PubMed Health⌕ Search

Biomedical subjects

J P Gallagher

Publications and source records attributed to J P Gallagher.

At least 19 recordsLinked to original sources
PubMed2002

Adaptation to chronic PCP results in hyperfunctional NMDA and hypofunctional GABA(A) synaptic receptors.

Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. In this study we tested the hypothesis that chronic treatment of rats with this antagonist may be a more appropriate animal model than acute exposure since it could result in adaptive synaptic responses that would model certain aspects of the schizophrenic state in humans. In vitro intracellular electrophysiological recordings employing brain slices from rats treated chronically in vivo with PCP demonstrated that chronic PCP caused a substantial increase in synaptic responses mediated by NMDA receptors without any significant changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-mediated synaptic responses. At the same time, GABA(A) receptor-mediated inhibitory responses were depressed significantly. Pharmacological and paired-pulse facilitation experiments demonstrated that these adaptive responses following chronic PCP administration were not the result of altered glutamate or GABA release. Immunoblot analyses suggest that the hyperfunctional NMDA response is at least partially mediated by an increased synthesis of NR1 and NR2A subunits as well as a change in the subunit stoichiometry of the NMDA receptor. This change in receptor composition was also supported by pharmacological experiments with a subunit selective NMDA antagonist. Our data support a reconsideration of NMDA and GABA(A) receptor responsiveness following a chronic, not acute, exposure to PCP and the adaptations that persist after such a regimen.

Animals↗
PubMed2002

International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function.

The gamma-aminobutyric acid(B) (GABA(B)) receptor was first demonstrated on presynaptic terminals where it serves as an autoreceptor and also as a heteroreceptor to influence transmitter release by suppressing neuronal Ca(2+) conductance. Subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K(+) conductance and associated neuronal hyperpolarization. (-)-Baclofen is a highly selective agonist for GABA(B) receptors, whereas the established GABA(A) receptor antagonists, bicuculline and picrotoxin, do not block GABA(B) receptors. The receptor is G(i)/G(o) protein-coupled with mixed effects on adenylate cyclase activity. The receptor comprises a heterodimer with similar subunits currently designated 1 and 2. These subunits are coupled via coiled-coil domains at their C termini. The evidence for splice variants is critically reviewed. Thus far, no unique pharmacological or functional properties have been assigned to either subunit or the variants. The emergence of high-affinity antagonists for GABA(B) receptors has enabled a synaptic role to be established. However, the antagonists have generally failed to establish the existence of pharmacologically distinct receptor types within the GABA(B) receptor class. The advent of GABA(B1) knockout mice has also failed to provide support for multiple receptor types.

Animals↗
PubMed2000

Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala.

G-protein-coupled metabotropic glutamate receptors (mGluRs) are being implicated in various forms of neuroplasticity and CNS disorders. This study examined whether the sensitivities of mGluR agonists are modulated in a distinct fashion in different models of synaptic plasticity, specifically, kindling and chronic cocaine treatment. The influence of kindling and chronic cocaine exposure in vivo was examined in vitro on the modulation of synaptic transmission by group II and III metabotropic glutamate receptors using whole cell voltage-clamp recordings of central amygdala (CeA) neurons. Synaptic transmission was evoked by electrical stimulation of the basolateral amygdala (BLA) and ventral amygdaloid pathway (VAP) afferents in brain slices from control rats and from rats treated with cocaine or exposed to three to five stage-five kindled seizures. This study shows that after chemical stimulation with chronic cocaine exposure or after electrical stimulation with kindling the receptor sensitivities for mGluR agonists are altered in opposite ways. In slices from control rats, group II agonists, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1) and (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), depressed neurotransmission more potently at the BLA-CeA than at the VAP-CeA synapse while group III agonist, L(+)-2-amino-4-phosphonobutyrate (LAP4), depressed neurotransmission more potently at the VAP-CeA synapse than at the BLA-CeA. These agonist actions were not seen (were absent) in amygdala neurons from chronic cocaine-treated animals. In contrast, after kindling, concentration response relationships for LCCG1 and LAP4 were shifted to the left, suggesting that sensitivity to these agonists is increased. Except at high concentrations, LCCG1, LY354740, and LAP4 neither induced membrane currents nor changed current-voltage relationships. Loss of mGluR inhibition with chronic cocaine treatment may contribute to counter-adaptive changes including anxiety and depression in cocaine withdrawal. Drugs that restore the inhibitory effects of group II and III mGluRs may be novel tools in the treatment of cocaine dependence. The enhanced sensitivity to group II and III mGluR agonists in kindling is similar to that recorded at the lateral to BLA synapse in the amygdala where they reduce epileptiform bursting. These findings suggest that drugs modifying mGluRs may prove useful in the treatment of cocaine withdrawal or epilepsy.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

GABA(B) auto- versus hetero-receptor sensitivity: implications for novel pharmacotherapy.

After uncoupling G-protein dependent post-synaptic GABA(B) receptors--without altering GABA(B) nerve terminal receptors--we demonstrate that the GABA(B) agonist, CGP44533, exhibits less efficacy and potency at GABA(B) auto- versus hetero-receptors. CGP44533 (1 and 10 microM) depressed monosynaptic GABA(A)-mediated transmission by 2 and 35%, but depressed glutamate mediated transmission by 41 and 78%, respectively. These data suggest a differential pharmacological sensitivity for CGP44533 at glutamate versus GABA releasing neurons.

Animals↗
PubMed1999

Different subtypes of GABAB receptors are present at pre- and postsynaptic sites within the rat dorsolateral septal nucleus.

GABAB receptor activation modulates neuronal activity mediated by multiple CNS transmitters and can occur at pre- and postsynaptic sites. In low concentrations, baclofen acts presynaptically to diminish transmitter release via both hetero- and autoreceptors, whereas at increasing concentrations, the same compound alters postsynaptic membrane excitability by inducing a membrane hyperpolarization. We have utilized electrophysiological techniques in vitro to focus on the possibility that pharmacologically different subtypes of GABAB receptors are present on presynaptic sites of glutamatergic terminals when compared with GABAB receptors on postsynaptic sites within the dorsolateral septal nucleus (DLSN). The glutamatergic terminal within the DLSN originates from a pyramidal cell body located within the hippocampus and most likely terminates on a GABAergic neuron from which recordings were made. Whole cell patch voltage-clamp methods were employed to record pharmacologically isolated excitatory postsynaptic currents (EPSCs) from DLSN neurons as an index of glutamatergic transmission. Using a modified internal pipette solution containing QX-314 and in which CsGluconate and GDPbetaS replaced Kgluconate and GTP, respectively, we recorded isolated monosynaptic EPSCs. The GABAA receptor antagonists bicuculline and picrotoxin were included in the external standard superfusion solution. Application of the GABAB receptor agonists, (+/-)-baclofen, CGP44533, and CGP35024 (10 nM to 10 microM) depressed glutamate-mediated EPSCs in a concentration-dependent manner. With the use of this combination of solutions, CGP44533 did not produce postsynaptic membrane property changes. Under these conditions, both (+/-)-baclofen and CGP35024 still induced increases of postsynaptic membrane conductance associated with an outward current. The GABAB receptor antagonist CGP55845A (1 microM) blocked the presynaptic CGP44533-mediated depressant effects of EPSCs, whereas CGP35348 (100 microM) or barium (2 mM) was ineffective. Furthermore, both CGP35348 (100 microM) and CGP55845A (1 microM) were effective in blocking the postsynaptic conductance changes associated with baclofen and CGP35024, whereas barium was ineffective. Our results demonstrate a distinct pharmacology for GABAB agonists acting at putative subtypes of GABAB receptors located on presynaptic sites of a glutamatergic terminal versus GABAB receptors on postsynaptic sites of a DLSN neuron. Furthermore, our results also suggest a different pharmacology and/or coupling of a GABAB receptor to different effectors at postsynaptic sites within the DLSN. Thus there may be three or more pharmacologically distinct GABAB receptors or receptor complexes associated with DLSN neurons: at least one pre- and two postsynaptic. If this distinct pharmacology and GABAB receptor distribution also extends to other CNS structures, such differences could provide development of selective drugs to act at these multiple sites.

Animals↗
PubMed1998

Cocaine administered in vitro to brain slices from rats treated with cocaine chronically in vivo results in a gamma-aminobutyric acid receptor-mediated hyperpolarization recorded from the dorsolateral septum.

Previous reports of membrane hyperpolarizations, associated with acute application of cocaine, have been recorded from brain slice preparations containing aminergic nuclei and have always been attributed to cocaine's ability to elevate levels of local biogenic amines followed by activation of their receptors. The majority of these studies were conducted with brain slices obtained from rats that had not received prior chronic in vivo treatment with cocaine. We observed that cocaine alone, at 3 microM, could induce a membrane hyperpolarization (COC-HYP) in 100% of rat dorsolateral septal nucleus (DLSN) neurons from brain slices of rats treated chronically with cocaine for either 14 or 28 days in vivo. The DLSN is a nucleus absent of biogenic amine cell bodies, but does contain biogenic amine terminals with GABAergic cell bodies and terminals. Cocaine applied to brain slices from rats not previously administered cocaine or administered cocaine for up to seven days in vivo yielded a maximum incidence of COC-HYPs at only 50%. COC-HYPs recorded from DLSN neurons were not blocked by previous treatment with amine receptor antagonists or by a TTX and zero calcium medium. Based on these results, the ability of DLSN neurons to respond to a cocaine challenge with a COC-HYP did not involve inhibition of amine reuptake/uptake or action potential release of neuroactive substances. Rather, the COC-HYP, with an apparent reversal potential of -80 mV, was reduced by the GABA receptor antagonists-bicuculline and CGP-55845A. Lowering extracellular Na+ or Cl-, lowering of temperature, or previous superfusion with the GABA uptake blocker NO-711 could block the COC-HYP. In summary, our data suggest that COC-HYPs, after application of a cocaine challenge to brain slices from rats treated chronically (14-28 days, but not acutely, 7 days) with cocaine are due to cocaine-induced changes in GABA release and/or transporter function. The latter changes in transporter function may involve the reversal of the GABA transporter with release of GABA and subsequent activation of postsynaptic GABAA and GABAB receptors.

Animals↗
PubMed1997

Chronic cocaine administration to rats alters the distribution of cell types recorded in vitro within the dorsolateral septal nucleus.

We investigated persistent changes in single-neuron activity in the dorsolateral septal nucleus (DLSN) induced by chronic administration of cocaine. Intracellular recording techniques were utilized with an in vitro brain slice preparation to examine the effects of in vivo chronic cocaine administration, for 7 days or 14 days, on the distribution of electrophysiologically characterized DLSN cells. We have previously distinguished DLSN neurons into three major types (I, II, and III), based upon their action potential configuration and firing pattern. This study demonstrated that type III neurons were over-represented in brain slices obtained from rats treated chronically with cocaine in vivo for 14 days when compared with brain slices obtained from rats treated either with cocaine for only 7 days or with saline and never exposed to cocaine. These data provide further evidence that neurons undergo plastic changes following chronic cocaine administration.

Action Potentials↗
PubMed1997

Chronic cocaine enhances gamma-aminobutyric acid and glutamate release by altering presynaptic and not postsynaptic gamma-aminobutyric acidB receptors within the rat dorsolateral septal nucleus.

Cocaine is a popular and sometimes deadly drug of abuse. Its mechanisms of action have previously not been linked with receptors localized to presynaptic sites for the major central nervous system amino acid transmitters gamma-aminobutyric acid (GABA) and glutamate. We demonstrate that, within the dorsolateral septal nucleus of in vitro brain slices from animals that had received cocaine chronically in vivo for 14 or 28, but not 7, days, control of both inhibitory (GABA) and excitatory (glutamate) amino acid transmission is impaired, due to the combined diminished effectiveness of presynaptic GABAB auto- and heteroreceptors. As a result, disinhibition of inhibitory and excitatory transmitters occurs, with enhanced transmitter release. Although the involvement of postsynaptic GABAB receptors has been suggested in the chronic actions of cocaine at other central nervous system nuclei, we do not see any change in the effectiveness of the postsynaptic GABAB receptors within the dorsolateral septal nucleus. Modulation of presynaptic GABAB receptors at central nervous system nerve terminals after chronic cocaine administration has not been reported previously. Our findings demonstrate that chronic intermittent cocaine administration for at least 14 days induces a persistent change in neuronal activity that involves both inhibitory and excitatory amino acid-mediated transmission within the dorsolateral septal nucleus. These results suggest that nerve terminal GABAB receptors have been overlooked as playing a role in either the etiology and treatment of chronic cocaine addiction or cocaine toxicity.

Animals↗
PubMed1996

Activation of a metabotropic excitatory amino acid receptor potentiates spike-driven calcium increases in neurons of the dorsolateral septum.

(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), an agonist for metabotropic glutamate receptors (mGluRs), causes depolarization and burst firing in rat dorsolateral septal nucleus (DLSN) neurons and results in long-term potentiation (LTP) at DLSN synapses. In the present study, we investigated whether these actions of 1S,3R-ACPD are attributable to the release of calcium from an inositol triphosphate-sensitive store after activation of mGluRs coupled to phospholipase C. Our data demonstrated that the ACPD-induced depolarization was associated with a small but significant decrease, not an increase, in [Ca2+]i; however, changes of [Ca2+]i, during ACPD-induced bursting were up to seven times larger than those produced by regular firing. Depletion of internal calcium stores by thapsigargin or ryanodine had a small to insignificant effect on the maximum changes of [Ca2+]i, associated with ACPD-induced bursting. Thus, elevation of [Ca2+]i, during firing by 1S,3R-ACPD is likely attributable to enhancement of calcium influx through voltage-gated channels and not to calcium release from internal stores. ACPD-induced burst firing elevated somatic and dendritic calcium levels up to 3 and 6 microM, respectively. Such an increase may be the underlying mechanism for ACPD-induced LTP as well as ACPD-induced acute cell death in rat DLSN.

Action Potentials↗
PubMed1996

Retrograde labeling of rat dorsolateral septal nucleus neurons following intraseptal injections of WGA-HRP.

Projection neurons in the rat dorsolateral septal nucleus (DLSN) were retrogradely labeled following intraseptal injection of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP). Injections of WGA-HRP centered in the medial septum (MS) and parts of the intermediate and ventrolateral subdivisions of the lateral septum retrogradely labeled only a few centrally scattered multipolar-shaped neurons. In contrast, injections placed in the nucleus of the diagonal band of Broca (DBB) consistently resulted in labeling of DLSN neurons of all sizes and shapes. Large injections in rostral DBB appeared to retrogradely label every DLSN neuron, while similar injections in caudal DBB only labeled neurons in restricted regions of the nucleus. A collection of small cells forming the ventricular border of caudal DLSN and a group of larger cells situated in the dorsolateral tip of rostral DLSN were consistently labeled following each DBB injection. The pattern of retrogradely labeled neurons in the DLSN appeared in a complementary fashion to that seen in the other lateral septal nuclei. Our findings support the conclusion that the DLSN is a morphologically heterogeneous nucleus consisting almost entirely of projection neurons. The pattern of retrograde labeling in the lateral septum suggests that these projection neurons may be topographically organized since distinct subpopulations of cells were labeled following different injections in the MS/DBB complex.

Animals↗
PubMed1996

Muscarine activates a nonselective cation current through a M3 muscarinic receptor subtype in rat dorsolateral septal nucleus neurons.

1. In the present study, we examined the cellular mechanism and receptor type responsible for a muscarine-induced inward current (Imi) in neurons of rat dorsolateral septal nucleus (DLSN) using single-microelectrode voltage-clamp and "slice" patch-clamp techniques. 2. Imi was associated with an increase of membrane conductance in 75% of DLSN neurons. There was no voltage-dependence of Imi between -60 and -140 mV; it exhibited a reversal potential of -17.0 +/- 5.3 mV (n = 14) determined by extrapolation of Imi and voltage relationship recorded using whole cell patch recording. Lowering extracellular sodium (26 mM) or potassium (1.4 mM) ions depressed Imi. 3. Imi was concentration dependent; 3 and 100 microM muscarine produced the minimum [22 +/- 4.6 pA, (mean +/- SE) n = 8] and maximum (167 +/- 28 pA, n = 7) responses, respectively. An EC50 was determined to be 15 microM (n = 8). Oxotremorine-methiodide (1-100 microM) also produced an inward current with similar potency compared with muscarine. On the other hand, McN-A-343 and pilocarpine (3-100 microM) did not produce any inward current in DLSN neurons. 4. Atropine (1 microM) completely reduced Im produced by 30 microM muscarine, whereas pirenzepine (PZP) shifted the concentration-response curve for muscarine in a parallel manner to the right. The EC50 for muscarine was shifted to 32, 52, and 204 microM by 0.2, 0.5, and 2 microM PZP, respectively. The apparent Kd value for PZP estimated by Schild plot analysis was 190 nM (n = 5). 5. Methoctramine (1 microM) also competitively depressed Imi; the calculated EC50 values were 26, 41, and 107 microM in concentrations of 0.2, 2, and 10 microM methoctramine, respectively. The apparent Kd for methoctramine was 420 nM. In contrast, AF-DX 116 (1 microM) did not significantly inhibit Imi. 6. Intracellular dialysis with guanosine 5'-O-(3-thiotriphosphate), a nonhydrolyzable analogue of GTP, suppressed irreversibly Imi. Pretreatment of DLSN neurons with pertussis toxin (PTX) did not prevent Imi (n = 8). 7. We suggest that muscarine causes this inward current by activating a M3 subtype of muscarinic receptor, which is coupled to a PTX-insensitive GTP-protein in rat DLSN neurons.

Animals↗
PubMed1996

The membrane hyperpolarization of rat dorsolateral septal nucleus neurons is mediated by a novel nicotinic receptor.

The pharmacology, calcium dependence and G protein mediation of the membrane hyperpolarization of rat dorsolateral septal nucleus (DLSN) neurons in response to nicotinic agonists was examined to classify the nicotinic receptor mediating the response. Intracellular recording from DSLN neurons in a brain slice preparation was used to determine whether chlorisondamine, trimethaphan, cytisine or strychnine inhibited the membrane hyperpolarization in response to application of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP). Chlorisondamine was found to block the response only at a high concentration (500 microM) although strychnine (100 microM) was without effect. Cytisine was neither an effective agonist nor an antagonist (500 microM). Surprisingly, trimethaphan appeared to act as an agonist, rather than an antagonist, with a potency and efficacy similar to that reported for nicotine at this receptor. The response was dependent on intracellular calcium stores because it persisted in the absence of extracellular calcium but was blocked by intracellular injection of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Injection of GTP gamma S into the neurons blocked the nicotinic response. Apamin, iberiotoxin and charybdotoxin reduced but did not block the response at concentrations that selectively block calcium-dependent potassium channels. These results indicate that the nicotinic response in DLSN neurons may be mediated by a metabotropic nicotinic receptor coupled to a calcium-dependent potassium channel through the activation of a G-protein and release of intracellular calcium stores. The unusual pharmacology of the nicotinic receptor on DLSN neurons indicates that it may be a novel receptor which has yet to be cloned.

Animals↗
PubMed1996

Modification of serotonin responses in rat dorsolateral septal nucleus neurons by acute and chronic cocaine.

We used standard intracellular current-clamp electrophysiological recording techniques in a brain slice preparation to determine whether chronic cocaine administration would: 1) alter the sensitivity of septal neurons to exogenous serotonin (5-HT) application and 2) modify the interaction of 5-HT with cocaine in vitro. Recordings were made from neurons in rat brain slices that contained the dorsolateral septal nucleus obtained from drug naive (DN) rats or rats give cocaine (15mg/kg, i.p., 2 X daily) for periods of 7 (CC7) or 14 (CC14) days. In addition, some of these rats also received intraventricular pertussis toxin (PTX) injections 2 to 3 days before experimentation to abolish the postsynaptic 5-HT1A receptor-mediated membrane hyperpolarization and to unmask a 5-HT-induced depolarization. In comparison with DN and CC7, CC14 slices showed an increased sensitivity to 5-HT as revealed by a 2-fold leftward shift in the 5-HT EC50 values. In addition, in PTX-CC14 slices, 5-HT could hyperpolarize the cell membrane, whereas the 5-HT1A agonist, 8-OH-DPAT, and the gamma-aminobutyric acidB agonist, baclofen, failed to do so. We also observed that cocaine (3 microM) in CC14 slices did not significantly potentiate and prolong 5-HT hyperpolarizations as found in DN slices. We conclude that in the CC14 septal slice a 5-HT transporter is down-regulated and that an atypical 5-ht response can be elicited. Additionally, 5-HT1A receptor up-regulation and/or 5-HT2 receptor down-regulation may contribute to the increased sensitivity of septal neurons to 5-HT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Muscarine increases a voltage-independent potassium conductance through an M4 receptor in rat dorsolateral septal nucleus neurons.

The direct effect of muscarine on neurons of the rat dorsolateral septal nucleus (DLSN) was examined by using conventional microelectrode and voltage-clamp techniques. Muscarine (1-50 microM) caused a hyperpolarization accompanied by an increase of a voltage-independent potassium conductance. Pirenzepine competitively antagonized the muscarine-induced hyperpolarization with an apparent dissociation constant (Kd) value of 54 nM. Furthermore, intracellular loading with GTP gamma S, a non-hydrolyzable GTP analog, blocked irreversibly the muscarine-induced hyperpolarization. In addition, pretreatment of neurons with pertussis toxin (PTX) prevented the hyperpolarization produced by muscarine. These results suggest that muscarine hyperpolarizes DLSN neurons via a voltage-independent potassium conductance by acting at M4 subtype receptors which are coupled to a PTX-sensitive G-protein in DLSN neurons.

Animals↗
PubMed1995

1S,3R-ACPD-preferring inward current in rat dorsolateral septal neurons is mediated by a novel excitatory amino acid receptor.

Metabotropic glutamate receptors (mGluRs) form a receptor family that consists of diverse receptor subtypes; now, numbering 8--exclusive of splice variants. (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) has been suggested to be a selective agonist for the mGluRs. We have recently reported that, in rat dorsolateral septal nucleus (DLSN) neurones, a 1S,3R-ACPD-preferring inward current (ACPDi) persists in pertussis toxin-treated rats. We now report that this ACPDi-current: (1) persists in DLSN neurones dialyzed with a stable analog of GTP, namely, GTP gamma S; (2) exhibits a negative slope region with inward rectification in its I-V relationship; (3) persists in neurones superfused with tetrodotoxin or low calcium solutions; (4) is dependent upon both sodium and calcium ions; and (5) is independent of a reduction in temperature. Furthermore, pharmacological data suggest that this current may be activated by a unique type of excitatory amino acid (EAA) receptor, i.e. a receptor which prefers "metabotropic" EAA agonists and is insensitive to AP5 or CNQX. Activation by ACPD of inward currents associated with a conductance increase have also been reported at cultured mouse cerebellar Purkinje neurones; in slices of rat hippocampal CA1 neurones and slice cultures of hippocampal CA3 neurones. We suggest that this ACPDi current may play an important role within the CNS in the induction of long-term potentiation and other neurological processes; processes attributed previously to currents associated with NMDA receptor activation.

2-Amino-5-phosphonovalerate↗