Neurochemical Effects Of Ethanol Research Articles

Behavioral sensitization to ethanol: Neural basis and factors that influence its acquisition and expression.

Ethanol-induced behavioral sensitization (EBS) was first described in 1980, approximately 10 years after the phenomenon was described for psychostimulants. Ethanol acts on γ-aminobutyric acid (GABA) and glutamate receptors as an allosteric agonist and antagonist, respectively, but it also affects many other molecular targets. The multiplicity of factors involved in the behavioral and neurochemical effects of ethanol and the ensuing complexity may explain much of the apparent disparate results, found across different labs, regarding ethanol-induced behavioral sensitization. Although the mesocorticolimbic dopamine system plays an important role in EBS, we provide evidence of the involvement of other neurotransmitter systems, mainly the glutamatergic, GABAergic, and opioidergic systems. This review also analyses the neural underpinnings (e.g., induction of cellular transcription factors such as cyclic adenosine monophosphate response element binding protein and growth factors, such as the brain-derived neurotrophic factor) and other factors that influence the phenomenon, including age, sex, dose, and protocols of drug administration. One of the reasons that make EBS an attractive phenomenon is the assumption, firmly based on empirical evidence, that EBS and addiction-related processes have common molecular and neural basis. Therefore, EBS has been used as a model of addiction processes. We discuss the association between different measures of ethanol-induced reward and EBS. Parallels between the pharmacological basis of EBS and acute motor effects of ethanol are also discussed.

Chronic treatment with a selective 5-HT6 receptor antagonist alters the behavioral and neurochemical effects of ethanol in young adult rats

Experimental evidence indicates a potential role of 5-HT6 receptors in the regulation of addictive behavior. We studied the effects of a potent and selective 5-HT6 receptor antagonist (compound A) on voluntary ethanol intake and behavioral/neurochemical changes induced by ethanol. The pharmacokinetic interaction of compound A and ethanol was assessed. The effect of compound A on schedule-induced ethanol polydipsia was studied to determine its effect on voluntary ethanol intake. Open-field and ethanol-induced loss of righting reflex assays were carried out to determine the effect of compound A on the ataxic and sedative effects of ethanol. The effect on motor learning was evaluated using rotarod and brain microdialysis was carried out to study the effect on monoaminergic neurotransmission. No significant changes were observed in the pharmacokinetic parameters of compound A when cotreated with ethanol. Compound A significantly decreased voluntary ethanol consumption and attenuated the effects of ethanol on motor learning. Compound A also antagonized the sedative and ataxic effects of ethanol. The effect of ethanol on the dopaminergic and noradrenergic neurotransmission was blocked by compound A. The effects of compound A were evident only after chronic treatment. Compound A may have attenuated the behavioral effects of ethanol by blocking the ethanol-induced efflux of dopamine and norepinephrine in the motor cortex.

Conessine, an H3 receptor antagonist, alters behavioral and neurochemical effects of ethanol in mice

Ethanol abuse potential is mainly due to its reinforcing properties, crucial in the transition from the recreational to pathological use. These properties are mediated by mesocorticolimbic and nigrostriatal dopaminergic pathways and neuroadaptations in these pathways seem to be responsible for addiction. Both pathways are modulated by other neurotransmitters systems, including neuronal histaminergic system. Among the histamine receptors, H3 receptor stands out due to its role in modulation of histamine and other neurotransmitters release. Thus, histaminergic system, through H3 receptors, may have an important role in ethanol addiction development. Aiming to understand these interactions, conessine, an H3 receptor antagonist, was given to mice subjected to the evaluation of ethanol-induced psychostimulation, ethanol CPP and quantification of norepinephrine, dopamine, serotonin and their metabolites in mesocorticolimbic and nigrostriatal pathways following acute ethanol treatment. Systemic conessine administration exacerbated ethanol effects on locomotor activity. Despite of conessine reinforcing effect on CPP, this drug did not alter acquisition of ethanol CPP. Ethanol treatment affects the serotoninergic neurotransmission in the ventral tegmental area, the dopaminergic neurotransmission in the pre-frontal cortex (PFC) and caudate-putamen nucleus (CPu) and the noradrenergic neurotransmission in the CPu. In the PFC, conessine blocked ethanol effects on dopaminergic and noradrenergic neurotransmission. The blockade of H3 receptors and ethanol seem to interact in the modulation of dopaminergic neurotransmission of nigrostriatal pathway, decreasing dopamine metabolites in substantia nigra. In conclusion, conessine was able to change psychostimulant effect of ethanol, without altering its reinforcing properties. This exacerbation of ethanol-induced psychostimulation would be related to alterations in dopaminergic neurotransmission in the nigrostriatal pathway.

Efficacy of d-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats

Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as D-penicillamine (DP), in relapse prevention has not been studied yet. The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment. Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5μg/h of DP directly into pVTA, and the appearance of ADE was evaluated. One milligram per hour, but not 0.25mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3-4μg/ml, and brain DP levels in these conditions were about 2-3% of those found in plasma. Intra-pVTA DP administration also suppressed ADE. DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients.

A single, moderate ethanol exposure alters extracellular dopamine levels and dopamine d receptor function in the nucleus accumbens of wistar rats.

The nucleus accumbens (NAc) has been implicated in the neurochemical effects of ethanol (EtOH). Evidence suggests that repeated EtOH exposures and chronic EtOH drinking increase dopamine (DA) neurotransmission in the NAc due, in part, to a reduction in D(2) autoreceptor function. The objectives of the current study were to evaluate the effects of a single EtOH pretreatment and repeated EtOH pretreatments on DA neurotransmission and D(2) autoreceptor function in the NAc of Wistar rats. Experiment 1 examined D(2) receptor function after a single intraperitoneal (i.p.) injection or repeated i.p. injections of 0.0, 0.5, 1.0, or 2.0 g/kg EtOH to female Wistar rats. Single EtOH pretreatment groups received 1 daily i.p. injection of 0.9% NaCl (saline) for 4 days, followed by 1 day of saline or EtOH administration; repeated EtOH pretreatment groups received 5 days of saline or EtOH injections. Reverse microdialysis experiments were conducted to determine the effects of local perfusion with the D(2)-like receptor antagonist (-)sulpiride (SUL; 100 uM), on extracellular DA levels in the NAc. Experiment 2 evaluated if pretreatment with a single, moderate (1.0 g/kg) dose of EtOH would alter levels and clearance of extracellular DA in the NAc, as measured by no-net-flux (NNF) microdialysis. Subjects were divided into the EtOH-naïve and the single EtOH pretreated groups from Experiment 1. Experiment 1: Changes in extracellular DA levels induced with SUL perfusion were altered by the EtOH dose (p < 0.001), but not the number of EtOH pretreatments (p > 0.05). Post-hoc analyses indicated that groups pretreated with single or repeated 1.0 g/kg EtOH showed significantly attenuated DA response to SUL, compared with all other groups (p < 0.001). Experiment 2: Multiple linear regression analyses yielded significantly (p < 0.05) higher extracellular DA concentrations in the NAc of rats receiving EtOH pretreatment, compared with their EtOH-naïve counterparts (3.96 +/- 0.42 nM and 3.25 +/- 0.23 nM, respectively). Extraction fractions were not significantly different between the 2 groups. The present results indicate that a single EtOH pretreatment at a moderate dose can increase DA neurotransmission in the NAc due, in part, to reduced D(2) autoreceptor function.

Lobeline attenuates behavioral and neurochemical effects of ethanol in a preclinical model of alcoholism

Lobeline is a plant alkaloid obtained from Lobelia inflata and a brain nicotinic acetylcholine receptor (nAChR) ligand that has been implicated in the behavioral and neurochemical effects of nicotine and amphetamine. Here, we examined the effects of acute lobeline injection on voluntary ethanol (10% v/v) consumption using 24h access two‐bottle free choice (water vs ethanol) drinking paradigm in C57BL/6J mice. Lobeline 4 mg/kg and 10 mg/kg significantly decreased (53%‐59%) and (58%‐68%) ethanol drinking, respectively without altering water consumption at 1 h‐12 h post injections. Using HPLC coupled with electrochemical detection, we determined the effects of lobeline (10 mg/kg) on acute ethanol (2.5 g/kg)‐induced increase in dopamine and dihydroxyphenylacetic acid (DOPAC) content in ventral striatum (VS) and medial prefrontal cortex (mPFC), known brain reward relevant regions for ethanol drinking. Lobeline (10 mg/kg) significantly reduced ethanol‐induced increase in dopamine (146% and 110% of control) and DOPAC (116% and 101% of control) in VS and mPFC, respectively. Overall, these data indicate that lobeline modulates the behavioral and neurochemical effects of ethanol by targeting nAChRs in brain reward relevant regions. Therefore, the preclinical profile suggests that lobeline can be developed as potential pharmacotherapy for alcoholism in humans. (AACP NIP RG (SR), SD 2010 RISG (SR).

Estrogen‐Dependent Enhancement of NO Production in the Nucleus Tractus Solitarius Contributes to Ethanol‐Induced Hypotension in Conscious Female Rats

Our previous pharmacological and cellular studies showed that peripheral (cardiac and vascular) nitric oxide synthase (NOS)-derived NO is implicated in the estrogen (E(2))-dependent hypotensive action of ethanol in female rats. The objective of this study was to test the hypothesis that enhanced NO production in the nucleus tractus solitarius (NTS) is implicated in the E(2)-dependent hypotensive action of ethanol. To achieve this goal, we utilized in vivo electrochemistry to measure real time changes in neuronal NO to investigate the acute effects of intragastric ethanol (0, 0.5, or 1 g/kg) on NO in NTS neurons, blood pressure (BP), and heart rate (HR) in conscious female rats in the absence (ovariectomized, OVX, rats) or presence of E(2). In sham operated (SO) rats, ethanol elicited dose-related increase in NTS NO and reduction in BP. These neurochemical and BP effects of ethanol were absent in OVX rats. Whether the neurochemical effect of ethanol and the associated hypotension are dependent on rapid E(2) signaling was investigated. In OVX rats pretreated, 30 minutes earlier, with E(2) (1 microg/kg), intragastric ethanol (1 g/kg) increased NTS NO and reduced BP and these responses were comparable to those obtained in SO rats. The present findings suggest that increased production of NO in NTS neurons contributes to ethanol-evoked hypotension in female rats. Further, ethanol enhancement of neuronal NO production in the brainstem is dependent on rapid E(2) signaling.

Role of different nicotinic acetylcholine receptors in mediating behavioral and neurochemical effects of ethanol in mice

Ethanol and nicotine are the most abused drugs, and it is well known that co-abuse of ethanol and nicotine is frequent in human beings. We have previously obtained results indicating that the ethanol-induced stimulation of both the mesolimbic dopamine system and locomotor activity may involve activation of central nicotinic acetylcholine receptors (nAChRs), especially those located in the ventral tegmental area. Different subpopulations of nAChRs have been identified, and, in the present series of experiments, we have studied the effects of various nAChR antagonists on the stimulation of dopamine overflow in the nucleus accumbens and on locomotor activity induced by ethanol in male mice. Ethanol (2.0 g/kg, i.p.) enhanced dopamine overflow in the nucleus accumbens by approximately 40%, measured by means of in vivo microdialysis in awake, freely moving mice. Mecamylamine (negative allosteric modulator of nAChR; 2.0 mg/kg, i.p.) blocked the ethanol-induced stimulation of both locomotor activity and accumbal dopamine overflow. Methyllycaconitine citrate (α 7 antagonist; 2.0 mg/kg, i.p.) and dihydro-β-erythroidine (competitive and selective α 4β 2 antagonist; 0.5 mg/kg, s.c.), in doses that had no marked effects per se, did not significantly reduce the behavioral and neurochemical stimulation caused by ethanol. The present results support the suggestion that the stimulatory effects of ethanol on locomotor activity and dopamine release do not involve the α 4β 2 or α 7 subunit compositions of the nAChR and that the effects of mecamylamine are mediated through a site not directly associated with the α 4β 2 or α 7 nAChR subunits.

Nefazodone attenuates the behavioral and neurochemical effects of ethanol

This study evaluated the influence of nefazodone, a combined 5-HT 2A receptor antagonist and 5-HT reuptake inhibitor, on the behavioral and neurochemical effects of ethanol in nonselected male Wistar rats. In microdialysis experiments, ethanol (2.5 g/kg, IP) increased extracellular accumbal dopamine levels by 36% ( p = 0.0073) compared to baseline levels, and elevated the maximal DOPAC and HVA levels by 26% ( p = 0.0093) and 52% ( p = 0.0010), respectively. Nefazodone (50 mg/kg, SC) per se increased accumbal dopamine levels by 28% ( p = 0.0199), but, when injected 40 min before ethanol, reduced the ethanol-induced elevation of accumbal dopamine overflow ( p = 0.0132) and decreased the ethanol-induced HVA levels ( p = 0.0159). In an ethanol(6% v/v)/water free-choice paradigm, nefazodone (50 mg/kg, SC) decreased ethanol intake by 51% ( p = 0.0251) and preference by 22% ( p = 0.0251) in high- but not low-preferring rats from a nonselected Wistar strain. These results show that nefazodone modulates the mesolimbic dopamine system in a dopamine activity-dependent manner, and influences the neurochemical and behavioral effects of ethanol in the rat.

Effects of ethanol on striatal dopamine overflow and clearance: An in vivo electrochemical study

Previous studies have shown that the neurotransmitter dopamine (DA) is implicated in the reinforcing effects of ethanol and other abused drugs. Ethanol also alters DA overflow and uptake in vivo. Further studies of the role of DA in the behavioral and neurochemical effects of ethanol may help explain the pharmacological mechanisms by which these effects are produced. In these studies we used in vivo electrochemical recordings to investigate the effects of ethanol (EtOH) on the dynamics of evoked DA overflow and DA uptake in rat dorsal striatum. Local applications of EtOH from a multibarrel micropipette did not produce detectable changes in extracellular levels of endogenous DA in the dorsal striatum. EtOH application did attenuate potassium (K +)-evoked overflow of DA in a time-dependent fashion. In contrast, tyramine-induced DA overflow, a calcium-independent process thought to be carrier mediated, was not altered by local EtOH application in the dorsal striatum. Striatal uptake of locally applied exogenous DA was decreased by nomifensine, an effect that was attenuated by locally applied EtOH. Taken together, these data suggest that one of the effects of EtOH on DA-containing nerve endings in the rat striatum involves functional changes in the high-affinity DA transporter associated with these nerve endings.

Neurochemical correlates of tolerance and strain differences in the neurochemical effects of ethanol

The behavioral and neurochemical effects of acute and chronic ethanol administration were studied in BALB/c, C57B1/6 and DBA/2 mice. The rates of dopamine synthesis and release in the striatum were estimated by measuring the accumulation of DOPA and DOPAC, respectively, after inhibition of aromatic amino acid decarboxylase with NSD-1024. Biphasic behavioral effects were found in BALB/c and DBA/2 mice, but not in C57B1/6 mice, with low doses of ethanol producing activation and high doses, depression. Biphasic effects were also found in the dopamine response to acute doses of ethanol. The BALB/c and DBA/2 mice showed larger suppressions of DA release in the lower dose ranges of ethanol, and smaller increases at the higher doses than did the C57B1/6 mice. Ethanol stimulated dopamine synthesis in a monophasic, dose-dependent manner, and C57B1/6 mice were less sensitive to this effect of ethanol compared to the other tested strains of mice. Chronic ethanol feeding produced behavioral tolerance to the high-dose depressant effects of ethanol, but not to the low-dose activating effects. Similarly, tolerance developed in the dopaminergic responses to a higher challenge dose of ethanol (3.5 g/kg). These findings demonstrate that genetically determined differences exist in the sensitivity of the dopaminergic systems of mice to ethanol, and suggest that central dopamine neurons may be important in the behavioral effects of ethanol.

Ethanol metabolism and striatal dopamine turnover.

In recent reports it has been indicated that acute and chronic ethanol treatments affect the central dopaminergic system. In particular, after acute ethanol administration it has been detected an increase of dopamine (DA) turnover measured as dihydroxyphenylacetic acid (DOPAC) content in rat corpus striatum. In order to verify the correlation between these neuronal events and the metabolism of ethanol, we measured striatal DA activity after different experimental manipulations of liver function. Ethanol metabolic rate has been stimulated by administering phenobarbital sodium, while liver ethanol metabolism was decreased with a subtotal hepatectomy. In these conditions we found a shift to the left of the time curve for DOPAC levels and a significant reduction of the peak of DOPAC increase respectively. In this paper we report that acetaldehyde induces modifications of the striatal DOPAC content, which become significant after a shorter latency period in comparison with the acute ethanol injection. Our data suggest the hypothesis that the neurochemical effects of ethanol may be mediated by the formation of specific metabolic products.