Acute Nicotine Exposure Alters Ventral Tegmental Area Inhibitory Transmission and Promotes Diazepam Consumption

Abstract

Nicotine use increases the risk for subsequent abuse of other addictive drugs, but the biological basis underlying this risk remains largely unknown. Interactions between nicotine and other drugs of abuse may arise from nicotine-induced neural adaptations in the mesolimbic dopamine (DA) system, a common pathway for the reinforcing effects of many addictive substances. Previous work identified nicotine-induced neuroadaptations that alter inhibitory transmission in the ventral tegmental area (VTA). Here, we test whether nicotine-induced dysregulation of GABAergic signaling within the VTA increases the vulnerability for benzodiazepine abuse that has been reported in smokers. We demonstrate in rats that nicotine exposure dysregulates diazepam-induced inhibition of VTA GABA neurons and increases diazepam consumption. In VTA GABA neurons, nicotine impaired KCC2-mediated chloride extrusion, depolarized the GABA A reversal potential, and shifted the pharmacological effect of diazepam on GABA neurons from inhibition toward excitation. In parallel, nicotine-related alterations in GABA signaling observed ex vivo were associated with enhanced diazepam-induced inhibition of lateral VTA DA neurons in vivo. Targeting KCC2 with the agonist CLP290 normalized diazepam-induced effects on VTA GABA transmission and reduced diazepam consumption following nicotine administration to the control level. Together, our results provide insights into midbrain circuit alterations resulting from nicotine exposure that contribute to the abuse of other drugs, such as benzodiazepines.

The serotonin 2A receptor agonist TCB‐2 attenuates heavy alcohol drinking and alcohol‐induced midbrain inhibitory plasticity

“…Electrophysiological recordings were performed as previously described 4,5,17,18 . Briefly, horizontal slices (230 μm) containing the VTA were cut using a vibratome (Leica Microsystems, Buffalo Grove, IL) in ice‐cold, carbogenated (95% O 2 /5% CO 2 ; Airgas, Philadelphia, PA) high sucrose, reduced Ca 2+ , elevated Mg 2+ artificial cerebrospinal fluid (aCSF, in mM): 205.0 sucrose, 2.5 KCl, 21.4 NaHCO 3 , 1.2 NaH 2 PO 4 , 0.5 CaCl 2 , 7.5 MgCl 2 and 11.1 glucose.…”

“…Electrophysiological recordings were performed as previously described. 4,5,17,18 Briefly, horizontal slices (230 μm) containing the VTA were cut using a vibratome (Leica Microsystems, Buffalo Grove, IL) in ice-cold, carbogenated (95% O 2 /5% CO 2 ; Airgas, Philadelphia, PA) high sucrose, reduced Ca 2+ , elevated Mg In VTA GABA neurons, activity-dependent depression of evoked inhibitory postsynaptic currents (eIPSCs) was recorded in whole-cell configuration at both À90 mV (Cl À efflux) and 0 mV (Cl À influx) holding potentials with the internal solution (in mM): 123.0 K + gluconate, Perforated cell-attached recordings were performed to measure the GABA reversal potential (E GABA ) under physiological Cl À conditions that do not disrupt the intracellular anionic milieu. Gramicidin was first dissolved in methanol (10 mg/ml) and then diluted to a final concentration of 150 μg/ml in the internal solution (in mM): 135.0 KCl, 12.0 NaCl, 2.0 Mg-ATP, 0.5 EGTA, 10.0 HEPES, 0.3 Tris-GTP and pH 7.2-7.3.…”

Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain

“…Based on the clinical observation that benzodiazepine abuse occurs more often in smokers, Ostroumov and colleagues sought to address the neurobiology behind this predisposition. Ostroumov et al, 2020 demonstrated that the state of KCC2 and thus, GABA inhibition, are rapidly altered by exposure to nicotine [ 158 ]. They found that a single nicotine exposure and volitional consumption downregulate KCC2, diminishing Cl − extrusion capacity, which dysregulates the GABA-A receptor activity on GABA neurons in the VTA [ 158 ].…”

“…Ostroumov et al, 2020 demonstrated that the state of KCC2 and thus, GABA inhibition, are rapidly altered by exposure to nicotine [ 158 ]. They found that a single nicotine exposure and volitional consumption downregulate KCC2, diminishing Cl − extrusion capacity, which dysregulates the GABA-A receptor activity on GABA neurons in the VTA [ 158 ]. As a result, diazepam, a commonly used benzodiazepine, drives VTA GABAergic neurons toward paradoxical excitation, increasing GABAergic inhibition of dopaminergic neurons and reducing dopamine release to diazepam administration.…”

“…Furthermore, the effects of nicotine exposure could be prevented by enhancing KCC2 activity. By administering CLP-290, Ostroumov and colleagues were able to correct diazepam-induced alterations in GABA activity in the VTA and reduce diazepam self-administration [ 158 ].…”