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Summary: Adolescent smoking is associated with pathological drinking later in life, but the biological basis for this vulnerability is unknown. To examine how adolescent nicotine exposure influences subsequent ethanol intake, nicotine was administered during adolescence or adulthood, and responses to alcohol were measured 1 month later. We found that adolescent, but not adult, nicotine exposure altered GABA signaling within the ventral tegmental area (VTA) and led to a long-lasting enhancement of alcohol self-administration. We detected depolarizing shifts in GABAA reversal potentials arising from impaired chloride extrusion in VTA GABA neurons. Alterations in GABA signaling were dependent on glucocorticoid receptor activation and were associated with attenuated dopaminergic neuron responses to alcohol in the lateral VTA. Importantly, enhancing chloride extrusion in adolescent nicotine-treated animals restored VTA GABA signaling and alcohol self-administration to control levels. Taken together, this work suggests that adolescent nicotine exposure increases the risk profile for increased alcohol drinking in adulthood. : Thomas et al. show that nicotine treatments during adolescence, but not adulthood, cause a long-term increase in alcohol self-administration in adult rodents. Adolescent nicotine exposure shifts GABAA receptor signaling within the ventral tegmental area circuitry, thereby altering subsequent responses to alcohol. Keywords: alcohol use disorder, reward, mesolimbic, nucleus accumbens, self-administration, chloride gradient, KCC2, glucocorticoid, gateway, dopamine

SummaryDopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA) training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP) underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.

Nicotine is a highly addictive drug found in tobacco that drives its continued use despite the harmful consequences. The initiation of nicotine abuse involves the mesolimbic dopamine system, which contributes to the rewarding sensory stimuli and associative learning processes in the beginning stages of addiction. Nicotine binds to neuronal nicotinic acetylcholine receptors (nAChRs), which come in a diverse collection of subtypes. The nAChRs that contain the α4 and β2 subunits, often in combination with the α6 subunit, are particularly important for nicotine's ability to increase midbrain dopamine neuron firing rates and phasic burst firing. Chronic nicotine exposure results in numerous neuroadaptations, including the upregulation of particular nAChR subtypes associated with long-term desensitization of the receptors. When nicotine is no longer present, for example during attempts to quit smoking, a withdrawal syndrome develops. The expression of physical withdrawal symptoms depends mainly on the α2, α3, α5, and β4 nicotinic subunits in the epithalamic habenular complex and its target regions. Thus, nicotine affects diverse neural systems and an array of nAChR subtypes to mediate the overall addiction process. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here we combine optogenetic and pharmacological manipulations to control dopamine transmission in the hippocampus during encoding of contextual fear memory. We show in mice that hippocampal dopamine can potently modulate aversive memory formation during contextual fear conditioning. Using retrograde tracing, we identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that send direct projections to the dorsal hippocampus. We separately demonstrate that activation of norepinephrine release in the hippocampus during encoding can also facilitate aversive memory formation. Moreover, we find that increasing norepinephrine release can ameliorate contextual fear learning impairments due to dopaminergic dysregulation in the hippocampus. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus, and we show that both dopamine from the midbrain and norepinephrine from the locus coeruleus modulate hippocampal contextual fear memory.

Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/-), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug-modulated DA signaling and argue that genetically imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD).

Epidemiological studies consistently find correlations between nicotine and alcohol use, yet the neural mechanisms underlying their interaction remain largely unknown. Nicotine and alcohol (i.e., ethanol) share many common molecular and cellular targets that provide potential substrates for nicotine–alcohol interactions. These targets for interaction often converge upon the mesocorticolimbic dopamine system, where the link to drug self-administration and reinforcement is well documented. Both nicotine and alcohol activate the mesocorticolimbic dopamine system, producing downstream dopamine signals that promote the drug reinforcement process. While nicotine primarily acts via nicotinic acetylcholine receptors, alcohol acts upon a wider range of receptors and molecular substrates. The complex pharmacological profile of these two drugs generates overlapping responses that ultimately intersect within the mesocorticolimbic dopamine system to promote drug use. Here we will examine overlapping targets between nicotine and alcohol and provide evidence for their interaction. Based on the existing literature, we will also propose some potential targets that have yet to be directly tested. Mechanistic studies that examine nicotine–alcohol interactions would ultimately improve our understanding of the factors that contribute to the associations between nicotine and alcohol use.

In this study, we examined the relationship between the level of daily cigarette consumption and the startle response to affective and cigarette-related cues among treatment-seeking smokers. Before receiving any behavioral or pharmacological treatment, 136 smokers attended a baseline laboratory session, during which we recorded their reflexive eyeblink responses to acoustic startle probes while they were viewing pleasant, unpleasant, neutral, and cigarette-related pictures. We found that 1) cigarette-related and pleasant pictures similarly reduced the startle magnitude compared to neutral pictures; 2) the magnitude of startle modulation rendered by pleasant or unpleasant pictures did not differ among light, moderate, and heavy smokers; and 3) startle attenuation by cigarette-related pictures was greater in heavy smokers than in light smokers. These results suggest that similar to pleasant stimuli, cigarette-related cues are motivationally salient for smokers, and that this salience increases with nicotine dependence.

Altered functional interactions among midbrain dopamine (DA) neurons contribute to the reinforcing properties of environmental stimuli and addictive drugs. To examine correlations among DA neurons, acute nicotine was administrated to rats via an intraperitoneal catheter and unit activity was measured using multi-tetrode in vivo recordings. Nicotine administration enhanced the correlated activity of simultaneously recorded DA neurons from the ventral tegmental area (VTA). The strength of the correlations between DA neuron pairs, as measured by cross covariance among two spike trains, showed dynamic firing changes over time. Nicotine produced a gradual rise in firing rate and burst activity that reached a stable plateau approximately 20 min after the intraperitoneal nicotine infusion. Shortly after that time the cross correlations measured using 5-ms bins increased significantly above baseline. In addition, nicotine increased the firing rates of DA neurons in the posterior VTA more than in the anterior VTA. Unlike nicotine, eticlopride administration also boosted DA neuron firing activity but did not enhance synchronization, indicating that the cross correlations induced by nicotine were not due to a non-specific increase in firing rate. The overall results show that nicotine induces nearly synchronous firing by a subset of DA neurons, and those changes in correlative firing will enhance the DA signal that contributes to nicotine-induced behavioral reinforcement.

SummaryAddictive drugs induce a dopamine signal that contributes to the initiation of addiction, and the dopamine signal influences drug-associated memories that perpetuate drug use. The addiction process shares many commonalities with the synaptic plasticity mechanisms normally attributed to learning and memory. Environmental stimuli repeatedly linked to addictive drugs become learned associations, and those stimuli come to elicit memories or sensations that motivate continued drug use. Applying in vivo recording techniques to freely moving mice, we show that physiologically relevant concentrations of the addictive drug nicotine directly cause in vivo hippocampal synaptic potentiation of the kind that underlies learning and memory. The drug-induced long-term synaptic plasticity required a local hippocampal dopamine signal. Disrupting general dopamine signaling prevented the nicotine-induced synaptic plasticity and conditioned place preference. These results suggest that dopaminergic signaling serves as a functional label of salient events by enabling and scaling synaptic plasticity that underlies drug-induced associative memory.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and participate in a variety of physiological functions. Recent advances have revealed roles of nAChRs in the regulation of synaptic transmission and synaptic plasticity, particularly in the hippocampus and midbrain dopamine centers. In general, activation of nAChRs causes membrane depolarization and directly and indirectly increases the intracellular calcium concentration. Thus, when nAChRs are expressed on presynaptic membranes their activation generally increases the probability of neurotransmitter release. When expressed on postsynaptic membranes, nAChR-initiated calcium signals and depolarization activate intracellular signaling mechanisms and gene transcription. Together, the presynaptic and postsynaptic effects of nAChRs generate and facilitate the induction of long-term changes in synaptic transmission. The direction of hippocampal nAChR-mediated synaptic plasticity - either potentiation or depression - depends on the timing of nAChR activation relative to coincident presynaptic and postsynaptic electrical activity, and also depends on the location of cholinergic stimulation within the local network. Therapeutic activation of nAChRs may prove efficacious in the treatment of neuropathologies where synaptic transmission is compromised, as in Alzheimer's or Parkinson's disease.

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.

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.

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 α7-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.

The hippocampus receives cholinergic afferents and expresses neuronal nicotinic acetylcholine receptors. In particular, the α 7 and β 2 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 α 7 subunits change with days in culture. Before 10 days in culture, α 7 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 α 7 appears in small patches on the soma and out along the neuronal processes. These patches of α 7 subunits on the surface of the neuronal processes often co-localize with the presynaptic marker, synaptotagmin. The other most common nicotinic subunit, β 2, stays confined mainly to the soma and proximal processes, and β 2 is distributed more uniformly and is not specifically localized at presynaptic areas. The two subunits, α 7 and β 2, have different expression patterns on the surface of the cultured hippocampal neurons. Taken together with previous physiological studies, the results indicate that α 7 subunits can be found at presynaptic terminals, and at these locations, these calcium-permeable channels may influence transmitter release.

While trying to mimic the dose and time course of nicotine as it is obtained by a smoker, we found the following results. The initial arrival of even a low concentration of nicotine increased the firing rate of dopaminergic neurons from the ventral tegmental area (VTA) and increased the spontaneous vesicular release of GABA from hippocampal neurons. Longer exposure to nicotine caused variable, but dramatic, desensitization of nicotine receptors and diminished the effects of nicotine. The addictive properties of nicotine as well as its diverse effects on cognitive function could be mediated through differences in activation and desensitization of nicotinic receptors in various areas of the brain.

Corticostriatal glutamate afferents and mesostriatal dopamine afferents commonly converge onto the same postsynaptic spines of medium projection neurons. The consequent synaptic triad provides an ideal configuration for dopamine modulation of glutamatergic transmission. In this issue of Neuron, Bamford et al. report that dopamine inhibits glutamate release in a selective manner by activating presynaptic D2 receptors.

Two properties were found to distinguish neuronal from muscle nicotinic acetylcholine receptors (nAChRs). First, neuronal nAChRs have a greater Ca 2+ permeability. The high Ca 2+ flux through neuronal nAChRs activates a Ca 2+ -dependent CI − conductance, and the Ca 2+ to Cs + permeability ratio (PCaPCs) is 7 times greater for neuronal than for muscle nAChRs. A second difference between the receptor types is that neuronal nAChRs are potently modulated by physiological levels of external Ca 2+ . Neuronal nAChR currents are enhanced by external Ca 2+ in a dose-dependent manner. The results indicate that changes in extracellular Call modulate neuronal nAChRs and may modulate cholinergic synapses in the CNS. Also, activation of neuronal nAChRs produces a significant influx of Ca 2+ that could be an important intracellular signal.

Single-channel records often show frequent currents at a main conductance level and occasional currents at subconductance levels. In some instances, the conductances occur at regular levels that are multiples of a minimum conductance. It is well-appreciated that multiple conductance levels may arise either from the co-operative gating of more than one pore or from changes that occur in a single pore. In this paper, we used theoretical models of ion permeation to examine subconductances arising in a single-pore channel. In particular, the work focuses on the following question: how can an ion channel that provides only one aqueous pore through the membrane produce regular subconductances and a main conductance that all have the same selectivity and the same ion binding affinity? The three types of ion permeation models used in this study showed that a single-pore channel can have subconductances because of long-lived conformational states, because of alterations in rapid fluctuations between conformational states, or because of slight alterations in the electrostatic properties in the channel's entrance vestibules. Regular subconductances with the same selectivity and binding affinity can arise in a single pore even if the energy profile changes do not meet the constant peak offset condition. The results show that the appearance of regular subconductance levels in a single-channel recording is not sufficient evidence to conclude that identical pores have co-operative gating, as would arise in a channel that is a multi-pore complex.

Compounds commonly used to modify protein phosphorylation have been found to interact directly with K channels, Ca channels, and acetylcholine receptor channels. We report that a general protein kinase inhibitor, H-7, directly affects N- methyl- d -aspartate (NMDA) receptors independent of protein kinase activity. Single-channel records in the presence of H-7 have fewer bursts of activity, and the currents are interrupted in a voltage-dependent manner by brief closures. Hippocampal whole-cell currents induced by NMDA are not decreased by H-7, in part, because the single-channel currents have longer burst lengths that compensate for the brief closures.

Morphological dynamics and membrane transport within the living Golgi apparatus of astrocytes labeled with NBD-ceramide were imaged using both electronically enhanced fluorescence video and laser confocal microscopy. In time-lapse recordings, continuous tubulovesicular processes are observed to emerge from trans -Golgi elements and extend along microtubules at average rates of 0.4 μm/s. In addition, discrete fluorescent particles are observed to emerge from the trans -Golgi and subsequently migrate along microtubules at comparable velocities. Frequently, tubulovesicular processes form stable connections that interlink adjacent trans -Golgi elements into an extensive reticulum. Laser photobleaching-recovery experiments reveal that tubulovesicular processes can provide direct pathways for the diffusion of membrane lipids between joined trans -Golgi elements. These results suggest that microtubule-based transport and membrane fusion can operate to interconnect certain cisternal membranes of adjacent Golgi elements within the cell.

Stress can induce cravings and relapse in abstinent drug addicts. In this issue of Neuron, Ungless et al. report that corticotropin-releasing factor (CRF), a key hormone in the stress response, potentiates the N-methyl-D-aspartate NMDA receptor (NMDAR) component of glutamatergic synaptic transmission onto midbrain dopamine neurons, a mechanism that may mediate some effects of stress on relapse.