation. These findings are considered in terms of putative neural mechanisms governing conditioned meal initiation, and implications for compulsive eating and bulimia are also discussed.

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The study of the neural substrates underlying stress and anxiety has in recent years been enriched by a burgeoning pool of genetic information gathered from rodent studies. Two general approaches have been used to characterize the interaction of genetic and environmental factors in stress regulation: the evaluation of stress-related behavioral and endocrine responses in animals with targeted deletion or overexpression of specific genes and the evaluation of changes in central nervous system gene expression in response to environmental perturbations. We review recent studies that have used molecular biology and genetic engineering techniques such as in situ hybridization, transgenic animal, and antisense oligonucleotide gene-targeting methodologies to characterize the function of corticotropin-releasing hormone (CRH) system genes in stress. The effects of genetic manipulations of each element of the CRH system (CRH, its two receptors, and its binding protein) on stress-related responses are summarized. In addition, the effects of stress (acute, repeated, or developmental) on CRH system gene expression are described. The results from these studies indicate that experimentally engineered or stress-induced dysregulation of gene expression within the CRH system is associated with aberrant responses to environmental contingencies. These results are discussed in the context of how CRH system dysfunction might contribute to stress-related psychopathology and are presented in conjunction with clinical findings of CRH system dysregulation in psychiatric illness. Finally, future research strategies (i.e., high-throughput gene screening and novel gene-targeting methodologies) that may be used to gain a fuller understanding of how CRH system gene expression affects stress-related functioning are discussed.

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Presentation of a weak stimulus immediately before a startling stimulus decreases the magnitude of the resultant startle response. This phenomenon, termed prepulse inhibition (PPI), provides an operational measure of sensorimotor gating, and is deficient in schizophrenia patients. Clinically observed PPI deficits can be modeled in rodents by housing rats individually from weaning until adulthood. The developmental time course of isolation rearing-induced PPI deficits, however, is unknown. The present studies characterized the ontogeny of isolation-induced PPI deficits and hyperactivity. Separate groups of Sprague-Dawley and Lister hooded rats were either singly housed (ISO) or socially housed (SOC, groups of two to three per cage) upon weaning and then maintained in these housing conditions for different periods of time until assessment of PPI and locomotor activity; animals were tested at time points that roughly corresponded to before puberty (2 weeks postweaning), during puberty (4 weeks postweaning), or after puberty (6-7 weeks post weaning). PPI deficits were seen in Sprague-Dawley ISO rats at either the 4- or 6-, but not the 2-week time points. In contrast, hyperactivity was noted in these animals starting at the 2-week time point. Lister rats showed the same general pattern of ISO-induced effects, with ISO-induced hyperactivity (observed 4 weeks postweaning) preceding ISO-induced PPI deficits (observed 7 weeks postweaning). Therefore, ISO produces dissociable effects on PPI and locomotor activity, with PPI deficits emerging only during or after puberty. ISO might thus provide a useful noninvasive tool with which to study the neural substrates of delayed-onset sensorimotor gating abnormalities.

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Prepulse inhibition refers to the inhibition by a weak prepulse of the startle response to an intense stimulus. Prepulse inhibition is thought to provide an operational measure of sensorimotor gating, a putative central inhibitory process by which an organism filters information from its environment. Prepulse inhibition deficits are observed in schizophrenia patients and in rats treated with psychotomimetic compounds, such as the non-competitive N-methyl-D-aspartate antagonists phencyclidine or dizocilpine maleate. In rats, phencyclidine-induced prepulse inhibition deficits are blocked by clozapine, olanzapine and quetiapine, which are multireceptor antagonists and atypical antipsychotics, or by prazosin, which is a selective alpha1-adrenergic antagonist. The dorsal hippocampus and amygdala are two of the brain regions shown to contribute to the disruption of prepulse inhibition produced by non-competitive N-methyl-D-aspartate antagonists. The present study tested the hypotheses that quetiapine or prazosin would prevent deficits in prepulse inhibition produced by dizocilpine infusion into the dorsal hippocampus or amygdala. In separate groups of rats, either quetiapine (0 or 5.0 mg/kg, s.c.) or prazosin (0 or 1.0 mg/kg, i.p.) was administered 15 min prior to bilateral infusion of dizocilpine (0 or 6.25 microg/0.5 microl/side) into either the dorsal hippocampus or amygdala. Rats were placed into startle chambers immediately after intracerebral drug infusion and prepulse inhibition was assessed. Confirming previous studies, prepulse inhibition was decreased after either intra-dorsal hippocampus or intra-amygdala infusions of dizocilpine. Both quetiapine and prazosin blocked the prepulse inhibition deficits produced by intracranial dizocilpine administration. Startle reactivity was increased by dizocilpine infusion into either region; these effects were not blocked by either quetiapine or prazosin. These results indicate that non-competitive N-methyl-D-aspartate antagonists may disrupt sensorimotor gating via actions within the dorsal hippocampus or amygdala, and that alpha1-adrenergic receptors distal to these sites might mediate this effect.

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In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin. Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains.

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Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine are psychotomimetics and disrupt prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Systemically administered competitive NMDA receptor antagonists do not disrupt PPI in rats, leading to speculation that these compounds might have use as neuroprotective agents without the risk of psychotomimetic side effects. The effects on sensorimotor gating and locomotor activity of competitive NMDA receptor antagonists that either penetrate (SDZ 220-581 and SDZ EAB-515) or poorly penetrate [SDZ EAA-494 (D-CPPene)] the blood-brain barrier were compared. Rats were treated with either SDZ 220-581 (0, 2.5, or 5.0 mg/kg) or SDZ EAB-515 (0, 3.0, 10.0, or 30.0 mg/kg) and tested for PPI and locomotor activity. Different rats were tested for PPI after either systemic (0, 0.5, 1.0, or 5.0 mg/kg) or intra-amygdala (0 or 1.0 microg/microl) administration of D-CPPene. Finally, rats were pretreated with clozapine (0 or 5.0 mg/kg) or haloperidol (0 or 0.1 mg/kg), together with SDZ 220-581 (0 or 2.5 mg/kg), and tested. SDZ 220-581 and SDZ EAB-515 decreased PPI without affecting startle magnitude. Reduced PPI was noted after central but not systemic administration of D-CPPene. The gating deficits produced by SDZ 220-581 were blocked by clozapine or haloperidol. Movement pattern analysis indicated that locomotor activity was increased by SDZ 220-581 and SDZ EAB-515 in a phencyclidine-like manner. These results indicate that competitive NMDA receptor antagonists, if they gain sufficient access to the brain, produce a behavioral profile that resembles that of the psychotomimetic noncompetitive antagonists.

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Prepulse inhibition (PPI), a phenomenon in which a weak prestimulus decreases the startle response to an intense stimulus, provides an operational measure of sensorimotor gating (a process by which an organism filters sensory information) and is diminished in schizophrenia and schizotypal patients. The psychotomimetic phencyclidine and its potent congener dizocilpine are noncompetitive antagonists of the NMDA receptor complex, and they disrupt PPI in rodents, mimicking the clinically observed PPI deficit. The neuroanatomical substrates mediating the PPI-disruptive effects of noncompetitive NMDA antagonists are unknown. The present study sought to identify brain regions subserving the disruption of PPI produced by noncompetitive NMDA antagonists in rats. PPI was measured in startle chambers immediately after bilateral infusion of dizocilpine (0, 0.25, 1.25, and 6.25 microgram/0.5 microliter/side) into one of six brain regions: amygdala, dorsal hippocampus, medial prefrontal cortex, nucleus accumbens, ventral hippocampus, and dorsomedial thalamus. Dizocilpine significantly decreased PPI after infusion into the amygdala or dorsal hippocampus. A trend toward PPI disruption was observed with administration into medial prefrontal cortex. In contrast, no change in PPI was produced by dizocilpine infusion into nucleus accumbens, ventral hippocampus, or dorsomedial thalamus. Startle reactivity was increased by dizocilpine infusion into amygdala, dorsal hippocampus, nucleus accumbens, and dorsomedial thalamus, but not medial prefrontal cortex. These findings indicate that multiple limbic forebrain regions mediate the ability of noncompetitive NMDA antagonists to disrupt PPI and that the PPI-disruptive and the startle-increasing effects of dizocilpine are mediated by different central sites.

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OBJECTIVE: Dopaminergic and serotonergic modulation potently influences the sequential organization of rat movements in a simple unconditioned motor paradigm. Rats reared in social isolation post-weaning differ profoundly from their socially reared litter mates on behavioral, neurochemical, and neuroanatomical measures. This investigation examined (1) whether social isolation significantly affects the sequential organization of rat movements, (2) whether these changes occur at different ages, and (3) whether these changes differ across strains. METHOD: male Lister and Sprague Dawley rats reared in isolation post-weaning and socially reared controls were tested at 2 and 8 weeks post-weaning, in the Behavioral Pattern Monitor for 30-min sessions. The amount of activity and the spatial patterns of movements as measured by both the spatial scaling exponent and the fluctuation spectrum of local spatial scaling exponents were assessed in 10-min intervals. RESULTS: Habituation of locomotor activity was significantly attenuated in isolation reared rats during the 30-min sessions irrespective of strain. Spatial patterns of movements were significantly affected by isolation rearing in movements in post-pubertal but not pre-pubertal Lister and Sprague-Dawley rats. The spatial scaling exponent and the fluctuation spectrum analysis revealed a shift towards straight, distance-covering, and repetitive movements rather than a complex re-organization of the behavioral repertoire. CONCLUSIONS: Isolation rearing profoundly affects the sequential organization of movements in post-pubertal rats, suggesting that emerging behavioral dysfunctions parallel developmentally those found in patients with schizophrenia.

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The role of the alpha-1 adrenoceptor in prepulse inhibition (PPI) was evaluated in rats. The alpha-1 adrenergic agonist cirazoline disrupted PPI; this effect was reversed by the alpha-1 adrenergic antagonist prazosin or the atypical antipsychotic quetiapine. Alpha-1 adrenoceptors may thus be involved in the regulation of PPI and in the psychotherapeutic actions of certain antipsychotics.

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BACKGROUND: Prepulse inhibition (PPI) of startle provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. PPI deficits observed in schizophrenia patients can be modeled in rats by individual housing from weaning until adulthood. Deficits in PPI produced by isolation rearing can be reversed by antipsychotics. METHODS: We evaluated the ability of Seroquel and olanzapine to reverse the isolation-induced disruption of PPI. Rats housed for 8 weeks singly or in groups of 3 were tested every 2 weeks after either Seroquel (0, 5.0 mg/kg) or olanzapine (0, 2.5, 5.0 mg/kg). Startle was elicited by 120-dB pulses presented either with or without prepulses (3, 6, or 12 dB above a 65-dB background). RESULTS: Isolation rearing repeatedly disrupted PPI and sometimes increased startle reactivity. Seroquel reversed these deficits without affecting PPI in socially reared controls. Olanzapine (2.5 mg/kg) reversed the isolation rearing-induced PPI deficit and tended to increase basal PPI levels. Both antipsychotics antagonized the isolation rearing-induced increase in startle reactivity. CONCLUSIONS: Isolation rearing produces deficits in sensorimotor gating in rats that are reversible by atypical antipsychotics, and may therefore aid in identifying new treatments for schizophrenia.

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Prepulse inhibition (PPI) is a form of plasticity of the startle response in which presentation of a weak stimulus immediately before an intense startling stimulus reduces the resultant startle response. Deficits in PPI, an operational measure of sensorimotor gating, are observed in schizophrenia patients and can be modeled in rats by the psychotogen phencyclidine (PCP). PCP-induced deficits in PPI in rats are resistant to dopamine and serotonin antagonists but can be antagonized by antipsychotics such as clozapine, olanzapine and Seroquel. These latter antipsychotics have antagonistic actions at several receptors, including alpha-1 and alpha-2 adrenergic, M1 muscarinic and gamma-aminobutyric acid (GABA)-A receptors. Although the direct actions of PCP are thought to be mediated by noncompetitive antagonism of N-methyl-D-aspartate sites, PCP thereby indirectly activates multiple neurotransmitter systems, including those affected by the aforementioned antipsychotics. The present studies examined the possibility that an antagonist action at a particular receptor subtype might be responsible for the interaction between PCP and the clozapine-like antipsychotics by testing whether a selective antagonist at alpha-1, alpha-2, M1 or GABA-A receptors would prevent the PCP-induced deficit in PPI in rats. Animals were pretreated with either the alpha-1 antagonist prazosin (0, 0.5, 1.0 or 2.5 mg/kg), the alpha-2 antagonist RX821002 (0, 0.2 or 0.4 mg/kg), the M1 muscarinic antagonist pirenzepine (0, 10 or 30 mg/kg) or the GABA-A antagonist pitrazepin (0, 1.0 or 3.0 mg/kg) and then treated with either saline or PCP (1.5 mg/kg). Because prazosin was effective in blocking the effects of PCP, an additional experiment tested the possibility that prazosin (0, 1.0 or 2.5 mg/kg) would block the PPI deficits produced by the dopamine agonist apomorphine (0 or 0.5 mg/kg). After drug administration, animals were tested in startle chambers. PCP was found repeatedly to decrease PPI. Prazosin (1.0 and 2.5 mg/kg) blocked this deficit in two separate experiments but did not increase base-line PPI levels. The effects on PPI were dissociable from changes in startle reactivity. Furthermore, prazosin did not antagonize apomorphine-induced disruptions of PPI, which suggests that the antagonism of the PCP effect was not simply due to a generalized improvement of deficient PPI. The antagonists for alpha-2, for M1 and for GABA-A receptors had no effect on base-line PPI or on PCP-induced disruptions in PPI. These findings indicate that the PPI-disruptive effect of PCP may be mediated in part by alpha-1 adrenergic receptors and that antagonism of alpha-1 receptors may play a major role in mediating the blockade of PCP-induced deficits in PPI by certain antipsychotics.

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Sensorimotor gating deficits characterize several neuropsychiatric disorders, including schizophrenia. Prepulse inhibition (PPI) and latent inhibition (LI) are measures that are used to assess sensorimotor gating and have been found to be reduced in schizophrenia patients. In PPI, a weak stimulus presented immediately prior to a startling stimulus attenuates the startle response. In LI, pre-exposure to a stimulus retards the subsequent association of that stimulus with a consequence (e.g. footshock). In rats, indirect dopamine (DA) agonists such as amphetamine disrupt both PPI and LI. Amphetamine has also been reported to increase exploratory locomotion at doses that decrease PPI and LI. Such behavioral activation might complicate the interpretation of amphetamine-induced changes in measures of sensorimotor gating. The present study was conducted in order to compare the effects of three behaviorally activating drugs on PPI, LI and locomotor activity. Separate groups of rats were treated with either vehicle, the DA releaser amphetamine (1.5mg/kg), the glycine antagonist strychnine (0.75mg/kg), or the adenosine receptor antagonist caffeine (10mg/kg) and then tested in either startle chambers (for PPI) or an active avoidance chamber (for LI). Locomotion was measured by inter-trial crossing in the avoidance chamber. Amphetamine stimulated locomotion and disrupted both PPI and LI, but did not elevate startle amplitude. In contrast, caffeine increased locomotion, but had no effect on PPI or LI. Strychnine did not increase locomotion significantly, but did increase startle amplitude and disrupt PPI and LI. Hence, neither increased startle amplitude nor locomotor activation are necessary or sufficient conditions for disruption of sensorimotor gating as measured by PPI and LI.

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Prepulse inhibition (PPI) of the startle reflex provides an operational measure of sensorimotor gating. Deficits in PPI are observed in schizophrenia patients and can be modelled in animals by administration of noncompetitive NMDA antagonists such as phencyclidine (PCP) or dizocilpine (MK-801). Previous studies indicate that the atypical antipsychotic clozapine restores PPI in PCP-treated animals while the typical antipsychotic haloperidol does not. Olanzapine (LY170053) is a novel putative atypical antipsychotic that shares many pharmacological and behavioral properties with clozapine. The present study assessed the ability of olanzapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg) to antagonize deficits in PPI produced by PCP (1.5 mg/kg) and dizocilpine (0.1 mg/kg). At the two highest doses, olanzapine significantly increased PPI in PCP- and dizocilpine-treated animals without affecting PPI or baseline startle reactivity by itself. These results support the notion that olanzapine is functionally similar to clozapine and may have utility as an atypical antipsychotic agent.

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Intense auditory stimuli elicit an involuntary startle response that is attenuated when the startling stimulus (the pulse) is preceded immediately by a low intensity stimulus (the prepulse). This phenomenon of prepulse inhibition (PPI) is utilized as a measure of sensorimotor gating and is significantly reduced in schizophrenic patients. Noncompetitive N-methyl-D-aspartate antagonists such as phencyclidine (PCP) and ((+)-D-aspartate 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (dizocilpine, or MK-801) have been found previously to disrupt PPI in animals. The present investigation assessed the ability of several antipsychotic drugs to reverse PCP-induced deficits in PPI in rats. Animals were pretreated with either the atypical antipsychotic clozapine (0, 1.25, 2.5, 5.0 or 10.0 mg/kg), the D2 dopamine antagonist raclopride (0, 0.1 or 0.5 mg/kg), the D1 dopamine antagonist SCH23390 (0, 0.01 or 0.05 mg/kg) or the 5-hydroxytryptamine2 antagonists ritanserin (0 or 2.0 mg/kg) or ketanserin (0 or 1.0 mg/kg) and then were given PCP (1.0 mg/kg). After drug administration, animals were tested in startle chambers. PCP repeatedly and robustly decreased PPI without affecting base-line startle reactivity. Clozapine (5.0 mg/kg) antagonized this effect of PCP without altering PPI by itself. Raclopride, SCH23390, ritanserin and ketanserin were ineffective at reversing the PCP-induced deficit in PPI. As with PCP, 0.1 mg/kg of MK-801 disrupted PPI; this disruption also was antagonized by 5.0 mg/kg of clozapine. Thus, it appears that the ability of clozapine to reverse deficits in PPI produced by noncompetitive N-methyl-D-aspartate antagonists cannot be attributed to a sole antagonism of either D1 dopamine, D2 dopamine or 5-hydroxytryptamine2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

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The effects of repeated morphine infusions (10 micrograms/0.5 microliter) into the nucleus accumbens on feeding were studied in sated rats. As shown previously, intra-accumbens morphine infusions induced a large increase in food intake. After undergoing repeated morphine treatment, animals consumed significant quantities of food in response to a saline or sham injection, compared to their pre-morphine baseline. This conditioned feeding was present up to 18 days after the final drug infusion. Additionally, repeated morphine administration caused a progressive sensitization of feeding; the final morphine infusion elicited nearly double the amount of food intake as the first. Multiple saline infusions had no behavioral effects. Repeated stimulation of opiate receptors may enhance associative mechanisms such that previously neutral environmental stimuli acquire the ability to elicit feeding. Abnormal activation of this system may be a possible neural substrate for compulsive feeding and bulimia.

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