Tobacco use in developed countries is estimated to be the single largest cause of premature death. Nicotine is the primary component of tobacco that drives use, and like other addictive drugs, nicotine reinforces self-administration and place preference in animal studies. Midbrain dopamine neurons normally help to shape behaviour by reinforcing biologically rewarding events, but addictive drugs such as cocaine can inappropriately exert a reinforcing influence by acting upon the mesolimbic dopamine system. Here we show that the same concentration of nicotine achieved by smokers activates and desensitizes multiple nicotinic receptors thereby regulating the activity of mesolimbic dopamine neurons. Initial application of nicotine can increase the activity of the dopamine neurons, which could mediate the rewarding aspects of tobacco use. Prolonged exposure to even these low concentrations of nicotine, however, can cause desensitization of the nicotinic receptors, which helps to explain acute tolerance to nicotine's effects. The effects suggest a cellular basis for reports that the first cigarette of the day is the most pleasurable, whereas the effect of subsequent cigarettes may depend on the interplay between activation and desensitization of multiple nicotinic receptors.

Although many psychopharmacological factors contribute to nicotine addiction, midbrain dopaminergic systems have received much attention because of their roles in reinforcement and associative learning. It is generally thought that the mesocorticolimbic dopaminergic system is important for the acquisition of behaviors that are reinforced by the salient drives of the environment or by the inappropriate stimuli of addictive drugs. Nicotine, as obtained from tobacco, can activate nicotinic acetylcholine receptors (nAChRs) and excite midbrain neurons of the mesocorticolimbic system. Using midbrain slices from rats, wild-type mice, and genetically engineered mice, we have found differences in the nAChR currents from the ventral tegmental area (VTA) and the substantia nigra compacta (SNc). Nicotinic AChRs containing the alpha7 subunit (alpha7* nAChRs) have a low expression density. Electrophysiological analysis of nAChR currents, autoradiography of [125I]-alpha-bungarotoxin binding, and in situ hybridization revealed that alpha7* nAChRs are more highly expressed in the VTA than the SNc. In contrast, beta2* nAChRs are move evenly distributed at a higher density in both the VTA and SNc. At the concentration of nicotine obtained by tobacco smokers, the slow components of current (mainly mediated by beta2* nAChRs) become essentially desensitized. However, the minority alpha7* component of the current in the VTA/SNc is not significantly desensitized by nicotine in the range < or =100 nm. These results suggest that nicotine, as obtained from tobacco, can have multiple effects on the midbrain areas by differentially influencing dopamine neurons of the VTA and SNc and differentially desensitizing alpha7* and non-alpha7 nAChRs.

Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs). A component of nicotine's addictive power is attributable to actions on the mesolimbic dopaminergic system, which serves a fundamental role in the acquisition of behaviors that are inappropriately reinforced by addictive drugs. Here we show that nicotine, in the same concentration and time ranges as obtained from tobacco, has three main actions that regulate the activity of midbrain dopamine (DA) neurons. Nicotine first activates and then desensitizes nAChRs on the DA neurons. This process directly excites the DA neurons for a short period of time before the nAChRs desensitize. Nicotine also enhances glutamatergic excitation and decreases GABAergic inhibition onto DA neurons. These events increase the probability for synaptic plasticity, such as long-term potentiation. The short-lived direct excitation of the DA neurons coupled with the enhanced glutamatergic afferent activity provides the presynaptic and postsynaptic coincidence necessary to initiate synaptic potentiation. In total, these synaptic events lead to a relatively long-lasting heightened activity of midbrain DA neurons. Consistent with other summarized studies, this work indicates that the synaptic changes normally associated with learning and memory can be influenced and commandeered during the nicotine addiction process.

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Traumatic brain injury (TBI) is a major public health concern affecting a large number of athletes and military personnel. Individuals suffering from a TBI risk developing anxiety disorders, yet the pathophysiological alterations that result in the development of anxiety disorders have not yet been identified. One region often damaged by a TBI is the basolateral amygdala (BLA); hyperactivity within the BLA is associated with increased expression of anxiety and fear, yet the functional alterations that lead to BLA hyperexcitability after TBI have not been identified. We assessed the functional alterations in inhibitory synaptic transmission in the BLA and one mechanism that modulates excitatory synaptic transmission, the α7 containing nicotinic acetylcholine receptor (α7-nAChR), after mTBI, to shed light on the mechanisms that contribute to increased anxiety-like behaviors. Seven and 30 days after a mild controlled cortical impact (CCI) injury, animals displayed significantly greater anxiety-like behavior. This was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents (IPSCs). Decreases in the mIPSC amplitude were associated with reduced surface expression of α1, β2, and γ2 GABAA receptor subunits. However, significant increases in the surface expression and current mediated by α7-nAChR, were observed, signifying increases in the excitability of principal neurons within the BLA. These results suggest that mTBI causes not only a significant reduction in inhibition in the BLA, but also an increase in neuronal excitability, which may contribute to hyperexcitability and the development of anxiety disorders.

BackgroundHexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a high-energy, trinitrated cyclic compound that has been used worldwide since World War II as an explosive in both military and civilian applications. RDX can be released in the environment by way of waste streams generated during the manufacture, use, and disposal of RDX-containing munitions and can leach into groundwater from unexploded munitions found on training ranges. For > 60 years, it has been known that exposure to high doses of RDX causes generalized seizures, but the mechanism has remained unknown.ObjectiveWe investigated the mechanism by which RDX induces seizures.Methods and resultsBy screening the affinity of RDX for a number of neurotransmitter receptors, we found that RDX binds exclusively to the picrotoxin convulsant site of the γ-aminobutyric acid type A (GABAA) ionophore. Whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency and amplitude of spontaneous GABAA receptor–mediated inhibitory postsynaptic currents and the amplitude of GABA-evoked postsynaptic currents. In extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharges.ConclusionsThese results suggest that binding to the GABAA receptor convulsant site is the primary mechanism of seizure induction by RDX and that reduction of GABAergic inhibitory transmission in the amygdala is involved in the generation of RDX-induced seizures. Knowledge of the molecular site and the mechanism of RDX action with respect to seizure induction can guide therapeutic strategies, allow more accurate development of safe thresholds for exposures, and help prevent the development of new explosives or other munitions that could pose similar health risks.

Acid-sensitive ion channels (ASICs) are proton-gated and belong to the family of degenerin channels. In the mammalian nervous system, ASICs are most well known in sensory neurons, where they are involved in nociception, occurring when injury or inflammation causes acidification. ASICs also are widely expressed in the CNS, and some synaptic roles have been revealed. Because neuronal activity can produce pH changes, ASICs may respond to local acidic transients and alter the excitability of neuronal circuits more widely than is presently appreciated. Furthermore, ASICs have been found to underlie calcium transients that contribute to neuronal death. Degeneration of midbrain dopamine neurons is characteristic of advanced idiopathic Parkinson's disease. Therefore, we tested for functional ASICs in midbrain dopamine neurons of the ventral tegmental area and substantia nigra compacta. Patch-clamp electrophysiology applied to murine midbrain slices revealed abundant acid-sensitive channels. The ASICs were gated and desensitized by extracellular application of millimolar concentrations of NH 4Cl. Although the NH4Cl solution contains micromolar concentrations of NH3 at pH 7.4, our evidence indicates that NH 4 ؉ gates the ASICs. The proton-gated and the ammonium-gated currents were inhibited by tarantula venom (psalmotoxin), which is specific for the ASIC1a subtype. The results show that acidsensitive channels are expressed in midbrain dopamine neurons and suggest that ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus. The ammonium sensitivity suggests a role for ASIC1s in hepatic encephalopathy, cirrhosis, and other neuronal disorders that are associated with hyperammonemia.hepatic encephalopathy ͉ mesolimbic dopamine ͉ Parkinson's disease ͉ proton gating ͉ cirrhosis P roton-gated channels or acid-sensitive ion channels (ASICs) are present in sensory neurons, where they have roles in nociception, taste, and possibly other modalities (1-5). Recently, six ASIC subunits were cloned (6, 7) and identified as belonging to a broad family of degenerin (Deg) channels. ASIC1a (also known as BNaC2) and ASIC1b (ASIC1␤) are the splice variants of the ASIC1 gene (6,8,9). ASIC2a (BNaC1, MDEG) and ASIC2b (MDEG2) are the spliced forms of the ASIC2 gene (10). Other subunits are ASIC3 (DRASIC) (7, 11) and ASIC4 (SPA-SIC) (12, 13). The ASIC subunits form a variety of heteromeric channels in heterologous expression systems, and subunits other than ASIC2b and ASIC4 also form functional homomeric channels in expression systems (14).Although there has been much progress, there is still uncertainty about the pharmacology, the endogenous subunit composition, and the functional significance of different CNS ASIC subtypes (4,5,15,16). ASIC1 is the subunit most abundantly expressed in the mammalian brain and has been shown to be involved in synaptic plasticity (17). ASICs in the CNS also have been implicated in Ca 2ϩ toxicity arising from ischemia, and inhibition or knockout of ASIC1 protected the ...

The drug addiction process shares many commonalities with normal learning and memory. Addictive drugs subvert normal synaptic plasticity mechanisms, and the consequent synaptic changes underlie long-lasting modifications in behavior that accrue during the progression from drug use to addiction. Supporting this hypothesis, it was recently shown that nicotine administered to freely moving mice induces long-term synaptic potentiation of the perforant path connection to granule cells of the dentate gyrus. The perforant path carries place and spatial information that links the environment to drug taking. An example of that association is the nicotine-induced synaptic potentiation of the perforant path that was found to underlie nicotine-conditioned place preference. The present study examines the influence of nicotine over local GABAergic inhibition within the dentate gyrus during the drug-induced synaptic potentiation. In vivo recordings from freely moving mice suggested that both feedforward and feedback inhibition onto granules cells were diminished by nicotine during the induction of synaptic potentiation. In vitro brain slice studies indicated that nicotine altered local circuit inhibition within the dentate gyrus leading to disinhibition of granule cells. These changes in local inhibition contributed to nicotine-induced in vivo synaptic potentiation, thus, likely contributed to drugassociated memories. Through this learning process, environmental features become cues that motivate conditioned drug-seeking and drug-taking behaviors.