Biomedical subjects

F J Wan

Publications and source records attributed to F J Wan.

27 records · Page 2Linked to original sources

PubMed1996

The ventral subiculum modulation of prepulse inhibition is not mediated via dopamine D2 or nucleus accumbens non-NMDA glutamate receptor activity.

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.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1996

Sensorimotor gating in rats is regulated by different dopamine-glutamate interactions in the nucleus accumbens core and shell subregions.

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.

Acoustic Stimulation↗

PubMed1996

Low ethanol concentrations enhance GABAergic inhibitory postsynaptic potentials in hippocampal pyramidal neurons only after block of GABAB receptors.

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.

Animals↗

PubMed1996

Do D1/D2 interactions regulate prepulse inhibition in rats?

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.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Adenosine and glutamate modulate the cardiovascular responses of angiotensins II and III in the area postrema of rats.

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.

Adenosine↗

PubMed1995

Presynaptic dopamine-glutamate interactions in the nucleus accumbens regulate sensorimotor gating.

Prepulse inhibition (PPI) is the normal reduction in startle reflex that occurs when a startling stimulus is preceded by a weak prepulse. PPI is reduced in patients with schizophrenia and in rats after central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus model some features of impaired sensorimotor gating in schizophrenia. Ascending DAergic and descending glutamatergic fibers converge within the nucleus accumbens (NAC), and interactions at this DA-glutamate interface have been implicated in the pathophysiology of schizophrenia. In this study, we examined the role of NAC DA-glutamate interactions in the regulation of PPI in rats. Intra-NAC infusion of the non-NMDA antagonist, CNQX, attenuated the PPI-disruptive effects of d-amphetamine (AMPH), but CNQX did not affect PPI when injected alone, nor did it reverse the PPI-disruptive effects of the direct D2/D3 agonist quinpirole. Intra-NAC infusion of the non-NMDA agonist AMPA significantly reduced PPI. The PPI-disruptive effects of AMPA were blocked by haloperidol and by 6-hydroxydopamine (6OHDA) lesions of the NAC. These data suggest that the PPI-disruptive effects of AMPH are dependent on tonic non-NMDA receptor activation in the NAC, and that non-NMDA receptor activation in the NAC results in a DA-dependent reduction in PPI. The parsimonious interpretation of these data is that non-NMDA glutamate receptors in the NAC facilitate presynaptic DA function, and that this DA-glutamate interaction is a critical regulatory substrate of sensorimotor gating.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Accumbens D2 modulation of sensorimotor gating in rats: assessing anatomical localization.

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.

Acoustic Stimulation↗

PubMed1993

Intra-accumbens infusion of quinpirole impairs sensorimotor gating of acoustic startle in rats.

Prepulse inhibition (PPI) of the startle reflex is reduced by systemic administration of dopamine (DA) agonists. Since PPI is impaired in patients with schizophrenia, the DA agonist-induced disruption of PPI in rats may be a useful model for studying the pathophysiology of impaired sensorimotor gating in schizophrenia. In the present study, we replicated the observation that PPI is disrupted by systemic administration of the D2 agonist quinpirole, but not by the D1 agonist SKF 38393. PPI caused by weak [1-5 dB(A)] or more intense [10 dB(A)] prepulses was also disrupted by quinpirole infusion into the nucleus accumbens (NAC). The effects of intraaccumbens quinpirole on PPI were blocked by pretreatment with the D2 antagonist haloperidol. These results support the notion that the reduction of PPI after systemic administration of DA agonists is mediated via stimulation of NAC D2 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Role of locus coeruleus and serotonergic drug actions on schedule-induced polydipsia.

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.

Animals↗