Alcohol withdrawal drives depressive behaviors by activating neurons in the rostromedial tegmental nucleus

Abstract

Rostromedial tegmental nucleus (RMTg) GABA neurons exert a primary inhibitory drive onto midbrain dopamine neurons and are excited by a variety of aversive stimuli. There is, however, little evidence that the RMTg-ventral tegmental area (VTA)-nucleus accumbens shell (Acb) circuit plays a role in the aversive consequences of alcohol withdrawal. This study was performed in adult male Long-Evans rats at 48-h withdrawal from chronic alcohol drinking in the intermittent schedule. These rats displayed clear anhedonia and depression-like behaviors, as measured with the sucrose preference, and forced swimming tests. These aberrant behaviors were accompanied by a substantial increase in cFos expression in the VTA-projecting RMTg neurons, identified by a combination of immunohistochemistry and retrograde-tracing techniques. Pharmacological or chemogenetic inhibition of RMTg neurons mitigated the anhedonia and depression-like behaviors. Ex vivo electrophysiological data showed that chemogenetic inactivation of RMTg neurons reduced GABA release and accelerated spontaneous firings of VTA dopamine neurons. Finally, using a functional hemispheric disconnection procedure, we demonstrated that inhibition of unilateral RMTg, when combined with activation of D1 and D2 dopamine receptors in the contralateral (but not ipsilateral) Acb, mitigated the anhedonia and depressionlike behaviors in alcohol-withdrawal rats. These data show that the integrity in the RMTg-VTA-Acb pathway in a single hemisphere is sufficient to elicit depression-like behavior during ethanol-withdrawal. Overall, the present results reveal that the RMTg-VTA-Acb pathway plays a crucial role in the depression-like behavior in animals undergoing alcohol withdrawal, further advocating the RMTg as a potential therapeutic target for alcoholism.

The Emerging Role of LHb CaMKII in the Comorbidity of Depressive and Alcohol Use Disorders

“…Studies using phalloidin anterograde labeling tracing techniques show www.videleaf.com that serotonergic fibers from the MRN and DRN are throughout the whole LHb [55,56]. Studies using transgenic mice expressing Cre recombinase in serotonin-positive raphe neurons show that DRN serotonin cells project to the lateral portion of the LHb [57,58], consistent with the evidence that serotonin and its transporter are in the presynaptic side in the LHb [59][60][61][62]. For an overview on how the LHb integrates serotonergic signals, please read the recent review by Tchenio and colleagues [63].…”

“…Recent evidence from www.videleaf.com serious electrophysiological, immunohistochemical, molecular, and behavioral experiments points to a significant role played by the LHb. LHb neurons' hyperactivity during alcohol withdrawal may inhibit VTA dopamine neurons and lead to dopamine hypofunction, causing depressive symptoms such as anhedonia and anxiety [9,60,71,73,74,102,103]. These results provide strong support for a key role of the LHb in the connection between DDs, AUDs, and their comorbidities (Figures 1, 2).…”

“…Neurons in the LHb are almost uniformly glutamatergic [64,65]. The LHb inhibits the brain's reward centers, including the dopaminergic VTA [23,40,66] and the serotonergic DRN [22], either via the direct projection to local interneurons within the VTA and DRN [9,29,38,40,[67][68][69] or indirectly via the GABAergic relay in the RMTg [29,30,60,[70][71][72] (Figure 1). The tight connection between the LHb and monoaminergic neurotransmitter systems suggests a crucial role of the LHb in neuropsychiatric diseases including DDs [20,21,36,39] and AUDs [9,[73][74][75].…”

“…Importantly, CaMKII in the LHb plays a significant role in aversive behaviors during alcohol withdrawal [9,60,115]. The protein level of phosphorylated AMPAR GluA1 subunit at a CaMKII locus (pGluA1-Ser831) was higher in the LHb of Long-Evans rats withdrawn from chronic intermittent alcohol drinking compared with alcohol-naive rats.…”

“…The protein level of phosphorylated AMPAR GluA1 subunit at a CaMKII locus (pGluA1-Ser831) was higher in the LHb of Long-Evans rats withdrawn from chronic intermittent alcohol drinking compared with alcohol-naive rats. These alcoholwithdrawn rats showed clear depressive-like behaviors, measured by forced swimming test and sucrose-preferring test [9,60,74], which were mitigated by intra-LHb injection of the AMPAR antagonist quinoxalinediones 6, 7-dinitroquinoxaline-2, 3-Dione(DNQX) or the CaMKII antagonist 1-[N,O-bis-(5isoquinolinesulphonyl)-N-methyl-L-tyrosy]-4-phenylpiperazine (KN-62), or inhibiting LHb activity with a chemogenetic tool or deep brain stimulation [9,118]. Conversely, in alcohol-naive rats, activation of LHb AMPARs induced depressive-like behaviors [9].…”