Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro

156

137

Acetaldehyde is the first and principal metabolite of ethanol administered systemically. To its rise in blood, after administration of disulfiram, is ascribed the aversive reaction that should discourage alcoholics from drinking. In the present study, we sought to determine the effect of acetaldehyde on the electrophysiological properties of dopamine (DA)-containing neurons in the ventro tegmental area (VTA) of rats in vivo. Intravenous (i.v.) administration of acetaldehyde (5-40 mg/kg) readily and dose-dependently increased the firing rate, spikes/burst, and burst firing of VTA neurons. Ethanol (250-1000 mg/kg/i.v.) administration produced similar increments in electrophysiological parameters. In addition, a second group of rats was pretreated with the alcohol-dehydrogenase inhibitor 4-methylpyrazole (90 mg/kg) intraperitoneally (i.p.), and ethanol and acetaldehyde were administered i.v. at the same doses, 48 h later. In this group, ethanol effects were drastically reduced and the firing rate, spikes/burst, and burst firing were not significantly altered. In contrast, acetaldehyde fully retained its capacity to stimulate electrophysiological indices. The results indicate that acetaldehyde produces electrophysiological actions on VTA neurons in vivo, similar to those produced by ethanol, and significantly participate in ethanol-induced increment in DA neuronal activity. These results also suggest that acetaldehyde, by increasing DA neuronal activity in the VTA, may significantly contribute to the centrally mediated positive motivational properties of ethanol, which would oppose the well-known peripherally originating aversive properties.

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Acetaldehyde Increases Dopaminergic Neuronal Activity in the VTA

Foddai

Dosia

Spiga

et al. 2003

156

137

“…At the systems level, the increased release of DA associated with the administration of toluene and the CNS-depressant EtOH has been temporally associated in vivo with an increase in the number of impulses originating within the VTA, the site of origin of the mesolimbic DA pathway (Gessa et al, 1985;Riegel and French, 1999a, b). At the cellular level both substances stimulate DA neuronal activityFan effect that has been attributed to disinhibitory mechanisms as well as the direct activation of VTA DA neurons (Brodie et al, 1990(Brodie et al, , 1999. Taken together, these noticeable similarities would appear to support the general conclusions that the abused inhalant toluene may trigger the release of DA in the NAC via impulse-dependent mechanisms initiated upstream at the level of the cell bodies in the VTA.…”

Section: -Ohda Studies and Toluenementioning

confidence: 68%

Toluene-Induced Locomotor Activity is Blocked by 6-Hydroxydopamine Lesions of the Nucleus Accumbens and the mGluR2/3 Agonist LY379268

Riegel

Ali

French

2003

The abuse of volatile inhalants remains a prominent, yet poorly understood, form of substance abuse among youth. Nevertheless, the identification of a mechanism underlying the reinforcing properties of inhalants has been hampered by the lack of a clearly identifiable neural substrate upon which these chemicals act. One ingredient that is common to many abused inhalants is toluene, an organic solvent that is self-administered by nonhuman primates and rodents. Most drugs of abuse have been found to elicit forward locomotion in rats, an effect owing to the activation of mesoaccumbal dopamine (DA) pathways. Thus, the present study was undertaken using two different approaches to determine whether toluene-induced locomotor hyperactivity is also ultimately dependent upon DA neurotransmission in the mesolimbic nucleus accumbens (NAC). Here we report on the effects of 6-hydroxydopamine (6-OHDA) lesions of the NAC or pretreatment with the metabotropic mGlu2/3 receptor agonist LY379268 on toluene-induced locomotor activity. Both procedures, which are known to alter neurotransmission within the NAC, significantly attenuated toluene's locomotor stimulatory effects. These results provide strong support for a central mechanism of action of inhalants, which in the past has been more typically attributed to general nonspecific mechanisms throughout the brain. Moreover, as with other drugs of abuse, the NAC may be the final common pathway subserving toluene's abuse liability.

“…For example, Bloom and Siggins (1987) described regionally distinct effects of ethanol on cell firing ranging from increased firing to depression when recording from inferior olive, hippocampal, cerebellar, and locus coeruleus neurons. In accord with this observation, Givens and Breese (1990a) showed that systemic administration of ethanol depressed neural activity in the medial septum, but not the lateral septum, whereas others described ethanol increases in firing rate of neurons in the ventral tegmental area (Brodie et al, 1990;Clark and Little, 2004). Mereu and Gessa (1985) found that low doses of systemically administered ethanol inhibited firing of neurons in the substantia nigra reticulataFan effect enhanced by muscimol and eliminated by bicuculline.…”

Section: Regional Specificity Of Ethanol On Functions Altered By Gabamentioning

confidence: 90%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.