Biomedical subjects

Anthony G Phillips

Publications and source records attributed to Anthony G Phillips.

At least 19 recordsLinked to original sources

PubMed2006

Kindling of basolateral amygdala but not ventral hippocampus or perirhinal cortex disrupts sensorimotor gating in rats.

The neural mechanisms mediating prepulse inhibition (PPI) appear to have relevance to neurological and psychiatric disorders. Patients with temporal lobe epilepsy exhibit psychotic symptoms and disrupted PPI, therefore the present experiments examined the consequences of seizures induced by kindling on PPI. Rats were chronically implanted with an electrode into the basolateral amygdala, perirhinal cortex, or ventral hippocampus and stimulated twice daily until 3 fully generalized, class 5 seizures were elicited. Kindling of basolateral amygdala, but not perirhinal cortex or ventral hippocampus, disrupted PPI when testing began 2min, but not 48h, following the elicitation of the third class 5 seizure. Startle amplitudes were unaffected by kindling. These results suggest that the anatomical origin of seizures is an important factor in determining their potentially disruptive effects on PPI.

Amygdala↗

PubMed2006

Dopamine efflux in the nucleus accumbens during within-session extinction, outcome-dependent, and habit-based instrumental responding for food reward.

RATIONALE: Dopamine (DA) activity in the nucleus accumbens (NAc) is related to the general motivational effects of rewarding stimuli. Dickinson and colleagues have shown that initial acquisition of instrumental responding reflects action-outcome relationships based on instrumental incentive learning, which establishes the value of an outcome. Given that the sensitivity of responding to outcome devaluation is not affected by NAc lesions, it is unlikely that incentive learning during the action-outcome phase is mediated by DA activity in the NAc. OBJECTIVES: DA efflux in the NAc after limited and extended training was compared on the assumption that comparable changes would be observed during both action-outcome- and habit-based phases of instrumental responding for food. This study also tested the hypothesis that increase in NAc DA activity is correlated with instrumental responding during extinction maintained by a conditioned stimulus paired with food. METHODS: Rats were trained to lever press for food (random-interval 30 s schedule). On the 5th and 16th day of training, microdialysis samples were collected from the NAc or mediodorsal striatum (a control site for generalized activity) during instrumental responding in extinction and then for food reward, and analyzed for DA content using high performance liquid chromatography. RESULTS: Increase in DA efflux in the NAc accompanied responding for food pellets on both days 5 and 16, with the magnitude of increase significantly enhanced on day 16. DA efflux was also significantly elevated during responding in extinction only on day 16. CONCLUSIONS: These results support a role for NAc DA activity in Pavlovian, but not instrumental, incentive learning.

Animals↗

PubMed2006

Effects of short-term abstinence from escalating doses of D-amphetamine on drug and sucrose-evoked dopamine efflux in the rat nucleus accumbens.

Abstinence from high doses of psychostimulant drugs, in both humans and rodents, is linked to adverse psychological effects including anhedonia, a core symptom of major depression, manifested behaviorally as decreased responding for rewarding stimuli. The present study used brain microdialysis in freely moving rats to examine the effect of D-amphetamine (D-amph) withdrawal on changes in extracellular dopamine (DA) levels in the nucleus accumbens (NAc) evoked by D-amph or behavior related to sucrose consumption. D-amph was administered intraperitoneally (i.p.) according to an escalating dose (ED) schedule (from 1 to 10 mg/kg, 3 doses/day). We first confirmed the development of tolerance by monitoring DA efflux in the NAc in response to 5 and 10 mg/kg doses of D-amph administered during the ED schedule of drug administration and again in response to the 5 mg/kg dose of D-amph 72 h following the last 10 mg/kg D-amph injection. In a separate study, DA efflux in the NAc was first shown to be increased significantly during both preparatory and consummatory phases of responding for a 4% sucrose solution. Withdrawal from the ED schedule of D-amph caused a selective attenuation of DA efflux only during the preparatory phase of the sucrose test. These results provided convincing evidence of neurochemical adaptation within the mesocorticolimbic DA pathway during and following the administration of an ED schedule of D-amph as well as suppressed neurochemical responses to a psychostimulant drug and cues associated with a natural reward after withdrawal from drug treatment. Accordingly, these findings support the hypothesis that downregulation of mesocorticolimbic DA function maintained during D-amph withdrawal may account for the selective disruption of motivated behavior reported in studies employing psychostimulant drug withdrawal as a model of depression in rodents.

Amphetamine↗

PubMed2005

Nucleus accumbens long-term depression and the expression of behavioral sensitization.

Drug-dependent neural plasticity related to drug addiction and schizophrenia can be modeled in animals as behavioral sensitization, which is induced by repeated noncontingent or self-administration of many drugs of abuse. Molecular mechanisms that are critical for behavioral sensitization have yet to be specified. Long-term depression (LTD) of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor (AMPAR)-mediated synaptic transmission in the brain has been proposed as a cellular substrate for learning and memory. The expression of LTD in the nucleus accumbens (NAc) required clathrin-dependent endocytosis of postsynaptic AMPARs. NAc LTD was blocked by a dynamin-derived peptide that inhibited clathrin-mediated endocytosis or by a GluR2-derived peptide that blocked regulated AMPAR endocytosis. Systemic or intra-NAc infusion of the membrane-permeable GluR2 peptide prevented the expression of amphetamine-induced behavioral sensitization in the rat.

Animals↗

PubMed2005

Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation.

RATIONALE: Working memory performance may be improved or decreased by amphetamine, depending on baseline working memory capacity and amphetamine dosage. This variable effect suggests an optimal range of monaminergic activity for working memory, either below or above which it is compromised. We directly tested this possibility with human participants by varying amphetamine dosage and measuring the efficiency of cortical processing in brain regions associated with working memory. OBJECTIVES: The modulation of cortical processing in a verbal working memory network by dextroamphetamine (D-amph) was examined using BOLD functional magnetic resonance imaging (fMRI) with healthy participants. The goal of the study was to test the hypothesis of an inverted U-shaped relationship between D-amph dose and processing efficiency of a verbal working memory system. METHODS: D-amph dosage was increased cumulatively every 2 h across four scanning sessions collected in a single day. The primary measure used for analyses in this study was the extent of activation in brain regions empirically defined as a working memory network. RESULTS: An inverted U-shaped relationship was observed between the amount of D-amph administered and working memory processing efficiency. This relationship was specific to brain areas functionally defined as working memory regions and to the encoding/maintenance phase (as opposed to the response phase) of the task. CONCLUSION: The results are consistent with the hypothesis that the neurochemical effects of amphetamine modulate the efficiency of a verbal working memory system. The effect of amphetamine on working memory in healthy individuals may provide insight regarding the working memory deficits seen in schizophrenia, given the overlap between neurochemical systems affected by amphetamine, and those disordered in schizophrenia.

Adult↗

PubMed2005

Selective effects of typical antipsychotic drugs on SNAP-25 and synaptophysin in the hippocampal trisynaptic pathway.

Recent studies indicate that levels of presynaptic proteins are altered in the post-mortem brain in schizophrenia. In particular, the hippocampus exhibits reduced levels of synaptophysin and the SNARE protein SNAP-25. The effects of treatment with antipsychotic drugs on levels of SNAP-25 in the hippocampus remains unknown. To determine the effects of typical antipsychotic drugs on levels of synaptophysin and SNAP-25 in the hippocampus, rats were treated with chlorpromazine, haloperidol or trifluoperazine for 21 d. Quantitative immunohistochemistry was used to measure immunoreactivity within the trisynaptic circuit of the hippocampus. Trifluoperazine decreased synaptophysin within the Schaffer collateral region of the radiatum lacunosum in CA1, while haloperidol and chlorpromazine increased SNAP-25 throughout the trisynaptic pathway of the hippocampus, with strongest effects in the mossy fibre region of CA3. These results indicate that presynaptic proteins represent a potential molecular substrate for the effects of antipsychotic drugs on hippocampal synaptic connectivity.

Animals↗

PubMed2005

Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.

BACKGROUND: Converging neuroimaging and postmortem evidence indicates synaptic terminals are abnormal in schizophrenia. A putative molecular mechanism implicates abnormalities of proteins involved in the presynaptic secretory machinery, including the modulator proteins complexin I and complexin II. OBJECTIVES: To determine the amount and distribution of complexin proteins in the hippocampus of subjects with schizophrenia, in parallel with markers for excitatory and inhibitory nerve terminals. The functional implications were also investigated. DESIGN: We used immunocytochemistry to study complexin I and complexin II proteins in hippocampus, as well as the vesicular transporters for gamma-aminobutyric acid (GABA) and for glutamate. Immunocytochemical findings were correlated with cognitive function assessed through medical record review. To further explore the implications of the human findings, we studied rats exposed to haloperidol, amphetamine, and ketamine as well as rats trained in memory tasks. SUBJECTS: We studied hippocampal sections from 12 subjects with schizophrenia and 12 subjects with no known neuropsychiatric disorder. RESULTS: The absolute values and ratio of the hippocampal presynaptic proteins complexin II-complexin I were lower in subjects with schizophrenia. Disturbances in the complexin proteins in subjects with schizophrenia were greater than those observed for vesicular gamma-aminobutyric acid or vesicular glutamate transporters. The lower complexin II-complexin I ratio in several hippocampal subfields in subjects with schizophrenia was inversely correlated with the severity of antemortem cognitive impairment. In contrast, the hippocampal complexin II-complexin I ratio was higher in rats trained in a memory task compared with untrained rats. Treatment of rats with antipsychotic drugs or with the psychotomimetic drugs amphetamine or ketamine did not alter the complexin II-complexin I ratio. CONCLUSIONS: The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances.

Adaptor Proteins, Vesicular Transport↗

PubMed2005

Prenatal ethanol exposure in rats decreases levels of complexin proteins in the frontal cortex.

BACKGROUND: Rodents that are prenatally exposed to ethanol have been shown to exhibit a wide range of cognitive deficits, including impairments in memory, attention and executive function. To determine a potential molecular substrate for cognitive dysfunction in adulthood, we measured regional levels of the presynaptic proteins complexin I and II in a rat model of prenatal ethanol exposure, as levels of these proteins are altered in cognitive-related synaptic plasticity. METHODS: Pregnant female rats received either a liquid ethanol diet (36% ethanol-derived calories) or a liquid control diet (maltose-dextrin isocalorically substituted for ethanol, matched in amount [g/kg body wt/day of gestation] to an ethanol-consuming partner), or were given ad libitum-fed access to standard laboratory chow and water. Levels of complexin I, II and the ubiquitous presynaptic marker synaptophysin were measured in the frontal cortex and hippocampus of adult male offspring, using ELISA. RESULTS: Prenatal exposure to ethanol did not alter levels of presynaptic proteins in the hippocampus or levels of synaptophysin in the prefrontal cortex. However, rats prenatally exposed to ethanol displayed significantly lower levels of both complexin I and II in the prefrontal cortex compared to control animals. CONCLUSIONS: These data indicate that prenatal exposure to ethanol is associated with a selective loss of complexin proteins in the frontal cortex. These proteins are known to be important for activity-dependent neurotransmission, and have previously been shown to mediate synaptic plasticity and cognition. These combined findings suggest that further study of complexin proteins as a substrate for cognitive impairment related to prenatal exposure to ethanol is warranted.

Adaptor Proteins, Vesicular Transport↗

PubMed2004

Attenuation of d-amphetamine self-administration by baclofen in the rat: behavioral and neurochemical correlates.

RATIONALE: Recent reports have demonstrated that gamma-aminobutyric acid (GABA)-ergic compounds attenuate the reinforcing effects of cocaine in rats. Baclofen, a GABA(B) receptor agonist, appears to be particularly effective in this respect, suggesting that GABA(B) receptor activation is critically involved in mediating anti-cocaine effects. Amphetamine, like cocaine, is a psychomotor stimulant with high abuse potential in humans. OBJECTIVES: The purpose of the present investigation was to determine whether baclofen may attenuate the reinforcing effects of d-amphetamine (dAMPH) in rats. Dose-response curves were generated to examine the effect of three doses of baclofen (1.8, 3.2 or 5.6 mg/kg, IP) on dAMPH intravenous self-administration (IVSA). Separate groups were trained to self-administer two doses of dAMPH (0.1 mg/kg or 0.2 mg/kg per injection) under either a fixed-ratio (FR) or progressive ratio (PR) schedule of reinforcement. Microdialysis was performed in an additional group of rats to examine the effect of baclofen on dAMPH-induced increases in dopamine (DA) efflux in the nucleus accumbens (NAc). RESULTS: Pretreatment with baclofen produced dose-dependent reductions in responding for dAMPH under both the FR and PR schedules, and attenuated dAMPH-induced increases in DA levels in the NAc. CONCLUSION: These results add to previous findings showing that baclofen attenuates the reinforcing effects of psychostimulant drugs, and suggest that further investigation into the effects of GABA(B) receptor agonists on drug self-administration is warranted.

Amphetamine-Related Disorders↗

PubMed2004

Electrical stimulation of the hippocampus disrupts prepulse inhibition in rats: frequency- and site-dependent effects.

Prepulse inhibition (PPI) is a normal reduction in the startle response produced when a brief, low intensity stimulus is presented prior to a startle-evoking stimulus. PPI is often disrupted in humans diagnosed with schizophrenia. As similar stimuli elicit PPI in rodents and humans, interventions in rodents that disrupt PPI may reveal aspects of neuronal dysfunction relevant to schizophrenia. Stimulation of the ventral hippocampus (vHip) with NMDA significantly increases dopamine (DA) efflux in the nucleus accumbens (NAc) and disrupts PPI, whereas NMDA infusion into the dorsal hippocampus (dHip) fails to alter PPI. Our previous research shows that brief periods of 20 Hz electrical vHip stimulation also significantly increase NAc DA efflux. The present experiments assessed the effects of stimulating the vHip or dHip on PPI and NAc DA efflux. As predicted, 20 Hz stimulation (10 s, 300 microA) of the vHip, but not the dHip, reversibly disrupted PPI. In contrast, 2 Hz stimulation (100 s, 300 microA) of the vHip failed to affect PPI. Microdialysis experiments revealed that 20 Hz stimulation of the vHip increased NAc DA efflux only in the hemisphere ipsilateral to the stimulating electrode, whereas 20 Hz stimulation of the dHip failed to affect NAc DA efflux. These data demonstrate the regional specificity and frequency-dependent effects of hippocampal activity on PPI. Additionally, it is intriguing that both chemical and electrical stimulation of the vHip disrupt PPI and increase NAc DA efflux, however, the relevance of these changes in NAc DA efflux to the disruption of PPI remains to be determined.

Animals↗

PubMed2004

Interaction between perirhinal and medial prefrontal cortex is required for temporal order but not recognition memory for objects in rats.

The present study investigated the roles of the perirhinal cortex, medial prefrontal cortex, and intrahemispheric interactions between them in recognition and temporal order memory for objects. Experiment 1 assessed the effects of bilateral microinfusions of the sodium channel blocker lidocaine into either the anterior perirhinal or medial prefrontal cortex immediately before memory testing in a familiarity discrimination task and a recency discrimination task, both of which involved spontaneous exploration of objects. Inactivation of the perirhinal cortex disrupted performance in both tasks, whereas inactivation of the medial prefrontal cortex disrupted performance in the recency, but not the familiarity, discrimination task. In a second experiment, the importance of intrahemispheric interactions between these structures in temporal order memory were assessed by comparing the effects of unilateral inactivation of either structure alone with those of crossed unilateral inactivation of both structures on the recency discrimination task. Crossed unilateral inactivation of both structures produced a significant impairment, whereas inactivation of either structure alone produced little or no impairment. Collectively, these findings suggest that the perirhinal cortex, but not the medial prefrontal cortex, contributes to retrieval of information necessary for long-term object recognition, whereas both structures, via intrahemispheric interactions between them, contribute to retrieval of information necessary for long-term object temporal order memory. These data are consistent with models in which attributed information is stored in posterior cortical sites and supports lower-order mnemonic functions (e.g., recognition memory) but can also be retrieved and further processed via interactions with the prefrontal cortex to support higher-order mnemonic functions (e.g., temporal order memory).

Animals↗

PubMed2004

Magnitude of dopamine release in medial prefrontal cortex predicts accuracy of memory on a delayed response task.

Modulation of neural function in the prefrontal cortex (PFC) by dopamine (DA) is essential for higher cognitive processes related to attention, working memory, and planning of future behavior. The present study demonstrates that DA efflux in the PFC is increased in a phasic manner when a rat engages in search behavior for food reward on an eight arm radial maze guided by memory, independent of whether or not reward is obtained for making the correct choice. Furthermore, disruption of accurate recall of the correct pattern of arms induced by increasing the delay period from 30 min to 1 or 6 hr, is associated with attenuated DA efflux during the retrieval phase of the task. The observed increase in DA efflux in the absence of reward at a 30 min delay and the minimal increase during consumption of the same quantity of food during poor performance after an unexpected 6 hr delay, argue against a simple relationship between DA function in the PFC and reward processes. Instead, these data demonstrate a close functional relationship between the release of DA from terminals within the PFC and the retrieval of specific trial unique memories; furthermore, the magnitude of mesocortical DA efflux is predictive of the accuracy of this form of memory.

Animals↗

PubMed2004

Attenuated dopamine efflux in the rat nucleus accumbens during successive negative contrast.

Rats shifted from 4% to 32% sucrose displayed successive negative contrast by initiating significantly fewer bouts of licking than control rats maintained on 4% sucrose. No significant increase in dopamine (DA) efflux in the nucleus accumbens (NAc) was observed during consumption of 4% sucrose by rats shifted from 32%. In contrast, consumption of 4% sucrose by control rats was accompanied by a significant increase in DA efflux in the NAc, which remained elevated 10 min postconsumption. These data are consistent with the hypothesis that DA efflux in the NAc reflects the current incentive valence of sucrose reward and its influence on initiation of individual bouts of sucrose consumption.

Adaptation, Psychological↗

PubMed2004

Abnormalities of presynaptic protein CDCrel-1 in striatum of rats reared in social isolation: relevance to neural connectivity in schizophrenia.

Post-weaning social isolation-rearing of rats leads to behavioural and neurochemical sequelae that model aspects of schizophrenia, and it may be useful to test hypotheses related to putative molecular mechanisms of the illness. In humans, the presynaptic protein CDCrel-1 represents an interesting candidate molecule for the mechanism and aetiology of schizophrenia. CDCrel-1 modulates dopamine neurotransmission, binds to the SNARE protein syntaxin and maps onto a region of chromosome 22q11 deleted in velo-cardio-facial and DiGeorge syndromes, which are associated with increased prevalence of schizophrenia. Using the isolation-rearing model, we measured immunoreactivity of the synaptic proteins CDCrel-1, synaptophysin and syntaxin. Male, Sprague-Dawley rats were raised in groups or in isolation for 12 weeks from weaning. Synaptic protein immunoreactivities were measured in striatal and hippocampal homogenates, using a sensitive enzyme-linked immunoadsorbent assay with monoclonal antibodies. Isolation-rearing produced region- and protein-specific effects. CDCrel-1 immunoreactivity was significantly lower in the striatum and marginally higher in the hippocampus of isolation-reared compared with socially reared animals. There were no statistically significant differences in synaptophysin immunoreactivity in either region. Confocal microscopy demonstrated a high degree of colocalization between the two presynaptic proteins. In striatum, a robust relationship between CDCrel-1 and syntaxin immunoreactivities was observed in socially reared rats, this was lost in the isolation-reared animals. Altered levels of the septin CDCrel-1 in isolation-reared rats may contribute to changes in neuronal connectivity and neurotransmission, and suggest a potential role for CDCrel-1 in schizophrenia related to chromosome 22q11 deletion syndrome.

Animals↗

PubMed2004

Delayed onset of prepulse inhibition deficits following kainic acid treatment on postnatal day 7 in rats.

Abnormal activity in corticolimbic circuits during development may be a predisposing factor for schizophrenia. Permanent or temporary lesions of limbic structures such as the ventral hippocampus and basolateral amygdala in rats on postnatal day (PND) 7 result in functional changes similar to some behavioural and cognitive signs of schizophrenia. The present experiments tested whether transient increases in the neural activity of corticolimbic circuits on PND 7 would result in similar behavioural changes. Long-Evans rats were treated with either kainic acid (KA, 1.5 mg/kg, i.p.) or saline on PND 7 and tested for prepulse inhibition (PPI) of the acoustic startle response and spontaneous locomotor activity both in a novel environment and following amphetamine treatment before puberty (PND 35) and in early adulthood (PND 56). In subgroups of animals PPI was also measured following apomorphine administration (0.2 mg/kg) and spatial learning and memory were tested in the water maze. Rats treated with KA were indistinguishable from saline-treated animals on PND 35. However, on PND 56, KA-treated animals showed a subtle consistent decrease in PPI relative to control animals, but did not show increased sensitivity to the disruptive effects of a low dose of apomorphine on PPI. Locomotor responses to novelty or amphetamine were not reliably altered in the KA-treated animals. KA- and saline-treated animals performed similarly in the water maze. These results support the hypothesis that neural hyperactivity on PND 7 in rats causes behavioural changes in early adulthood that resemble some symptoms of schizophrenia. These pharmacological data suggest that the changes are not mediated by postsynaptic alterations in mesolimbic dopamine transmission.

Acoustic Stimulation↗

PubMed2003

Neurochemical correlates of relapse to d-amphetamine self-administration by rats induced by stimulation of the ventral subiculum.

RATIONALE AND OBJECTIVES: Previous studies show that electrical stimulation of the ventral subiculum (vSub) can reinstate drug-seeking behavior in rats following extinction. This study examined whether vSub stimulation could also evoke reinitiation of d-amphetamine (d-AMPH) self-administration during voluntary abstinence following a prolonged bout of drug intake. Dynamic changes in extracellular levels of dopamine (DA) and metabolites in the nucleus accumbens (NAc) during 48-h unlimited access to d-AMPH by rats were monitored. Neurochemical correlates of relapse to d-AMPH administration induced by vSub stimulation or by experimenter administered d-AMPH infusions were also examined during voluntary abstinence in separate experiments. METHODS AND RESULTS: In vivo microdialysis using high-pressure liquid chromatography with electrochemical detector (HPLC-EC) was used to monitor changes in DA and metabolite efflux in the NAc during a continuous access-abstinence-relapse cycle of d-AMPH self-administration in a 48-h test. The initial pattern of drug intake was associated with significant increases in DA efflux in the NAc. During the abstinence phase, DA efflux was near pre-session baseline values. Electrical stimulation at the vSub after 2 h of abstinence immediately induced a significant increase in DA efflux and reinstatement of drug self-administration behavior. Evoked DA release and responses on drug-paired lever induced by vSub stimulation were significantly greater than those induced by experimenter-administered d-AMPH. CONCLUSIONS: Relapse to drug-taking behavior can be triggered by activation of the subicular glutamatergic pathway to the NAc. This study also confirmed that during abstinence the neurochemical response of the mesolimbic DA system to d-AMPH is attenuated and this can be reversed by vSub stimulation.

Animals↗

PubMed2003

Amygdalar control of the mesocorticolimbic dopamine system: parallel pathways to motivated behavior.

The present review focuses on recent findings from our laboratory showing that there are major differences in the influence exerted by the central (CeN) and basolateral (BLA) nuclei of the amygdala on dopamine (DA) efflux in the nucleus accumbens (NAc) of the rat. Based on these data, we propose that the CeN maintains control, via an indirect pathway, of the tonic activity of a population of ventral tegmental dopamine neurons that specifically regulate basal DA efflux in the NAc. Related experiments also support the hypothesis that control of mesocorticolimbic DA activity by the CeN can influence the incentive value of the sensory property of food and its modulation by the drive-state of the animal. In contrast, we suggest that activation of the BLA can evoke transient increases in DA efflux in the NAc and medial prefrontal cortex (mPFC) and may also stabilize the activity of dopaminergic neurons projecting to the mPFC. We hypothesize that the rapid transient regulation of DA efflux in the NAc by the BLA plays an essential role in the selection and co-ordination of specific sequences of behaviors appropriate to incentive stimuli present in the environment. In this manner, the amygdala may exert differential control on motivated behavior, thereby ensuring the selection of behavioral responses that are optimal for survival.

Amygdala↗

PubMed2003

Tolerance to the anhedonic effects of lipopolysaccharide is associated with changes in syntaxin immunoreactivity in the nucleus accumbens.

The bacterial endotoxin lipopolysaccharide (LPS) produces a host of effects in mammals known collectively as 'sickness' behaviours. Acute treatment with LPS also results in a loss of hedonic capacity in rodents that can be measured by changes in responding for reinforcing electrical stimulation of the lateral hypothalamus. In contrast, repeated exposure to LPS typically leads to the development of tolerance to many of the physiological and behavioural effects of endotoxin, although the effect of chronic treatment with LPS on anhedonia remains unknown. In the present experiment, rats were trained to respond on an ascending-series current-intensity intracranial self-stimulation (ICSS) protocol, and were then treated with either acute or sub-chronic LPS (100 microg). Compared to vehicle-treated subjects, acute exposure to LPS induced a dramatic loss of ICSS responding; however, with repeated exposure to LPS, rats developed a behavioural tolerance to its anhedonic effects. To investigate a potential molecular substrate for the anhedonic effects of LPS, quantitative immunohistochemistry was used to measure levels of the synaptic proteins syntaxin, SNAP-25 and synaptophysin in the dorsal and ventral striatum of rats treated acutely and sub-chronically with LPS. A single injection of LPS produced a significant decrease in syntaxin immunoreactivity in the nucleus accumbens core and shell, while similar treatment in chronically treated rats that displayed behavioural tolerance had no effect. These results demonstrate a novel molecular substrate for the effects of LPS, and imply that the underlying physiology of the transient anhedonic effects of LPS may differ from that involved in chronic psychiatric disorders in humans.

Analysis of Variance↗