0000000000188443
AUTHOR
Lucía Martí-prats
Opposite motor responses elicited by ethanol in the posterior VTA: The role of acetaldehyde and the non-metabolized fraction of ethanol
Recent electrophysiological evidence suggests that ethanol simultaneously exerts opposite effects on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) through two parallel mechanisms, one promoting and the other reducing the GABA release onto VTA DA neurons. Here we explore the possible behavioural implications of these findings by investigating the role displayed by acetaldehyde (the main metabolite of ethanol) and the non-metabolized fraction of ethanol in motor activity of rats. We analyse the appearance of motor activation or depression after intra-VTA administration of ethanol in rats subjected to different pharmacological pre-treatments designed to preferential…
Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences
Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethano…
Disposition ofd-penicillamine, a promising drug for preventing alcohol-relapse. Influence of dose, chronic alcohol consumption and age: studies in rats
Pharmacokinetic studies concerning d-penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose d-penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on d-penicillamine disposition in order to guide future clinical studies on the anti-relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on d-penicillamine disposition, w…
Revisiting the controversial role of salsolinol in the neurobiological effects of ethanol: old and new vistas.
The possible involvement of salsolinol (Sal), an endogenous condensation product of ACD (the first metabolite of ethanol) and dopamine, in the neurochemical basis underlying ethanol action has been repeatedly suggested although it has not been unequivocally established, still being a controversial matter of debate. The main goal of this review is to evaluate the presumed contribution of Sal to ethanol effects summarizing the reported data since the discovery in the 1970s of Sal formation in vitro during ethanol metabolism until the more recent studies characterizing its behavioral and neurochemical effects. Towards this end, we first analyze the production and detection of Sal, in different…
Systemic administration of D-penicillamine prevents the locomotor activation after intra-VTA ethanol administration in rats.
Although recently published studies seem to confirm the important role displayed by acetaldehyde (ACH), the main metabolite of ethanol, in the behavioral effects of ethanol, the origin of ACH is still a matter of debate. While some authors confer more importance to the central (brain metabolism) origin of ACH, others indicate that the hepatic origin could be more relevant. In this study we have addressed this topic using an experimental approach that combines local microinjections of ethanol into the ventral tegmental area (VTA) (which guarantees the brain origin of the ACH) to induce motor activation in rats together with systemic administration (i.p.) of several doses (0, 12.5, 25 and 50 …
P-56LOCAL BLOCKADE OF THE MU OPIOID RECEPTOR REVEALS THE DUAL MOTOR EFFECT OF ETHANOL IN pVTA
Previous electrophysiological and behavioral data have revealed the existence of ethanol opposite effects (excitatory and inhibitory) on the posterior ventral tegmental area (pVTA) dopamine (DA) neurons activity. These activating and depressing effects of ethanol could be the result of two concurrent and opposing mechanisms, one increasing and the other reducing GABA release …
A subset of ventral tegmental area dopamine neurons responds to acute ethanol
The mechanisms by which alcohol drinking promotes addiction in humans and self-administration in rodents remain obscure, but it is well known that alcohol can enhance dopamine (DA) neurotransmission from neurons of the ventral tegmental area (VTA) and increase DA levels within the nucleus accumbens and prefrontal cortex. We recorded from identified DA neuronal cell bodies within ventral midbrain slices prepared from a transgenic mouse line (TH-GFP) using long-term stable extracellular recordings in a variety of locations and carefully mapped the responses to applied ethanol (EtOH). We identified a subset of DA neurons in the medial VTA located within the rostral linear and interfascicular n…
Improved effect of the combination naltrexone/D-penicillamine in the prevention of alcohol relapse-like drinking in rats
Opioid antagonists are licensed drugs for treating alcohol use disorders; nonetheless, clinical studies have evidenced their limited effectiveness. Preclinical findings indicate that opioid receptor (OR) antagonists, such as naltrexone (NTX), reduce the alcohol deprivation effect (ADE). However, a detailed analysis of published data shows the existence of a delayed increase in ethanol consumption after continuous OR blockade, a phenomenon originally called as ‘delayed ADE’. We have recently reported that D-penicillamine (DP) is able to prevent ADE through a mechanism dependent on the inactivation of acetaldehyde, the main metabolite of ethanol. Hypothetically, OR activation would be trigge…
Dose-dependent induction of CPP or CPA by intra-pVTA ethanol: Role of mu opioid receptors and effects on NMDA receptors.
AbstractThe neurobiological mechanisms underlying alcohol motivational properties are still not fully understood, however, the mu-opioid receptors (MORs) have been evidenced as central elements in the manifestation of the alcohol reinforcing properties. Drug-associated environmental stimuli can trigger alcohol relapse and promote alcohol consumption whereby N-methyl-D-aspartate (NMDA) receptors play a pivotal role. Here we sought to demonstrate, for the first time, that ethanol induces conditioned place preference or aversion (CPP or CPA) when administered locally into the ventral tegmental area (VTA) and the associated role of MORs. We further analyzed the changes in the expression and mRN…
P-78D-PENICILLAMINE PREVENTS THE ALCOHOL DEPRIVATION EFFECT IN THE OPERANT SELF-AMINISTRATION PARADIGM
Although pharmacological treatments for relapse prevention have experienced some progress, their general effectiveness can be considered low and the problem could not be considered solved. In recent years, our group has explored the use of acetaldehyde (ACD) sequestering agents as a new and very promising strategy. These agents, such as …
SY26-4REVIEWING THE NEUROBIOLOGICAL EFFECTS OF SALSOLINOL: ROLE OF THE MU OPIOID RECEPTORS
During the last decades Salsolinol (SAL), a condensation product from dopamine (DA) and acetaldehyde that appears in the brain of humans and rodents as a consequence of brain metabolism of ethanol, has been proposed as a key component in the development of alcohol use disorders. Although evidence has been published …
P-76D-PENICILLAMINE, AN ACETALDEHYDE SEQUESTERING AGENT, REDUCES ETHANOL PREFERENCE IN ALCOHOL-NAÏVE RATS
In previous investigations, we demonstrated that D-penicillamine (DP), a sulfhydryl aminoacid which has been studied as sequestration agent of acetaldehyde (ACD), is able to prevent the alcohol deprivation effect (ADE) but not voluntary ethanol consumption. Both results were obtained in long-term ethanol-experienced Wistar rats. Based on a previous …
P-77D-PENICILLAMINE, A POTENTIAL ETHANOL ANTI-RELAPSE DRUG, DOES NOT REDUCE THE VOLUNTARY ETHANOL INTAKE IN LONG-TERM EXPERIENCED RATS
Experimental evidence has demonstrated that the reinforcing effects of ethanol crucially depend on the brain formation of acetaldehyde (ACD). Rationally supported by this basis, we previously evaluated a novel strategy to prevent relapse in alcoholism based on chemical ACD inactivation using D-Penicillamine (DP). Under our experimental …
Induction of conditioned place preference and dopamine release by salsolinol in posterior VTA of rats: involvement of μ-opioid receptors.
Salsolinol (Sal), locally administered into the posterior VTA (pVTA) of rats, produces psychomotor responses and reinforcing effects, probably, through the activation of μ-opioid receptors (MORs). The neurochemical correlates of these phenomena are, however, practically unknown. In this paper, we explore the neurochemical events and the mechanisms involved in these behaviors. To do that, we test the ability of Sal, directly microinjected into the pVTA, to induce conditioned place preference (CPP) and to increase dopamine levels in the nucleus accumbens shell. Bilateral injections of 30 pmol of Sal induced a strong CPP (rats spent around 70% of the total test time), a result that could be ex…
Regional differences in mu-opioid receptor-dependent modulation of basal dopamine transmission in rat striatum
Abstract The nigrostriatal dopamine system is implicated in the regulation of reward and motor activity. Dopamine (DA) release in dorsal striatum (DS) is controlled by the firing rate of DA neurons in substantia nigra pars compacta. However, influences at terminal level, such as those involving activation of mu opioid receptors (MORs), can play a key role in determining DA levels in striatum. Nonetheless, published data also suggest that the effect of opioid drugs on DA levels may differ depending on the DS subregion analyzed. In this study, in vivo microdialysis in rats was used to explore this regional dependence. Changes in basal DA levels induced by local retrodialysis application of DA…
SY09EXPLORING CURRENT AND PROMISING PHARMACOTHERAPIES IN THE TREATMENT OF ALCOHOLISM: CLINICAL AND PRECLINICAL EVIDENCESY09-1COMBINED THERAPIES DO MATTER: OPTIMIZING NALTREXONE ANTI-RELAPSE EFFECT
Naltrexone (NTX), a non-selective opioid receptor, is a licensed drug for treating alcohol use disorders almost from 20 years ago. During this time, more than 50 clinical trials have been conducted to evaluate its effects in patients suffering for alcoholism. Although these studies have confirmed its effectiveness, …
Dual motor responses elicited by ethanol in the posterior VTA: Consequences of the blockade of μ-opioid receptors
A recent hypothesis, based on electrophysiological and behavioural findings, suggests that ethanol simultaneously exerts opposed effects on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) through two parallel mechanisms, one promoting and the other reducing the GABA release onto VTA DA neurons. In this sense, the activating effects are mediated by salsolinol, a metabolite of ethanol, acting on the μ-opioid receptors (MORs) located in VTA GABA neurons. The inhibitory effects are, however, triggered by the non-metabolized fraction of ethanol which would cause the GABAA receptors-mediated inhibition of VTA DA neurons. Since both trends tend to offset each other, only…