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Objective: The G‐allele of the ‐1019C/G (rs6295) promoter polymorphism of the serotonin receptor 1A (HTR1A) gene has been implicated in anxiety; however, the underlying neurophysiological processes are still not fully understood. Recent evidence indicates that low parasympathetic (vagal) tone is predictive of anxiety. We thus conducted a structural equation model (SEM) to examine whether the HTR1A rs6295 variant can affect anxiety by altering parasympathetic nervous activity. Method: A sample of 1141 drug‐free healthy Han Chinese was recruited for HTR1A genotyping. Autonomic nervous function was assessed by short‐term spectral analysis of heart rate variability (HRV). Anxiety and stress levels were evaluated by the Beck Anxiety Inventory (BAI) and the Perceived Stress Scale (PSS) respectively. Results: The number of the HTR1A G allele was inversely correlated with high‐frequency power (HF), a parasympathetic index of HRV. The HF index was negatively associated with BAI scores. Furthermore, the good‐fitting SEM, adjusting for confounding variables (e.g., age and PSS levels), revealed a significant pathway linking rs6295 variant to BAI scores via HF index modulation. Conclusion: These results are the first to show that HTR1A ‐1019C/G polymorphism influences anxiety levels by modulating parasympathetic tone, providing a neurophysiological insight into the role of HTR1A in human anxiety. [ABSTRACT FROM AUTHOR]

Hyperbaric oxygen (HBO2) has been shown to inhibit the adhesion function of beta(2)-integrin, which is important in mediating cell-to-cell adhesion and extravasation of inflammatory cells. In the present study, we examined the effects of HBO2 exposure on neutrophil infiltration and tissue injury in a model of acute lung inflammation induced by lipopolysaccharide (LPS) inhalation. Male C57BL/6 mice of 8 weeks old were exposed to 3 atmosphere absolute (ATA) 100% HBO2, 3 ATA hyperbaric air (HBA), or room air for 90 min. After exposure, they were exposed to aerosolized LPS solution (1 mg/ml) or saline in a plexiglass chamber for 10 min. Four hours after inhalation, bronchoalveolar lavage (BAL) was performed to determine protein concentration, LDH activity, total cells, and differential cell counts in the lavage fluid (BALF). Myeloperoxidase (MPO) content, lung histopathology, and plasma nitric oxide (NO) metabolite concentrations were also determined in separate sets of animals. We observed that LPS inhalation increased neutrophil number in the BALF, which was significantly inhibited by HBO2 but not HBA pre-exposure. However, MPO content in the lung was prominently increased by HBO2 pre-exposure, which correlated with increased PMN infiltration in lung tissues. Further, HBO2 plus LPS, but not saline inhalation caused a significant increase in the BALF protein level and LDH activity compared with that of LPS inhalation alone. LPS exposure induced significant increase in plasma NO metabolites, which was not potentiated by HBO2 pre-exposure. The inducible nitric oxide synthase inhibitor, aminoguanidine, significantly attenuated the increases in plasma NO metabolites and tissue MPO content as well as lung injuries. In summary, our data suggest that HBO2 pre-exposure increases the lung's susceptibility to inhaled LPS, which may be related to increased tissue neutrophil infiltration and dependent on interaction(s) between HBO2 exposure with LPS-induced nitric oxide production.

This study aims to investigate the relationship between the determination of dopamine level by high performance liquid chromatography (HPLC) with electrochemical detection (ECD) and the detection of dopamine transporter (DAT) counts using autoradiography with DAT image agent [99mTc]TRODAT-1. For striatal lesions, pretreatment of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle shows that autoradiogaphic labeling of striatum region is reduced to near-background level. Using HPLC with ECD, unilateral 6-OHDA treatment is associated with significant (p < 0. 0002) reductions of dopamine levels. For the striatum of the 6-OHDA-lesioned side, dopamine content and DAT counts are reduced to 97% and 90%, respectively. Thus, our observation indicates a potential of using [99mTc]TRODAT-1 for the evaluation of animal DAT.

This study investigated the performance of schedule-induced polydipsia (SIP) rats in novel or intermittent-reward SIP sessions after arecoline (AREC) and amphetamine sulfate (AMPH) treatments. Either automatic monitors or observers extensively examined the functional changes of parameters in behavioral performance followed by increasing drug dosage. The parameters included locomotion and stereotyped behaviors in the novel sessions; schedule-induced licks, water intake, schedule-dependent nose-pokes, pellets earned and stereotyped behaviors of the facultative stage in the SIP sessions. It was found that when the rats received AMPH (0.5 - 2.0 mg/kg) but not AREC (0.1 - 1.6 mg/kg) in the novel sessions, locomotion increased in a dose-dependent manner. However, when AREC (0.8 mg/kg) and AMPH (1.0 mg/kg) were both given, the effect of AMPH on locomotion was significantly attenuated. In the SIP sessions, a single injection of AMPH increased the number of schedule-dependent nose-pokes at a dose of 1.0 mg/kg, whereas it decreased the number of schedule-induced licks and the amount of water intake at a dose of 2.0 mg/kg. On the other hand a single injection of AREC caused no operant behavior changes at doses below 0.8 mg/kg. However, when the dose was increased to over 0.8 mg/kg (1.6 mg/kg), the number of schedule-induced licks and water intake increased, but the number of schedule-induced nose-pokes decreased. The effects of large doses of AREC on SIP were attenuated after co-administration of scopolamine (0.1 mg/kg), a muscarinic receptor antagonist. Furthermore, the effects of AMPH on SIP performance were not changed by co-administration of AREC at a dose of 0.8 mg/kg. These results are discussed based on the hypothesis that combined utilization of the main component in chewing betel quid, AREC, and AMPH may yield changes of AMPH-induced psychomotor responses in a special environmental context.

In dopaminergic neurons, free radicals are likely produced via dopamine metabolism by monoamine oxidase or via its auto-oxidation, a process facilitated by transition metals. In this study we examined the effect and possible mechanisms of apomorphine to reduce iron- and dopamine-induced 2,3-dihydroxybenzoic acid (2,3-DHBA) formation by microdialysis. We have shown that (1) FeSO(4).7H(2)O reduced both the release of dopamine and the output of dihydroxyphenylacetic acid (DOPAC); (2) apomorphine may reduce FeSO(4).7H(2)O-induced increases of 2,3-DHBA formation; (3) apomorphine has substantially reduced DOPAC output in early phase and blocked dopamine-induced increase of 2,3-DHBA levels. It is concluded that apomorphine is a potent hydroxyl radical scavenger in vivo, especially for the dopamine formation.

We have previously demonstrated that integrin-associated protein is involved in memory consolidation of one-way inhibitory avoidance learning in rats and mice. In the present study, we examined the effects of functional blocking of integrin-associated protein on memory retention, long-term potentiation and glutamate release in mice as well as on cell attachment to extracellular matrix protein in primary cultures. The results indicated that integrin-associated protein monoclonal antibody miap301, when directly injected into the dentate gyrus of the hippocampus at moderate doses, significantly impairs memory retention in mice in the same one-way inhibitory avoidance task and decreases the amplitude of tetanic stimulation-induced long-term potentiation in dentate gyrus neurons. At a dose that effectively impairs both memory retention and long-term potentiation, integrin-associated protein monoclonal antibody also significantly blocks potassium chloride-induced glutamate release from the hippocampus in vivo. Results from western blot confirmed the presence of integrin-associated protein at the synaptic area. Cell adhesion experiments further revealed that integrin-associated protein monoclonal antibody markedly inhibits granular cell attachment to thrombospondin, the extracellular matrix protein known to bind integrin-associated protein, but not to collagen and laminin, the extracellular matrix proteins known to bind integrin. From these results we suggest that integrin-associated protein monoclonal antibody may impair synaptic plasticity and behavioral plasticity in mice through blockade of granular cell attachment to extracellular matrix protein and the subsequent signal transduction, and through inhibition of glutamate release from the hippocampus.

While seizure attack is one of the serious complications during the hyperbaric oxygen (HBO) therapy, there is still no direct evidence showing that HBO can induce neuronal damage in the brain. The objective of this study was first to investigate whether HBO would lead to neurotoxicity in the primary rat cortical culture. Second, since alterations in neurotransmitters have been suggested in the pathophysiology of central nervous system (CNS) oxygen toxicity, the protective effects of the N-methyl-D-aspartate (NMDA) receptor antagonism and nitric oxide (NO) synthase inhibition on the HBO-induced neuronal damage were examined. The results showed that HBO exposure to 6 atmosphere absolute pressure (ATA) for 30, 60, and 90 min increased the lactate dehydrogenase (LDH) activity in the culture medium in a time-dependent manner. Accordingly, the cell survival, measured by the 3,(4,5-dimethyl-2-thiazolyl)2, 5-diphenyl-tetrazolium bromide (MTT) assay, was decreased after HBO exposure. Pretreatment with the NMDA antagonist MK-801 protected the cells against the HBO-induced damage. The protective effect was also noted in the cells pretreated with L-N(G)-nitro-arginine methyl ester, an NO synthase inhibitor. Thus, our results suggest that activation of NMDA receptors and production of NO play a role in the neurotoxicity produced by hyperbaric oxygen exposure.

Nitric oxide (NO) and glutamate are both important mediators of the central cardiovascular regulation in the nucleus tractus solitarii. Our previous studies revealed that the central cardiovascular effects of NO in the nucleus tractus solitarii could be inhibited by glutamate receptor blockade. On the other hand, nitric oxide synthase (NOS) inhibitor attenuated the cardiovascular effects of glutamate. Thus, NO and glutamatergic systems appear to interact in central cardiovascular regulation. The present study examined whether NO and glutamate may affect each other's release/production in the nucleus tractus solitarii. A microdialysis probe was implanted into the nucleus tractus solitarii of male Sprague-Dawley rats, and the changes in the extracellular levels of glutamate and NO were determined by high performance liquid chromatography coupled with electrochemical detection and an NO analyzer, respectively. The results showed that NO solution elicited >10 fold increases in the extracellular level of glutamate, which returned to normal 60 min after the end of NO perfusion. The NO donor N-acetyl-penicillamine (SNAP) had an effect similar to NO solution. Furthermore, the glutamate level was reduced to 61% of basal value by perfusion with the NOS inhibitor, N(G)-monomethyl-L-arginine (L-NMMA). When glutamate receptor agonist N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methylixoxazole-4-propionic acid (AMPA) was administered into the nucleus tractus solitarii, the extracellular NO level was increased by 70-100%, whereas glutamate receptor antagonists (MK-801 hydrogen maleate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)) did not alter the basal levels of NO. These results suggest that NO and glutamate may enhance each other's release/production in the nucleus tractus solitarii. This reciprocal regulation of NO and glutamate may be important in central cardiovascular control in the nucleus tractus solitarii.

Long-term or high dose administration of d-amphetamine (AMPH) in the rat has been shown to result in dopamine terminal neurotoxicity in the striatum of rats. This phenomenon includes depletion of dopamine content, decreased activity of tyrosine hydroxylase and diminish in the number of dopamine reuptake transporter. Recent studies implicate a role of oxidative stress induced by dopamine in the AMPH-induced neurotoxicity. However, the primary source of dopamine responsible for radical formation during AMPH challenge has remained elusive. To elucidate this issue, the study was designed to examine the effects of nomifensine, a dopamine transporter blocker, and deprenyl, a monoamine oxidase B (MAO-B) inhibitor, on the prevention of striatal dopamine neurotoxicity in AMPH-treated rats. The results showed that nomifensine but not deprenyl protected against AMPH-induced long-term dopamine depletion. Correspondingly, the hydroxyl radical formation caused by AMPH in the striatum was attenuated by nomifensine, whereas its formation was not abolished by deprenyl. In conclusion, this study suggests that intracellular oxidative stress is more likely involved in the AMPH-induced dopamine terminal toxicity in the rat striatum, while this phenomenon is not mediated by MAO-B pathway.

The long-term effect of d-amphetamine (AMPH) on the induction of oxidative stress was examined in vivo in the rat brain. In this study, 2,3-dihydroxybenzoic acid (2,3-DHBA) and malonaldehyde (MDA) were used as the index of the hydroxyl radical and lipid peroxidation, respectively. The levels of 2,3-DHBA, MDA and dopamine (DA) in striatal homogenates were examined 7 days following injection of a single large dose of AMPH (7.5 mg/kg, i.p.) in rats pretreated with desipramine (10 mg/kg, i.p.), an agent that inhibits the metabolism of AMPH. Our results showed that 2,3-DHBA and MDA levels were significantly increased by AMPH, whereas DA and its metabolites, DOPAC and HVA were depleted in the striatum. Pretreatment with the glutamate NMDA receptor subtype antagonist MK-801 (1 mg/kg, i.p.) attenuated the increases of 2,3-DHBA and MDA, and provided partial protection against the long-lasting loss of DA produced by AMPH. Overall, the results demonstrate that AMPH could induce sustained production of free radical and oxidative damage, and lead to DA terminal degeneration in the striatum of the rat.

Recent evidence suggests that free radicals can be produced in the brain following systemic administration of repeated or high doses of D-amphetamine (AMPH). However, it has been proposed that the toxic effects of AMPH are mostly secondary to AMPH-induced hyperthermia, and agents that protect against AMPH neurotoxicity do so by blocking AMPH-induced hyperthermia or causing hypothermia. In this study, we examined the effects of AMPH on the formation of hydroxyl radicals (*OH) following its infusion into the rat striatum via a microdialysis probe. We found that intra-striatal perfusion of AMPH (10 microM) caused an increased formation of hydroxyl radicals but did not raise the core temperatures of the rats. Pretreatment with the NMDA antagonist MK-801 (0.5 mg/kg) attenuated hydroxyl radical production elicited by AMPH infusion, although core body temperatures in AMPH-treated rats were not significantly altered. Additionally, infusion of AMPH in the striatum increased extracellular dopamine concentration and this effect was potentiated by MK-801 pretreatment. Thus, these results demonstrate that direct infusion of AMPH in the striatum induces hydroxyl radical production without causing hyperthermia, and also imply that activation of glutamate NMDA receptors mediates, at least in part, AMPH-induced hydroxyl radical formation in the rat striatum.

Nitric oxide (NO) is a free-radical gas with a role in various signal transduction processes. In the CNS, NO acts as an important central nervous messenger, but in excess it may be neurotoxic. Chronic or high dose administration of D-amphetamine (AMPH) has been shown to induce striatal neurotoxicity in rodents and primates. In this study, we studied whether AMPH given systemically elicits NO formation in the striatum of rats and determined the relationship between NO formation and striatal DAergic terminal damage. Our results demonstrated that a single large dose administration of AMPH with desipramine elicited a delayed production of NO and concomitant long-term DA loss in the striatum. These phenomena were blocked by treatment with either the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or the glutamate N-methyl-D-aspartate antagonist MK-801. It appears that AMPH-induced NO formation is critical for development of long-lasting DAergic terminal toxicity in the striatum of rats.

We have previously demonstrated that L-arginine produces profound cardiovascular effects when microinjected into the nucleus tractus solitarii (NTS) of the rat. The present study extended our earlier work and examined further the underlying mechanisms of action of L-arginine in the NTS. Our results showed that intra-NTS microinjection of L-arginine (0.1-10 nmol) elicited dose-dependent depressor and bradycardic effects that were not significantly evoked by equivalent doses of D-arginine. The effects of L-arginine were blocked by pre-injection of 7-nitroindazole (0.02-1 nmol), a neuronal nitric oxide synthase inhibitor. Additionally, application of the calmodulin inhibitor W-7 (0.01-0.33 nmol) reduced cardiovascular responses to L-arginine (10 nmol) in a dose-dependent manner. Pre-injections of soluble guanylyl cyclase inhibitors, LY83583 (0.01-0.33 nmol) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 0.03-1 pmol) both suppressed the L-arginine-induced depressor and bradycardic effects. Finally, the cardiovascular effects of L-arginine in the NTS were attenuated by HA1004 (0.1-1 nmol), a cGMP-dependent protein kinase inhibitor, but not by the protein kinase C inhibitor H-7 (1 nmol). Taken together, the results indicate that the cardiovascular effects produced by L-arginine in the NTS are inhibited by pharmacological interventions that block nitric oxide production and cGMP-PKG signaling pathway within the nucleus.

The present study examined the effects of nicotinamide on the D-amphetamine (AMPH)-induced dopamine (DA) depletion and energy metabolism change in the rat striatum. In chronic studies, co-administration of AMPH with desipramine, a drug that retards the metabolism of AMPH, (10 mg/kg, intraperitoneal [i.p.], respectively) caused a significant decrease of striatal DA content measured 7 days later. Pretreatment with nicotinamide (500 mg/kg, i.p.), the precursor molecule for the electron carrier molecule nicotinamide adenine dinucleotide (NAD), attenuated this effect of AMPH, whereas itself exerted no long-term effect on striatal DA content. In acute studies, a decrease in striatal adenosine triphospate/adenosine diphosphate (ATP/ADP) ratio was found 3 h after co-injection of AMPH and desipramine. However, nicotinamide pretreatment blocked the reduced striatal ATP/ADP ratio and resulted in a striking increase in striatal NAD content in AMPH-treated rats. Furthermore, nicotinamide was noted to increase striatal ATP/ADP ratio and NAD content in saline-treated rats. These findings suggest that nicotinamide protects against AMPH-induced DAergic neurotoxicity in the striatum of rats via energy supplement.

Both nitric oxide (NO) and glutamate in the brain stem nuclei are involved in central cardiovascular regulation. In the present study, we investigated possible functional interactions between NO and glutamate in the modulation of cardiovascular function in the nucleus tractus solitarii (NTS) of anesthetized rats. In Sprague-Dawley rats, intra-NTS unilateral microinjections of L-glutamate (0.1 nmol/60 nl) and its ionotropic agonists NMDA (5 pmol) and AMPA (2 pmol) resulted in significant decreases in mean blood pressure (MBP) and heart rate (HR). The cardiovascular effects of L-glutamate, NMDA and AMPA were significantly blocked by prior administration of the neuronal NO synthase (nNOS) inhibitor, 7-nitroindazole (7-NI, 0.5 nmol), or by the soluble guanylyl cyclase (sGC) inhibitor, 1H-[1.2.4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 0.03-1 pmol). Conversely, a depressor and bradycardic effect was elicited by microinjection of either the NO precursor L-arginine (10 nmol) or the NO donor sodium nitroprusside (SNP, 0.2 nmol) into the NTS. Prior administration of the NMDA receptor antagonists MK-801 (0.1-1 nmol) and APV (0.1-4 nmol) significantly attenuated these effects of L-arginine. Similarly, cardiovascular responses to L-arginine in the NTS were inhibited by pre-injections with the non-NMDA receptor antagonists CNQX (10-330 pmol) and NBQX (2-10 pmol). Furthermore, APV (4 nmol) and CNQX (330 pmol) attenuated the depressor and bradycardic effects of SNP, respectively. This study demonstrates that baroreflex-like responses to microinjections of L-glutamate and its ionotropic agonists into the NTS involve synthesis of NO and activation of sGC. Reciprocally, central cardiovascular effects of NO also depend on responsive ionotropic glutamate receptors.

The aim of the present study was to examine the effects of nicotinamide, a co-factor in the electron transport chain, on the relationship between methamphetamine (MA)-induced striatal dopamine (DA) depletion and energy metabolism change. Four injections of MA (10 mg/kg, i.p.) at 2 h intervals resulted in decreases of 51% and 23%, respectively, in striatal DA and adenosine 5'-triphosphate (ATP) levels 5 days later. Nicotinamide (500 mg/kg, i.p.) treatment prior to each MA injection attenuated the reductions of striatal DA and ATP contents. Nicotinamide had no long-term effects on striatal DA and ATP levels. These findings suggest that energy impairment might play a role in MA-induced DAergic neurotoxicity in the striatum.

The acoustic startle reflex is a coordinated contraction of the skeletal musculature in response to a sudden, intense sound. One form of startle plasticity, "prepulse inhibition", is the normal suppression of the startle reflex when the intense startling stimulus is immediately preceded by a weak pre-stimulus. Prepulse inhibition is utilized as an operational measure of sensorimotor gating, and is significantly impaired in several neuropsychiatric disorders that are characterized by symptoms associated with central inhibitory deficits. In rats, prepulse inhibition is disrupted by central dopamine activation or by manipulations of limbic cortical structures including the prefrontal cortex and hippocampus. In the present study, we assessed prepulse inhibition in rats after surgical and pharmacologic manipulations of the basolateral amygdala. Quinolinic acid lesions of the basolateral amygdala significantly reduced prepulse inhibition without significantly changing startle amplitude. These lesions also blocked fear-potentiated startle, which is known to be regulated by the basolateral amygdala. The prepulse inhibition-disruptive effects of basolateral amygdala lesions were not reversed by systemic injection of the dopamine antagonist haloperidol at doses that totally restored prepulse inhibition in apomorphine-treated rats. In other studies, intra-amygdala infusion of the competitive N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonovaleric acid (0, 0.15, 1.5, 4.5 microg) dose-dependently reduced prepulse inhibition. These data suggest that the basolateral amygdala regulates sensorimotor gating by mechanisms that are independent of central dopamine hyperactivity.

Amphetamine-induced hydroxyl radical formation in the striatum of rats was investigated in this study. With the utilization of the microdialysis and HPLC-ECD, the striatal dopamine (DA) release and the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA), derived from the reaction of hydroxyl radicals (.OH) and salicylate in perfusion, were monitored and detected during desipramine and/or amphetamine (AMPH) administration. Our data revealed that after desipramine treatment AMPH injections not only amplified striatal DA release and 2,3-DHBA formation, but also intensified the stereotyped behaviors induced by AMPH. Furthermore, we discovered that alpha-methyl-para-tyrosine (alpha-MT) pretreatment prevented the onset of the above responses. In desipramine-treated rats, the tissue homogenization study demonstrated that a single dose of AMPH produced long-term depletion of striatal DA; this was not seen in saline-treated rats. Moreover, striatal DA depletion could be lessened by pretreatment with mannitol, a .OH scavenger. These results indicate that AMPH-induced striatal .OH formation might be DA-related in desipramine-treated rats, and suggest that .OH formation might be correlated with AMPH-induced neurodegeneration.

Prepulse inhibition of the acoustic startle reflex is an operational measure of sensorimotor gating. The neural substrates of prepulse inhibition may be relevant to the pathophysiology of neuropsychiatric disorders that are characterized by sensorimotor gating deficits, including schizophrenia. Studies have demonstrated abnormalities within the hippocampal formation of schizophrenia patients, and animal studies have revealed that the hippocampus, and specifically the ventral subiculum, regulates prepulse inhibition. The ventral subiculum sends a dense glutamatergic projection to the nucleus accumbens, and the nucleus accumbens is known to potently regulate prepulse inhibition via dopaminergic and non-N-methyl-D-aspartate (non-NMDA) glutamatergic mechanisms. In the present study, we examined whether the hippocampal regulation of prepulse inhibition is mediated through subiculo-accumbens glutamatergic efferents. Intra-ventral subiculum infusion of NMDA dose dependently reduced prepulse inhibition, and this effect of NMDA was reversed by co-infusion of the NMDA receptor antagonist D,L-amino-5-phosphonovaleric acid (AP5). The prepulse inhibition-disruptive effect of intra-ventral subiculum NMDA infusion was not prevented by infusion of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into the nucleus accumbens core or shell subregions. Pretreatment with the D2 receptor antagonist haloperidol also failed to block the prepulse inhibition-disruptive effects of intra-ventral subiculum NMDA infusion. Thus, the present findings suggest that while prepulse inhibition is regulated by NMDA activity in the ventral subiculum, this effect does not appear to be mediated via nucleus accumbens dopamine D2 receptors or via nucleus accumbens non-NMDA glutamatergic substrates.

The amplitude of the acoustic startle reflex is normally reduced when the startling stimulus is preceded by a weak click or "prepulse'. Prepulse inhibition (PPI) of acoustic startle has been used as an operational measure of sensorimotor gating or inhibition, and is reduced in schizophrenia patients and in rats with central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus offer a useful animal model to study impaired sensorimotor gating in schizophrenia. We have previously reported that DA-glutamate interactions in the nucleus accumbens (NAC) regulate PPI. The NAC has at least two major subregions-the core and shell-that have distinct anatomical and neurochemical properties. In this study, we compared changes in PPI after manipulations of DA-glutamate activity in these two NAC subregions. Consistent with previous findings, infusion of the non-NMDA agonist AMPA into the NAC core subregion significantly reduced PPI, and this effect was opposed by systemic administration of the D2 antagonist haloperidol. Also consistent with previous reports, infusion of the non-NMDA antagonist CNQX into the NAC core subregion did not alter PPI, but its co-infusion with D-amphetamine (AMPH) attenuated the AMPH-disruption of PPI. In contrast, while PPI was reduced after AMPA infusion into the NAC shell subregion, this effect of AMPA could not be blocked by pretreatment with haloperidol. Infusion of either AMPH or CNQX into the NAC shell subregion reduced PPI independently. The PPI-disruptive effects of intra-shell CNQX infusion were not blocked by haloperidol. The present results suggest striking differences between the NAC core and shell subregions in their neurochemical modulation of sensorimotor gating of acoustic startle in the rat.

Despite considerable evidence that ethanol can enhance chloride flux through the gamma-aminobutyric acid type A (GABA/A/) receptor-channel complex in several central neuron types, the effect of ethanol on hippocampal GABAergic systems is still controversial. Therefore, we have reevaluated this interaction in hippocampal pyramidal neurons subjected to local monosynaptic activation combined with pharmacological isolation of the various components of excitatory and inhibitory synaptic potentials, using intracellular current- and voltage-clamp recording methods in the hippocampal slice. In accord with our previous findings, we found that ethanol had little effect on compound inhibitory postsynaptic potentials/currents (IPSP/Cs) containing both GABA/A/ and GABA/B/ components. However, after selective pharmacological blockade of the GABA/B/ component of the IPSP (GABA/B/-IPSP/C) by CGP-35348, low concentrations of ethanol (22-66 mM) markedly enhanced the peak amplitude, and especially the area, of the GABA/A/ component (GABA/A/-IPSP/C) in most CA1 pyramidal neurons. Ethanol had no significant effect on the peak amplitude or area of the pharmacologically isolated GABA/B/-inhibitory postsynaptic current (IPSC). These results provide new data showing that activation of GABAB receptors can obscure ethanol enhancement of GABA/A/ receptor function in hippocampus and suggest that similar methods of pharmacological isolation might be applied to other brain regions showing negative or mixed ethanol-GABA interactions.

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is reduced in schizophrenia patients and in dopamine (DA)-activated rats. We previously found that PPI is disrupted by systemic administration of the D2 agonist quinpirole, but not by the D1 agonist SKF 38393. In this report we further characterize the D1 and D2 substrates and their potential interactions in the regulation of PPI in rats. PPI is reduced by concomitant administration of the D1 agonist SKF 38393 (5 mg/kg; relative affinity D1:D2 = 50:1) and by a subthreshold dose (0.1 mg/kg) of the D2 agonist quinpirole, but not by either drug given alone at these doses. Pretreatment with the D2 antagonist raclopride (0.05 mg/kg), but not the D1 antagonist SCH 23390 (0.05 mg/kg), blocks the SKF 38393/quinpirole synergistic reduction of PPI. The relative D1 agonist SKF 82958 (5 mg/kg; relative affinity D1:D2 = 10:1) disrupts PPI, and this effect of SKF 82958 is reversed by the D2 antagonist raclopride but not by the D1 antagonist SCH 23390. Consistent with a recent report (Hoffman and Donovan 1994), the PPI-disruptive effects of the D1/D2 agonist apomorphine (0.5 mg/kg) could be blocked by pretreatment with the D1 antagonist SCH 23390. Surprisingly the PPI-disruptive effects of quinpirole are also opposed by pretreatment with SCH 23390. Our present findings confirm that D2 receptors are important for the regulation of PPI in rats, but they also suggest that there exists a synergistic interaction between D1 and D2 substrates in the regulation of PPI. D1 receptors might modulate PPI in a "rate-dependent" manner in which tonic D1 activity is essential for the full manifestation of the D2-mediated modulation of PPI. However, D1 receptors do not appear to participate in the modulatory mechanisms of sensorimotor gating as an independent substrate.

The purpose of this study was to determine the interactions of the renin-angiotensin system with adenosine and glutamate in the area postrema (AP) of rats. Male Sprague-Dawley rats were anesthetized with urethane. Adenosine, angiotensins (Ang) II, III and their antagonist 1,3-Dipropyl-8-p-sulfophenylxanthine (DPSPX), [Sar1Ile7]Ang III and glutamate antagonist, L-glutamic acid diethyl ester (GDEE) were microinjected into the AP of rats. Our results demonstrated that microinjection of DPSPX significantly attenuated the depressor and bradycardic effects of Ang II and III at low (9.6 pmol) and high dose (480 pmol) of Ang II in normotensive rats. To test the interaction of glutamate and renin-angiotensin system, we found that glutamate antagonist, GDEE, markedly lowered depressor and bradycardic responses of Ang II but did not influence Ang III in rats. On the other hand, microinjection of the Ang antagonist [Sar1Ile7]Ang III 10 min prior to the injection of adenosine significantly altered the cardiovascular effects of adenosine in the AP. In conclusion, the endogenous adenosine and glutamate may influence the renin-angiotensin system on cardiovascular responses in the AP of rats.

The normal reduction in acoustic startle amplitude caused by a weak prepulse (prepulse inhibition; PPI) is deficient in schizophrenic patients and in rats after systemic or intraaccumbens treatment with the D2 dopamine agonist quinpirole. We examined the anatomical substrates of the PPI-disruptive effects of intraaccumbens quinpirole. PPI was significantly reduced in a dose-dependent manner by quinpirole infusion into the medial accumbens shell region, the lateral accumbens core region, and an intermediate central region. There was a weak tendency for this quinpirole effect to be more pronounced in core and central accumbens regions than in the medial and anteromedial accumbens. Using the retrograde tracer Nuclear yellow, shell and core regions were verified to receive different patterns of limbic cortical innervation. Although the accumbens appears to have a complex and functionally diversified intrinsic anatomy, the accumbens D2 modulation of sensorimotor gating appears to be distributed across several different accumbens subregions.

Schedule-induced polydipsia (SIP) poses a general buffering property to reduce the heightened arousal produced by a schedule of intermittent feeding. It thus provides a unique opportunity to study CNS integration in stress-coping reactions. In the present study, we examined the role of the locus coeruleus (LC) and the pharmacological actions of serotonergic (5-HT2) analogs on SIP. Water intake, licking, and bar presses per minute in rats were recorded as indices of SIP activity after they had been subjected to 1-h performance of a fixed-interval 1-min operant pellet conditioning. Our results showed that SIP was progressively decreased after lesions were placed bilaterally in the LC areas and then followed by further lesioning in the bilateral ventral tegmental area. Neurotoxin DSP-4 also had an inhibitory action on the SIP potency. In addition, SIP was attenuated by 2,5-dimethoxy-4-iodoamphetamine (0.1, 0.5, or 1.0 mg/kg, IP), a 5-HT2 agonist, and activated by ritanserin (2.5 mg/kg, IP), a 5-HT2 agonist. After bilateral LC lesions, SIP was attenuated and the activating effect of RIT was abolished. Our data suggest that the LC is involved in the central integration of SIP and that the modulating effects of 5-HT2 receptors on SIP depend upon the integrity of LC function.