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J A Dani

Publications and source records attributed to J A Dani.

At least 19 recordsLinked to original sources
PubMed2004

Potential applications of nicotinic ligands in the laboratory and clinic.

The nicotinic acetylcholine receptor (nAChR) is a receptor, ion channel complex composed of five polypeptide subunits. There are many different nAChR subtypes constructed from a variety of different subunit combinations. This structural diversity contributes to the varied roles of nAChRs in the peripheral and central nervous system, and this diversity offers an excellent opportunity for chemists who are producing ligands. Subunit specific ligands could have wide and varied effects in the laboratory as experimental tools and in the clinic as therapeutic agents. Because presynaptic nAChRs have been shown to enhance the release of many neurotransmitters, new nicotinic ligands that potentiate nAChR activity would be very useful. Such ligands could enhance the release of various neurotransmitters during degenerative diseases that cause neurotransmitter systems to decrease their output. For example, boosting the release from cholinergic neurons would help patients with Alzheimer's disease, and boosting the release from dopaminergic neurons would help patients with Parkinson's disease.

Alzheimer Disease↗
PubMed2001

Synaptic plasticity and nicotine addiction.

Nicotine, the main addictive component of tobacco, activates and desensitizes nicotinic acetylcholine receptors (nAChRs). In that way, nicotine alters normal nicotinic cholinergic functions. Among the myriad of psychopharmacological effects that underlie the addiction process, nicotine influences nAChR participation in synaptic plasticity. This influence has particular importance in the mesocorticolimbic dopamine system, which serves during the reinforcement of rewarding behaviors.

Animals↗
PubMed2001

Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity.

This study reveals mechanisms in the mouse hippocampus that may underlie nicotinic influences on attention, memory, and cognition. Induction of synaptic plasticity, arising via generally accepted mechanisms, is modulated by nicotinic acetylcholine receptors. Properly timed nicotinic activity at pyramidal neurons boosted the induction of long-term potentiation via presynaptic and postsynaptic pathways. On the other hand, nicotinic activity on interneurons inhibited nearby pyramidal neurons and thereby prevented or diminished the induction of synaptic potentiation. The synaptic modulation was dependent on the location and timing of the nicotinic activity. Loss of these synaptic mechanisms may contribute to the cognitive deficits experienced during Alzheimer's diseases, which is associated with a loss of cholinergic projections and with a decrease in the number of nicotinic receptors.

2-Amino-5-phosphonovalerate↗
PubMed2001

Overview of nicotinic receptors and their roles in the central nervous system.

Alzheimer's disease is a complex disorder affecting multiple neurotransmitters. In particular, the degenerative progression is associated with loss within the cholinergic systems. It should be anticipated that both muscarinic and nicotinic mechanisms are affected as cholinergic neurons are lost. This review focuses on the basic roles of neuronal nicotinic receptors, some subtypes of which decrease during Alzheimer's disease. Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels that play key roles in synaptic transmission throughout the central nervous system. Neuronal nicotinic receptors, however, are not a single entity, but rather there are many different subtypes constructed from a variety of nicotinic subunit combinations. This structural diversity and the presynaptic, axonal, and postsynaptic locations of nicotinic receptors contribute to the varied roles these receptors play in the central nervous system. Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, and postsynaptic nicotinic receptors mediate a small minority of fast excitatory transmission. In addition, some nicotinic receptor subtypes have roles in synaptic plasticity and development. Nicotinic receptors are distributed to influence many neurotransmitter systems at more than one location, and the broad, but sparse, cholinergic innervation throughout the brain ensures that nicotinic acetylcholine receptors are important modulators of neuronal excitability.

Aged↗
PubMed2001

Cellular mechanisms of nicotine addiction.

In developed countries, tobacco use is estimated to be the largest single cause of premature death [Lancet 339 (1992) 1268]. Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the mammalian central nervous system (CNS), where they normally respond to acetylcholine (ACh) and modulate neuronal excitability and synaptic communication. Nicotinic receptors are structurally diverse and have varied roles. Presynaptic and preterminal nAChRs enhance neurotransmitter release. Postsynaptic and somal nAChRs mediate a small proportion of fast excitatory transmission and modulate cytoplasmic second messenger systems. Although the impact of nicotine obtained from tobacco is not completely understood, a portion of nicotine's addictive power is attributable to actions upon the dopaminergic systems, which normally help to reinforce rewarding behaviors. As obtained from tobacco, nicotine activates and desensitizes nAChRs, and both processes contribute to the cellular events that underlie nicotine addiction.

Animals↗
PubMed2001

Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum.

Dopamine is vital for coordinated motion and for association learning linked to behavioral reinforcement. Here we show that the precise overlap of striatal dopaminergic and cholinergic fibers underlies potent control of dopamine release by ongoing nicotinic receptor activity. In mouse striatal slices, nicotinic antagonists or depletion of endogenous acetylcholine decreased evoked dopamine release by 90%. Nicotine at the concentration experienced by smokers also regulated dopamine release. In mutant mice lacking the beta2 nicotinic subunit, evoked dopamine release was dramatically suppressed, and those mice did not show cholinergic regulation of dopamine release. The results offer new perspectives when considering nicotine addiction and the high prevalence of smoking in schizophrenics.

Acetylcholine↗
PubMed2000

Regulation of the sensitivity of acetylcholine receptors to nicotine in rat habenula neurons.

Time-dependent changes in nicotinic acetylcholine receptor (nAChR) function were studied in acutely isolated medial habenula neurons during whole-cell perfusion. The peak amplitude of inward currents induced by 1 s pulses of nicotinic agonists, applied at 30 s intervals, gradually increased over the first several minutes of whole-cell recording. The ratio of response amplitudes at 1 and 15 min (t15/t1) was 1.9. Run-up of responses occurred independently of channel activation and was specific to nAChRs. The channel blocker chlorisondamine (30 microM), co-applied with nicotine, was used to irreversibly block the majority (91 %) of the nAChRs that opened in the first 2 min of recording. Run-up in the remaining 9 % unblocked channels assessed at 15 min (t15/t2 = 3.4) was similar to that in control cells not exposed to nicotine and chlorisondamine simultaneously, implying that run-up is not due to the incorporation of new receptors. A marked alteration in the sensitivity of nAChRs to extracellular Ca2+ was also observed during whole-cell perfusion. The ratio of current amplitudes obtained in 0.2 and 4.0 mM Ca2+ changed from 0.54 (t = 5 min) to 0.82 (t = 30 min). Inward rectification of nicotine-induced responses was reduced during internal dialysis. Voltages for half-maximal conductance were -23.0 and -13.8 mV at 2 and 15 min, respectively. Inclusion of either free Mg2+ ( approximately 2 mM) or spermine (100 microM) in the internal solution counteracted the change in rectification, but did not prevent run-up. The period of run-up was followed by a use-dependent run-down phase. Little run-down in peak current amplitude was induced provided that agonist was applied infrequently (5 min intervals), whereas applications at 30 s intervals produced a loss of channel function after approximately 15 min whole-cell perfusion. The time at which run-down began ( approximately 5-30 min) was correlated with the initial rate of nAChR desensitization ( approximately 200-4000 ms); slowly desensitizing nicotinic currents demonstrated delayed run-down. We suggest that run-up of nAChR-mediated responses does not require receptor activation and may result from a change in channel open probability. We also hypothesize that channel run-down reflects accumulation of nAChRs in long-lived desensitized/inactivated states.

Animals↗
PubMed2000

Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas.

This study addresses two issues arising from the desensitization of nicotinic acetylcholine receptors from the hippocampus, ventral tegmental area, and substantia nigra. First, biophysical studies can find potent and complete desensitization of nicotinic receptors; but in vivo studies often find that desensitization affecting a behavior is less than complete, or that desensitization is important over a different nicotine concentration range. Our results show that there can be significant differences in desensitization when comparing nearby neurons from the same area of the brain. Thus, nicotinic receptors on a minority of neurons may remain active and maintain a behavior under conditions that can produce significant desensitization. Second, agonist applications that are intended to active nicotinic receptors also cause desensitization. The prevailing conditions and the rate of agonist application and removal will control the degree of activation vs. desensitization. These and other factors regulate the efficacy of nicotinic agonists experimentally and physiologically.

Animals↗
PubMed2000

Nicotinic receptors on hippocampal cultures can increase synaptic glutamate currents while decreasing the NMDA-receptor component.

Activation of presynaptic nicotinic acetylcholine receptors (nAChRs) can enhance the release of glutamate from synapses in hippocampal slices and cultures. In hippocampal cultures making autaptic connections, rapid application of a high concentration of nicotine activated presynaptic, postsynaptic, and somatic nAChRs, which consequently enhanced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) mediated by glutamate receptors. The increased eEPSC amplitudes arose from enhanced glutamate release caused by presynaptic nAChRs (Radcliffe and Dani, 1998, Journal of Neuroscience 18, 7075). The same whole-cell nicotine applications that enhanced non-NMDA eEPSCs often decreased the NMDA-receptor component of the eEPSCs. Furthermore, whole-cell activation of nAChRs by nicotine selectively reduced the amplitude of the whole-cell NMDA-receptor currents without affecting the non-NMDA receptor currents. The inhibition by nicotine was prevented by the alpha7-specific antagonist, methyllycaconitine, and required the presence of extracellular Ca(2+). The calmodulin antagonist fluphenazine prevented inhibition of the NMDA-receptor current by nAChR activity, suggesting that a Ca(2+)-calmodulin-dependent process mediated the effect of nicotine. Our results indicate that activation of nAChRs can modulate glutamatergic synapses in several ways. Presynaptic nAChR activity enhances synaptic transmission by increasing transmitter release. Additionally, somatic or postsynaptic nAChRs can initiate a Ca(2+) signal that can act via calmodulin to reduce the responsiveness of NMDA receptors.

Animals↗
PubMed2000

Mice homozygous for the L250T mutation in the alpha7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth.

The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated in modulating neurotransmitter release and may play a role in the regulation of neuronal growth and differentiation. A threonine for leucine 247 substitution in the channel domain of the chick alpha7 nAChR increases agonist affinity and decreases the rate of desensitization, creating a "gain of function" model for this receptor. We have generated mice that express the analogous mutation (L250T) in the alpha7 nAChR using the techniques of homologous recombination and here report their characteristics. Mice heterozygous (+/T) for the L250T mutation are viable, fertile, and anatomically normal compared with wild-type littermates. In contrast, homozygous (T/T) L250T mice die within 2-24 h of birth. Brains of T/T mouse pups exhibit a marked reduction in alpha7 nAChR protein levels and show extensive apoptotic cell death throughout the somatosensory cortex. Furthermore, alpha7 L250T nAChRs are functionally expressed on neurons within the brains of T/T neonatal mice and have properties that are consistent with those observed for the rat alpha7 L250T and the chick alpha7 L247T mutant nAChRs expressed in oocytes. These findings indicate that neurons in the developing brain expressing only alpha7 L250T mutant nAChRs are susceptible to abnormal apoptosis, possibly due to increased Ca2+ influx.

Animals↗
PubMed2000

Properties underlying the influence of nicotinic receptors on neuronal excitability and epilepsy.

The great diversity of neuronal nAChRs equips them for many roles. The broad, diffuse projections of the cholinergic system and their influence on multiple neurotransmitter systems enable nAChRs to have a wide modulatory influence on excitability on multiple time scales. Both excitatory and inhibitory synapses are directly modulated by nAChR activity. Although fast nicotinic transmission is not a major excitatory drive, it may alter the excitability of many synapses at one time. Depending on the neural area and stage of development, nAChRs of multiple subtypes will have varying degrees of importance in regulating neuronal excitability.

Brain↗
PubMed2000

Inhibition and disinhibition of pyramidal neurons by activation of nicotinic receptors on hippocampal interneurons.

Nicotinic acetylcholine receptors (nAChRs) are expressed in the hippocampus, and their functional roles are beginning to be delineated. The effect of nAChR activation on the activity of both interneurons and pyramidal neurons in the CA1 region was studied in rat hippocampal slices. In CA1 stratum radiatum with muscarinic receptors inhibited, local pressure application of acetylcholine (ACh) elicited a nicotinic current in 82% of the neurons. The majority of the ACh-induced currents were sensitive to methyllycaconitine, which is a specific inhibitor of alpha7-containing nAChRs. Methyllycaconitine-insensitive nicotinic currents also were present as detected by a nonspecific nAChR inhibitor. The ACh-sensitive neurons in the s. radiatum were identified as GABAergic interneurons by their electrophysiological properties. Pressure application of ACh induced firing of action potentials in approximately 70% of the interneurons. The ACh-induced excitation of interneurons could induce either inhibition or disinhibition of pyramidal neurons. The inhibition was recorded from the pyramidal neuron as a burst of GABAergic synaptic activity. That synaptic activity was sensitive to bicuculline, indicating that GABA(A) receptors mediated the ACh-induced synaptic currents. The disinhibition was recorded from the pyramidal neuron as a reduction of spontaneous GABAergic synaptic activity when ACh was delivered onto an interneuron. Both the inhibition and disinhibition were sensitive to either methyllycaconitine or mecamylamine, indicating that activation of nicotinic receptors on interneurons was necessary for the effects. These results show that nAChRs are capable of regulating hippocampal circuits by exciting interneurons and, subsequently, inhibiting or disinhibiting pyramidal neurons.

Acetylcholine↗
PubMed1999

Nicotinic modulation of glutamate and GABA synaptic transmission of hippocampal neurons.

Although the hippocampus expresses nicotinic acetylcholine receptors (nAChRs) and receives cholinergic innervation, the functional roles of these receptors are not completely understood. Our results indicated that presynaptic nAChRs mediated a calcium influx that enhanced the release of both glutamate and GABA. Fura-2 detection of calcium in single mossy fiber presynaptic terminals indicated that nAChRs directly mediated a calcium influx. In hippocampal neurons in primary culture, both spontaneous vesicular release and evoked release of glutamate and GABA were enhanced by nicotine. The nicotinic current displayed rapid desensitization kinetics, and the response to nicotine was inhibited by alpha-bungarotoxin and methyllcaconitine, suggesting that nAChRs containing the alpha 7 subunit mediated the effect. Modulation of synaptic activity by presynaptic calcium influx may represent a physiological role of acetylcholine in the brain, as well as a mechanism of action of nicotine.

Acetylcholine↗
PubMed1999

Distributions of nicotinic acetylcholine receptor alpha7 and beta2 subunits on cultured hippocampal neurons.

The hippocampus receives cholinergic afferents and expresses neuronal nicotinic acetylcholine receptors. In particular, the alpha7 and beta2 nicotinic subunits are highly expressed in the hippocampus. There has been controversy about the location, distribution and roles of neuronal nicotinic acetylcholine receptors [Role L. W. and Berg D. K. (1996) Neuron 16, 1077-1085; Wonnacott S. (1997) Trends Neurosci. 20, 92-98]. Using immunocytochemistry and patch-clamp techniques, we examined the density and distribution of nicotinic receptors on rat hippocampal neurons in primary tissue culture. The density and distribution of alpha7 subunits change with days in culture. Before 10 days in culture, alpha7 expression, monitored immunocytochemically, is low and nicotinic currents are small or absent. In older cultures, about two-thirds of the neurons express nicotinic currents, and alpha7 appears in small patches on the soma and out along the neuronal processes. These patches of alpha7 subunits on the surface of the neuronal processes often co-localize with the presynaptic marker, synaptotagmin. The other most common nicotinic subunit, beta2, stays confined mainly to the soma and proximal processes, and beta2 is distributed more uniformly and is not specifically localized at presynaptic areas. The two subunits, alpha7 and beta2, have different expression patterns on the surface of the cultured hippocampal neurons. Taken together with previous physiological studies, the results indicate that alpha7 subunits can be found at presynaptic terminals, and at these locations, these calcium-permeable channels may influence transmitter release.

Animals↗