An essential role of acetylcholine-glutamate synergy at habenular synapses in nicotine dependence

Abstract

A great deal of interest has been focused recently on the habenula and its critical role in aversion, negative-reward and drug dependence. Using a conditional mouse model of the ACh-synthesizing enzyme choline acetyltransferase (Chat), we report that local elimination of acetylcholine (ACh) in medial habenula (MHb) neurons alters glutamate corelease and presynaptic facilitation. Electron microscopy and immuno-isolation analyses revealed colocalization of ACh and glutamate vesicular transporters in synaptic vesicles (SVs) in the central IPN. Glutamate reuptake in SVs prepared from the IPN was increased by ACh, indicating vesicular synergy. Mice lacking CHAT in habenular neurons were insensitive to nicotine-conditioned reward and withdrawal. These data demonstrate that ACh controls the quantal size and release frequency of glutamate at habenular synapses, and suggest that the synergistic functions of ACh and glutamate may be generally important for modulation of cholinergic circuit function and behavior.DOI: http://dx.doi.org/10.7554/eLife.11396.001

Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons

“…We have previously observed that the vesicular coentry of glutamate through VGLUT can increase the driving force for VMAT2-mediated exchange in both mice and flies (6,54). This mechanism can increase the quantal content of DA and other cationic transmitters (6,(55)(56)(57)(58), but could also help sequester toxic VMAT2 substrates, such as 6-OHDA or 1-methyl-4-phenylpyridinium (MPP + ), away from sensitive cellular compartments or processes. Thus, increased resistance of VGLUT2-expressing DA neurons to neurotoxins is likely to explain at least some of the effects we observe following DA neuron injury with striatal 6-OHDA or systemic MPTP.…”

Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei

“…Moreover, some of our PHA‐L or CTb injections were small enough to permit well‐founded conclusions about the topography of some IP inputs and outputs. For example, MHb projections to the IP have been investigated in great detail using conventional tracing techniques (Contestabile & Flumerfelt, ; Kim, ), immunohistochemical studies (Contestabile et al, ), as well as several distinct approaches in genetically modified mice (e.g., Broms, Antolin‐Fontes, Tingström, & Ibañez‐Tallon, ; Frahm et al, ; Hsu et al, ; Quina et al, ; Ren et al, ; Shih et al, ). Altogether, these studies highlighted that, whereas the IPL and dorsal cap of the IP are mainly innervated by glutamate/substance P axons arising from the MHbD, all remainder IP subnuclei are abundantly innervated by glutamate/acetylcholine axons emerging from MHbV (for a recent review, see Antolin‐Fontes et al, ).…”

“…There is now broad consensus that the MHb‐IP axis plays a major role in nicotine mediated reward and withdrawal behaviors (for reviews, see Antolin‐Fontes et al, ; Fowler & Kenny, ; Jackson, Muldoon, De Biasi, & Damaj, ). Thus, distinct nAChRs have been shown to mediate key responses to nicotine through mechanisms including presynaptic facilitation of glutamate release by MHb axons in the IP (Frahm et al, ), and the regulation of pacemaker activity of cholinergic neurons in the MHbV (Görlich et al, ), which remarkably are able to co‐release acetylcholine and glutamate in the IP via different transmission modes (Ren et al, ).…”

“…Co‐transmitter‐specific topographical projections emerging from distinct MHb subdivisions and targeting specific IP subregions have been documented in detail in rats (Contestabile et al, ) and mice (Qin & Luo, ; Quina, Wang, Ng, & Turner, ). Notably, the MHb is a glutamatergic structure, with neurons from the ventral MHb co‐releasing acetylcholine and glutamate in the IP (Frahm et al, ; Ren et al, ).…”

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

“…Together, these data indicate that, under conditions of nicotine abstinence, the IPN is activated through mHb signaling (most notably via excitatory glutamatergic input), triggering an anxiety-like response. The distinct regulatory pathways of IPN glutamatergic signaling may pass through a mechanism whereby ACh is able to control the release frequency of Glu at habenular synapses and hence, the behavioral responses to nicotine [47]. …”