Differential Effects of Toluene and Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area

Abstract

Drugs of abuse increase the activity of dopaminergic neurons of the ventral tegmental area (VTA), and output from the VTA is critical for both natural and drug-induced reward and reinforcement. Ethanol and the abused inhalant toluene both enhance VTA neuronal firing, but the mechanisms of this effect is not fully known. In this study, we used extracellular recordings to compare the actions of toluene and ethanol on DA VTA neurons. Both ethanol and toluene increased the firing rate of DA neurons, although toluene was ~100 times more potent than ethanol. The mixed ion channel blocker quinine (100 μM) blocked the increases in firing produced by ethanol and toluene, indicating some similarity in mechanisms of excitation. A mixture of antagonists of GABA and cholinergic receptors did not prevent toluene-induced or ethanol-induced excitation, and toluene-induced excitation was not altered by co-administration of ethanol, suggesting independent mechanisms of excitation for ethanol and toluene. Concurrent blockade of NMDA, AMPA, and metabotropic glutamate receptors enhanced the excitatory effect of toluene while having no significant effect on ethanol excitation. Nicotine increased firing of DA VTA neurons, and this was blocked by the nicotinic antagonist mecamylamine (1 μM). Mecamylamine did not alter ethanol or toluene excitation of firing but the muscarinic antagonist atropine (5 μM) or a combination of GABA antagonists (bicuculline and CGP35348, 10 μM each) reduced toluene-induced excitation without affecting ethanol excitation. The Ih current blocker ZD7288 abolished the excitatory effect of toluene but unlike the block of ethanol excitation, the effect of ZD7288 was not reversed by the GIRK channel blocker barium, but was reversed by GABA antagonists. These results demonstrate that the excitatory effects of ethanol and toluene have some similarity, such as block by quinine and ZD7288, but also indicate that there are important differences between these two drugs in their modulation by glutamatergic, cholinergic, and GABAergic receptors. These findings provide important information regarding the actions of abused inhalants on central reward pathways, and suggest that regulation of the activation of central dopamine pathways by ethanol and toluene partially overlap.

Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol

“…We have demonstrated previously that ethanol-induced excitation of VTA DA neurons in our recordings is unaltered by GABAergic or glutamatergic antagonists [ 90 ]. In the present study, we also found that the enhancement of ethanol-stimulated firing of VTA DA neurons by E2 is not altered by GABA receptor antagonists.…”

Ethanol actions on the ventral tegmental area: novel potential targets on reward pathway neurons

“…While these studies illuminate the variety of systems affected by ethanol, they do not address the primary response to ethanol, i.e., increased VTA neuron firing rate and increased dopamine release. However, ethanol excitation of DA VTA neurons is not diminished by dissociating the neurons from synaptic and glial connections (Brodie et al 1999 ), nor by the presence of antagonists of GABA A , GABA B , NMDA, AMPA, metabotropic glutamate, muscarinic or nicotinic cholinergic receptors (Nimitvilai et al 2016 ), indicating that these receptors are not necessary for the excitatory action of ethanol on DA VTA neurons in vitro. Although the specific target of ethanol action responsible for excitation of DA VTA neurons has not been identified, from a therapeutic standpoint, it is not necessary that a receptor or ion channel be the primary target of ethanol to have an important influence on the rewarding action of alcohol.…”

“…HDAC inhibition also reversed morphine-induced changes in DA VTA activity (Authement et al 2016 ). The volatile organic solvent toluene is another addictive drug that shares physiological effects with other drugs of abuse, including alcohol (Nimitvilai et al 2016 ). Repeated toluene exposure altered acetylation of H3 in NAc and H4 in the VTA (Sanchez-Serrano et al 2011 ).…”

Chemogenetic Excitation of Accumbens-Projecting Infralimbic Cortical Neurons Blocks Toluene-Induced Conditioned Place Preference

“…To determine whether the reduction in CPP observed following CNO injection was due to nonspecific CNO-induced changes in exploratory behavior (MacLaren et al, 2016), the number of chamber entries for each animal following injection of saline or CNO were compared. There was no difference in chamber entries between air-exposed hM4Di DREADD-expressing rats following an injection of saline vehicle (109.3 Ϯ 11.6) or CNO (103.5 Ϯ 10.4; CNO effect: t (7) ϭ 0.65, p ϭ 0.54).…”

“…Controlling for potential off-target effects of CNO Although CNO activation of DREADDs has been used extensively to analyze circuit-specific control of various behaviors (Roth, 2016), findings from a recent study suggest that CNO metabolites, including clozapine, produce off-target effects, such as locomotor deficits, that may confound interpretation of the data (MacLaren et al, 2016;Gomez et al, 2017). This is of particular concern when studying drugs of abuse, such as psychostimulants, where enhanced locomotor activity is a notable effect of the drug.…”