Inhibition of Morphine- and Ethanol-Mediated Stimulation of Mesolimbic Dopamine Neurons by Withania somnifera

Abstract

Morphine- and ethanol-induced stimulation of neuronal firing of ventral tegmental area (VTA) dopaminergic neurons and of dopamine (DA) transmission in the shell of the nucleus accumbens (AcbSh) represents a crucial electrophysiological and neurochemical response underlying the ability of these compounds to elicit motivated behaviors and trigger a cascade of plasticity-related biochemical events. Previous studies indicate that the standardized methanolic extract of Withania somnifera roots (WSE) prevents morphine- and ethanol-elicited conditioned place preference and oral ethanol self-administration. Aim of the present research was to investigate whether WSE may also interfere with the ability of morphine and ethanol to stimulate VTA dopaminergic neurons and thus AcbSh DA transmission as assessed in male Sprague-Dawley rats by means of patch-clamp recordings in mesencephalic slices and in vivo brain microdialysis, respectively. Morphine and ethanol significantly stimulated spontaneous firing rate of VTA neurons and DA transmission in the AcbSh. WSE, at concentrations (200–400 μg/ml) that significantly reduce spontaneous neuronal firing of VTA DA neurons via a GABA A - but not GABA B -mediated mechanism, suppressed the stimulatory actions of both morphine and ethanol. Moreover, in vivo administration of WSE at a dose (75 mg/kg) that fails to affect basal DA transmission, significantly prevented both morphine- and ethanol-elicited increases of DA in the AcbSh. Overall, these results highlight the ability of WSE to interfere with morphine- and ethanol-mediated central effects and suggest a mechanistic interpretation of the efficacy of this extract to prevent the motivational properties of these compounds.

Impact of Caffeine on Ethanol‐Induced Stimulation and Sensitization: Changes in ERK and DARPP‐32 Phosphorylation in Nucleus Accumbens

“…EtOH acutely and repeatedly has been shown to increase DA release in Acb in mice (Pavón et al, 2019) and in rats (Bassareo et al, 2019; Vena et al, 2016). However, the effects of caffeine on DA release in Acb are not very conclusive.…”

Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine

“…Under deep anesthesia by equitesin (0.97 g pentobarbital, 4.25 g chloral hydrate, 2.1 g MgSO 4 , 42.8 ml propylene glycol, 11.5 ml 90% ethanol/100 ml; 5 ml/kg i.p.) ( Bassareo et al, 2019 ), vertical microdialysis probes were stereotaxically implanted in the pVTA and in the AcbSh using the following coordinates according to Paxinos and Watson (1998) : AP: –5.8 mm and ML: ± 0.5 mm from bregma and DV: –8.0 mm from dura, for the pVTA; AP: 1.8 mm and ML: ± 1 mm from bregma and DV: –7.6 mm from dura, for the AcbSh. After surgery, rats were housed in individual hemispheric cages under the same standard conditions, left undisturbed for at least 24 h, and fed with 20 g of standard chow (their weight being maintained at ∼95% of their ad libitum weight).…”

“…Vertical dialysis probes (dialyzing portion: 1.5 mm; outer diameter: 300 μm) were prepared with AN69 fibers ( Bassareo et al, 2019 ) (Hospal-Dasco, Bologna, Italy) for both the pVTA and the AcbSh. In the case of pVTA, however, we acknowledge that such length of the dialyzing portion may have extended dorsally outside the anatomical border of the targeted area.…”

“…Monoamines are involved in ethanol’s reinforcing and euphoriant effects ( Ahlenius et al, 1973 ), and ethanol activates the ventral tegmental area (VTA) mesolimbic DA neurons ( Gessa et al, 1985 ). Ensuing research demonstrated that ethanol’s reinforcing properties are mediated by actions on the mesolimbic DA system ( Di Chiara et al, 2004 ; Howard et al, 2008 ; Bassareo et al, 2017 , 2019 ; Volkow et al, 2017 ; Wise and Robble, 2020 ), but the underlying mechanism and molecular target have remained not fully understood. However, as extensively discussed in a recent review ( Sanchez-Catalan et al, 2014 ), a pivotal role is recognized to DA neurons in the posterior, but not anterior, ventral tegmental area (pVTA) ( Rodd et al, 2004 ; Hauser et al, 2011 ; Ding et al, 2012 ) and their projections ( Ungerstedt, 1971 ) to the nucleus accumbens shell (AcbSh) ( Di Chiara et al, 2004 ).…”

Behavioral and neurochemical assessment of the role of ERK pathway in the psychopharmacological effects of ethanol, caffeine and of their interaction

“…Thus, it is possible that ethanol activates pERK expression in both subregions of Acb, and in the amygdala, through a mechanism mediated by D1 receptors . Otherwise ethanol increases alongside dopaminergic transmission in the AcbC and in the AcbSh, either after contingent (Bassareo et al 2017) and non-contingent administration (Bassareo et al 2003(Bassareo et al , 2019. Thus, a functional antagonism between caffeine and ethanol that is related to actions on adenosine receptors might be at least partially responsible for the behavioral interactions between these two substances seen in the present studies.…”