0000000000040033
AUTHOR
Alejandro Orrico
Glutamate and opioid antagonists modulate dopamine levels evoked by innately attractive male chemosignals in the nucleus accumbens of female rats
Sexual chemosignals detected by vomeronasal and olfactory systems mediate intersexual attraction in rodents, and act as a natural reinforcer to them. The mesolimbic pathway processes natural rewards, and the nucleus accumbens receives olfactory information via glutamatergic projections from the amygdala. Thus, the aim of this study was to investigate the involvement of the mesolimbic pathway in the attraction toward sexual chemosignals. Our data show that female rats with no previous experience with males or their chemosignals display an innate preference for male-soiled bedding. Focal administration of the opioid antagonist b-funaltrexamine into the posterior ventral tegmental area does no…
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…
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 …
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…
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 …
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…