Biomedical subjects

S T Connelly

Publications and source records attributed to S T Connelly.

5 recordsLinked to original sources

PubMed1999

Pertussis toxin lesions of the rat substantia nigra block the inhibitory effects of the gamma-hydroxybutyrate agent, S(-)HA-966 without affecting the basal firing properties of dopamine neurons.

S(-)3-amino-1-hydroxypyrrolidone-2 (S(-)HA-966), a potent gamma-hydroxybutyrate-like drug, inhibits spontaneous firing and induces a pacemaker-like discharge pattern in nigral dopamine (DA)-containing neurons. Recent evidence has suggested that these effects could be mediated by GABAB receptors and, thus, is likely to involve G protein intermediaries. To test this hypothesis, extracellular single-unit recording techniques were used to assess the effects of S(-)HA-966 in animals that had received an intranigral injection of pertussis toxin (PT). Failure to respond to the inhibitory effects of apomorphine was taken as presumptive evidence that PT-sensitive G protein-coupled receptors had been inactivated. No significant differences were observed in the basal firing properties of DA cells recorded in control and PT-lesioned animals. However, in marked contrast to the inhibitory effects observed in uninjected and sham-lesioned animals, S(-)HA-966 significantly increased the firing rate of apomorphine-insensitive DA neurons in PT-lesioned rats. The excitatory effects of S(-)HA-966 were accompanied by a significant reduction in bursting activity and an increase in the regularity of firing. These data indicate that the inhibitory effects of S(-)HA-966 are mediated locally within the substantia nigra by a PT-sensitive substrate, presumably a G protein-coupled receptor.

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PubMed1997

Competitive NMDA receptor antagonists differentially affect dopamine cell firing pattern.

Alterations in the firing pattern of mesencephalic dopamine (DA) neurons appear to constitute a physiological mechanism through which these cells modify their effects on target neurons. Several lines of evidence suggest that the activity patterns exhibited by DA cells in vivo are contingent on tonic activation of N-methyl-D-aspartate (NMDA) receptors. In the present series of experiments, extracellular single unit recording techniques were used to assess the effects of the centrally acting, competitive NMDA receptor antagonists CGS-19755, (+/-)-CPP, NPC-12626 and NPC-17742 on the firing properties of nigral DA neurons in the chloral hydrateanesthetized rat. Each of the drugs tested produced a modest increase in firing rate accompanied by a significant regularization of neuronal firing pattern. Although the number of bursts and the percentage of spikes in bursts were reduced, the proportion of cells operationally defined as bursting was not appreciably altered. This appeared to be due to the ability of these drugs to reduce the number of spike doublets without affecting the incidence of longer bursts. Although generally consistent with the notion that NMDA receptors modulate DA neuronal firing pattern, the present data do not support the contention that tonic activation of these receptors is solely responsible for the expression of bursting activity in vivo.

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PubMed1997

Responses of rat substantia nigra dopamine-containing neurones to (-)-HA-966 in vitro.

1. Extracellular single unit recording techniques were used to compare the effects of (-)-3-amino-1-hydroxypyrrolidin-2-one ((-)-HA-966) and (+/-)-baclofen on the activity of dopamine-containing neurones in 300 microns slices of rat substantia nigra. Electrophysiological data were compared with the outcome of in vitro binding experiments designed to assess the affinity of (-)-HA-966 for gamma-aminobutyric acid (GABAB) receptors. 2. Bath application of (-)-HA-966 produced a concentration-dependent inhibition of dopaminergic neuronal firing (EC50 = 444.0 microM; 95% confidence interval: 277.6 microM - 710.1 microM, n = 27) which was fully reversible upon washout from the recording chamber. Although similar effects were observed in response to (+/-)-baclofen, the direct-acting GABAB receptor agonist proved to be considerably more potent than (-)-HA-966 (EC50 = 0.54 microM; 95% confidence interval: 0.44 microM - 0.66 microM, n = 29) in vitro. 3. Low concentrations of chloral hydrate (10 microM) were without effect on the basal firing rate of nigral dopaminergic neurones but significantly increased the inhibitory effects produced by concomitant application of (-)-HA-966. 4. The inhibitory effects of (-)-HA-966 were completely reversed in the presence of the GABAB receptor antagonists, CGP-35348 (100 microM) and 2-hydroxysaclofen (500 microM). Bath application of CGP-35348 alone increased basal firing rate. However, the magnitude of the excitation (9.2 +/- 0.3%) was not sufficient to account for the ability of the antagonist to reverse fully the inhibitory effects of (-)-HA-966. 5. (-)-HA-966 (0.1-1.0 mM) produced a concentration-dependent displacement of [3H]-GABA from synaptic membranes in the presence of isoguvacine (40 microM). However, the affinity of the drug for GABAB binding sites was significantly less than that of GABA (0.0005 potency ratio) and showed no apparent stereoselectivity. 6. These results indicate that while (-)-HA-966 appears to act as a direct GABAB receptor agonist in vitro, its affinity for this receptor site is substantially less than that of GABA or baclofen and unlikely to account for the depressant actions of this drug which occur at levels approximately ten fold lower in vivo.

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PubMed1995

Effects of the enantiomers of (+/-)-HA-966 on dopamine neurons: an electrophysiological study of a chiral molecule.

The present study was conducted to evaluate the effects of the resolved enantiomers of (+/-)-1-1 hydroxy-3-aminopyrrolidone-2 ((+/-)-HA-966) on the electrophysiological properties of dopamine-containing neurons in the substantia nigra of the chloral hydrate anesthetized rat. Both (+)- and (-)-HA-966 produced a dose-dependent reduction in firing rate that eventually resulted in total cessation of spontaneous neuronal activity (ID50 = 5.7 and 57.8 mg/kg i.v., respectively). The inhibitory effects of both drugs were accompanied by a marked increase in the regularity of neuronal firing and a concomitant suppression of bursting activity. Although approximately 10-fold less potent than the (-) enantiomer, the inhibitory effects of (+)-HA-966 were completely antagonized by the centrally active, GABAB receptor antagonist, CGP-35348 (300 mg/kg i.v.). These data suggest that the complementary electrophysiological effects of the enantiomers of (+/-)-HA-966 on nigral dopamine neurons are mediated through a common mechanism of action possibly involving a novel interaction with GABAB receptors.

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PubMed1994

Effects of NPC16377, a potent and selective sigma receptor ligand, on the activity of mesencephalic dopamine-containing neurons in the rat.

NPC16377 is a highly selective sigma receptor ligand with low affinity for other neurotransmitter receptors. Preclinical studies indicate that the drug exhibits a pharmacological profile similar to that previously ascribed to atypical antipsychotic drugs. In the present series of experiments, extracellular recording techniques were used to assess the acute effects of NPC16377 on the electrophysiological properties of mesencephalic dopamine-containing neurons in the rat. Systemic administration of NPC16377 produced marginal increases in the firing rate of these neurons but failed to fully reverse the inhibitory effects of the dopamine agonists apomorphine and d-amphetamine. Low doses of the drug potentiated the rate-decreasing effects of d-amphetamine in the substantia nigra but not in the ventral tegmental area. Some of these effects are similar to the actions of atypical antipsychotic drugs, while others appear to be unique to this compound and may involve a direct interaction with sigma sites.

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