• Energy Research

It is well established that combination of heavy drinking and smoking has severe health consequences. However, at relatively low concentrations, both alcohol and nicotine may have beneficial effects including neuroprotection. Thus, protective effects of low alcohol concentration against beta-amyloid-induced toxicity in organotypic hippocampal slices and protective effects of nicotine against salsolinol-induced toxicity in human-derived neuroblastoma cells (SH-SY5Y) have been reported. In this study, we sought to determine whether alcohol might also be protective against salsolinol-induced toxicity in SH-SY5Y cells and whether the combination of low doses of alcohol and nicotine might have an additive or synergistic effect. Pre-exposure of SH-SY5Y cells to either ethanol (1 or 10 mM) or nicotine (20 or 50 μM) significantly attenuated salsolinol-induced toxicity. However, contrary to the expectation the combination of low doses of alcohol and nicotine not only did not provide any synergistic or additive protective effect, but exacerbated salsolinol-induced toxicity. Indeed, simple combination of low alcohol and nicotine resulted in significant toxicity in SH-SY5Y cells. This toxicity, reflected in a reduction in cell viability was associated with an increase in apoptosis as determined by caspase-3 measurement. These in vitro results suggest that combination of even low concentrations of alcohol and nicotine may activate apoptotic mechanisms that can lead to cell toxicity and detrimental consequences.

Although strong positive association between alcoholism and depression is a common epidemiological observance, the causal relationship and the neurobiological substrates of such observations are far from clear. We have reported that chronic daily exposure to a relatively high dose of alcohol in rats can induce or exacerbate an already existing depressive-like behavior (Pharm Biochem Behav 91:97-103, 2008). Moreover, these effects of alcohol were blocked by pretreatment with desipramine, a tricyclic antidepressant, implicating a role for the biogenic amines in this type of depressive symptoms. In order to further delineate the involvement of specific neurotransmitters in alcohol-induced depressive symptoms, we examined the concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the frontal cortex and hippocampus following alcohol administration as well as pretreatment with two antidepressants, nomifensine and imipramine selective NE/DA and NE/5-HT uptake inhibitors, respectively. Adult female Wistar and Wistar-Kyoto (WKY) rats were exposed to alcohol via inhalation chambers (3h/day for 10 days) to achieve daily blood alcohol concentration of approximately 150 mg%. On day 11, the animals were evaluated for general locomotor activity (LCA) and performance in the forced swim test (FST), followed by neurochemical analyses. As expected WKY rats had lower LCA and higher immobility in the FST compared to Wistar rats. WKY rats also had lower levels of all three biogenic amines compared to Wistar rats in both areas. However, only cortical NE was reduced in both strains following alcohol administration. Treatments with nomifensine and imipramine blocked the behavioral and most of the neurochemical deficits caused by alcohol in both strains. These results implicate cortical NE as a major player in alcohol-induced depression. Moreover, it is suggested that selective NE uptake inhibitors may be of particular therapeutic potential in co-morbid condition of alcoholism and depression.

Adolescence drinking and subsequent development of alcohol use disorder (AUD) is a worldwide health concern. In particular, mood dysregulation or early alcohol exposure can be the cause of heavy drinking in some individuals or a consequence of heavy drinking in others.This study investigated the effects of voluntary alcohol intake during adolescence, i.e. continuous 10% alcohol access between postnatal days (PND) 29 to 43 and olfactory bulbectomy (OBX) model of depression (performed on PND 59) on alcohol drinking in Wistar rats during adulthood (PND 80-120, intermittent 20% alcohol access). In addition, the effect of NBQX, an AMPA/kainate receptor antagonist (5 mg/kg, IP) on spontaneous alcohol consumption was examined.Rats exposed to 10% alcohol during adolescence exhibited a lower 20% alcohol intake in the intermittent paradigm during adulthood, while the OBX-induced phenotype did not exert a significant effect on the drinking behaviour. NBQX exerted a transient reduction on alcohol intake in the OBX rats.Our results indicate that exposure to alcohol during adolescence can affect alcohol drinking in adulthood and that further exploration of AMPA and/or kainate receptor antagonists in co-morbid alcoholism-depression is warranted.

The dose-dependent effects of alcohol, where the initial euphoric and stimulant effects initiated by the exposure to low ethanol levels can quickly lead to a deadly consequence are well established. Thus, high blood alcohol concentration (BAC), as seen in alcoholics, can cause significant damage to various organs. At low concentrations (e.g., 10 mg% or lower), however, beneficial effects of alcohol, particularly on cardiovascular function have been reported. Although, the latter assertion has been challenged by recent epidemiological studies, protective effects of low alcohol concentrations in vitro and in vivo relevant to the central nervous system (CNS) is well documented. In this review, the mechanism(s) leading to the detrimental effects of high BAC, as well as the beneficial effects of low BAC will be discussed. In addition, gender consideration is touched upon. Although further investigation is clearly warranted, it may be concluded that at least some of the beneficial outcomes of low BAC, including possible neuroprotection and antidepressant-like effects, may be due to elevation of the neurotropic factors and reduction of inflammatory mediators, whereas detrimental outcomes associated with high BAC, including neurotoxicity and depressive-like behavior may be due to reduction in neurotropic factors and elevation of inflammatory mediators. Furthermore, new research strategies are suggested.

The high incidence of smoking among alcoholics may be partially due to nicotine's ability to counteract some of the adverse effects of ethanol on motor coordination and/or cognitive functions. Neuroprotective effects of nicotine on ethanol-induced toxicity in cerebellar granular cells have been observed. In this study, we sought to determine whether similar protection is observed in neocortical cells and if so, what specific nicotinic receptor subtypes may be mediating the actions of nicotine. Primary cultures of neocortical cells were prepared from 20-day embryos obtained from time-pregnant Sprague-Dawley rats. Cells were cultured for 10 days and were then exposed for 3 days to various concentrations of ethanol with and without pretreatment with nicotine and nicotinic antagonists. Cellular toxicity was evaluated by measuring the lactate dehydrogenase level. Administration of ethanol (10-100 mM) resulted in a dose-dependent toxicity. Pretreatment with nicotine 5-20 microM resulted in a dose-dependent protection against ethanol-induced toxicity. The effects of nicotine were blocked by pretreatment with nicotinic antagonists such as mecamylamine (1-20 microM), dihydro-beta-erythroidine (DHBE) 50 nM-1.0 microM and methyllycaconitine (MLA) 5 nM-1 microM in a dose-dependent manner. Compared to previous studies, higher ethanol concentrations were required to induce toxicity in neocortical vs cerebellar granule cells. Moreover, the effects of nicotine in the neocortical cells were blocked by lower concentrations of MLA, but higher concentrations of DHBE compared to cerebellar cells. Collectively, the results suggest differential sensitivity of various neuronal populations to the toxic effect of ethanol. Furthermore, protective effects of nicotine against alcohol in various regions appear to be mediated by different nicotinic receptor subtypes. The neuroprotective effect of nicotine against ethanol-induced toxicity may be a contributing factor to the high incidence of smoking among alcoholics.

Strong positive correlation between depression and alcoholism is evident in epidemiological reports. However, a causal relationship for this co-morbidity has not been established. We have observed that chronic daily exposure to a relatively high dose of alcohol can induce depressive-like behavior in rats and that pretreatment with nomifensine or imipramine can block the "depressogenic" effects of alcohol. Since brain derived neurotrophic factor (BDNF) is considered to play an important role in depressive-like behaviors and its elevation, particularly in the hippocampus, appears to be critical for the action of many antidepressants, we hypothesized that: 1. WKY rats, a putative animal model of depression, will show a lower hippocampal BDNF compared to their control Wistar rats, 2. Alcohol-induced depressive like behavior will be associated with a significant decrease in hippocampal BDNF and 3. Treatments with antidepressants will normalize hippocampal BDNF. These postulates were verified by measuring hippocampal BDNF in Wistar and WKY rats at baseline, following chronic (10 day) treatment with alcohol and combination of alcohol with nomifensine or imipramine. Alcohol was administered via inhalation chamber (3 h/day) such that a blood alcohol level of approximately 150 mg% was achieved. Nomifensine (10 mg/kg) or imipramine (10 mg/kg) was administered i.p. daily immediately after alcohol exposure. BDNF was measured by standard ELISA kit. The results support a role for central BDNF in depressogenic effects of alcohol and antidepressant effects of nomifensine and imipramine. Moreover, depression per se as manifested in WKY rats may be associated with a reduction in hippocampal BDNF.

Ethanol (EtOH) is one of the most frequently abused drugs with heavy health, economic, and societal burdens. Although moderate to low EtOH may have some neuroprotective effects, heavy EtOH consumption associated with high blood alcohol level (BAL) can be quite detrimental. The brain is particularly vulnerable to the damaging effects of high BAL, leading to neuronal loss, cognitive, and behavioral deficits. Although the exact causes of these detriments are not fully elucidated, it is believed that damage to the cholinergic system is at least partially responsible for the cognitive impairment. Thus, high BAL may result in selective apoptotic damage to the cholinergic neurons. Donepezil (DON), a centrally acting, reversible and non-competitive acetylcholinesterase (AChE) inhibitor, approved for use in Alzheimer's disease (AD), may also attenuate EtOH-induced cognitive impairment. Cognitive effects of DON might be due to an anti-apoptotic activity as some AChE inhibitors have been shown to have this property. The aim of this study was to determine whether DON might protect against EtOH-induced toxicity and whether such protection might be apoptotically mediated. We exposed the human neuroblastoma-derived, SH-SY5Y cells to a relatively high concentration of EtOH (500 mM) for 24 h and evaluated the effects of two concentrations of DON (0.1 and 1.0 μM) on alcohol-induced toxicity and caspase-3, an apoptotic marker. We found a dose-dependent protection of DON against EtOH-induced toxicity as well as dose-dependent attenuation of EtOH-induced increases in caspase-3 levels. Thus, DON may inhibit apoptosis as well as alcohol-induced toxicity.

Nicotine and alcohol are two of the most commonly abused legal substances. Heavy use of one drug can often lead to, or is predictive of, heavy use of the other drug in adolescents and adults. Heavy drinking and smoking alone are of significant health hazard. The combination of the two, however, can result in synergistic adverse effects particularly in incidences of various cancers (e.g., esophagus). Although detrimental consequences of smoking are well established, nicotine by itself might possess positive and even therapeutic potential. Similarly, alcohol at low or moderated doses may confer beneficial health effects. These opposing findings have generated considerable interest in how these drugs act. Here we will briefly review the negative impact of drinking-smoking co-morbidity followed by factors that appear to contribute to the high rate of co-use of alcohol and nicotine. Our main focus will be on what research is telling us about the central actions and interactions of these drugs, and what has been elucidated about the mechanisms of their positive and negative effects. We will conclude by making suggestions for future research in this area.