Symposium 16 Monday Sept. 24th 1.30 pm–3.00 pm; Room: Lecture Hall 4
Neuroadaptive alterations underlying vulnerability to ethanol consumption and efficacy to drug treatment: Chairpersons: Manzanares J (Spain), Rubio G (Spain)
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Abstract |
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Presentation S16-1
Long-term alterations of drugs vulnerability and brain gene expression after early life ethanol exposure
Barbier E, Warnault V, Houchi H, Pierrefiche O, Daoust M, Naassila M (France)
Aims. Exposure to alcohol early in life can have long-lasting implications on brain function and drugs of abuse response later in life. These long-lasting effects on the pups' subsequent drugs response may have important implications in drug abuse and vulnerability to the development of dependence. In the present study with both behavioral measures of sensitivity to drugs and analysis of brain expression of several candidate genes, we investigated the long-term behavioral consequences on drugs consumption/reward and the molecular targets affected after early life (pre- and postnatal or adolescence) ethanol exposure in rats.
Results. Our results show that progeny exposed to early life ethanol displayed increased consumption of both ethanol and morphine solutions and increased sensitivity to cocaine rewarding effects assessed in the conditioned place preference test. In addition, the sensitivity to hypothermic effects of ethanol and ethanol metabolism were not altered by early life ethanol exposure. In contrast, the sensitization to psychostimulants was facilitated after early life ethanol exposure. Gene expression analysis revealed that expression of a large number of genes was altered in brain regions involved in the reinforcing effects of drugs of abuse.
Conclusions. Such long-term alterations of expression of genes involved in synaptic transmission, plasticity, development and of behavioral responses to ethanol and other drugs of abuse may confer an increased liability for addiction in exposed offspring.
This work is supported by INSERM/Mildt, and IREB grant.
Presentation S16-2
Alcohol-induced cognitive impairments: possible involvement of brain pro-dynorphin system
Kuzmin A (Sweden)
Presentation S16-3
Neuroadaptative alterations underlying vulnerability to ethanol consumption. Role of drug treatments
Manzanares J (Spain)
Aims. Over the past few years, advances in the investigation of the neurochemical circuits involved in the development and treatment of alcohol dependence have identified peptides and receptors as potential key targets for the treatment of problems related with alcohol consumption. The endogenous opioid system is modified by alcohol intake in brain areas related to reward, and differential basal levels of opioid gene expression are found in rodents with a high preference for ethanol. This suggests greater vulnerability to alcohol consumption in relation to differences in genetic background. Further evidence of the involvement of opioid peptides in alcohol dependence is the ability of the opioid antagonist naltrexone to reduce alcohol intake in animal models of dependence and in alcohol-dependent patients.
Abundant evidence indicates that activation of cannabinoid receptors stimulates the release of opioid peptides, so presumably cannabinoid receptor antagonists may alter opioid peptide release, thus facilitating the reduction of ethanol consumption. However, little is known about the effects of ethanol on the endogenous cannabinoid system, the role of cannabinoid receptors in vulnerability for alcohol intake, or their neurochemical implications in reducing consumption.
In this talk the role of opioid and cannabinoid receptor systems in vulnerability to alcohol and the development of dependence and the targeting of these systems in the treatment of alcoholism are reviewed.
Presentation S16-4
The use of cocaine in heavy drinkers increases the vulnerability for alcohol dependence
Rubio G, Manzanares J, Jiménez M, Rodríguez-Jiménez R, Martínez I, Iribarren MM, Jiménez-Arriero MA, Ponce G, Palomo T (Spain)
Background. The development of alcohol dependence is associated with specific individual personality traits and previous consumption of other drugs of abuse. However, there is scarce information analyzing these risk factors in heavy drinkers before and after reaching the criteria of alcohol dependence. This study examined the influence of cocaine use and the role of impulsivity on the development of alcohol dependence in non-dependent drinkers in a 4-year follow-up period.
Methods. Four hundred and seventy one (non-dependent) heavy drinkers were enrolled in a prospective study. At baseline, 280 were classified as heavy drinkers (HD) and 191 as heavy drinkers and cocaine users (HD + Co). Clinical variables related to alcohol and cocaine were assessed at 2-years and at the end of the 4-year follow-up period.
Results. At 4-year follow-up assessment, 67.9% of the HD + Co group met criteria for alcohol dependence compared to 13.6% of the HD group. Odds ratios for alcohol dependence were 12.3 and 7.0 for male and female cocaine users, respectively. Clinical and psychological variables related to impulsivity and amount of cocaine used during follow-up were associated with the development of alcohol dependence. The amount of cocaine used during follow-up was associated with a more rapid progression to alcohol dependence.
Conclusions. This study revealed that the use of cocaine or an impulsive personality in heavy drinkers increased 5 to 12 times the risk of developing alcohol dependence. These results may be useful to design new strategies to prevent the development of alcohol dependence in certain type of patients.
Presentation S16-5
Gene effects on serotonin transporter expression, alcohol sensitivity and neurotoxicity
Heinz A (Germany)
In neuropsychiatric disorders, dysfunction of central serotonergic neurotransmission has been associated with negative affect in alcoholism and major depression. Animal experiments revealed that neurodevelopmentally early social isolation stress exposure is associated with altered serotonin turnover and transporters. In human studies, serotonin transporters and receptors interact with central processing of affective stimuli, and specific alterations in these interactions can be observed in alcoholism and affective disorders. Monoamine effects on central processing of emotionally salient stimuli are genetically influenced, and besides single gene effect, gene-gene interactions have been postulated. Additive gene-gene effects are often assumed but difficult to test in behavioral genetics due to the small explained behavioral variance. Processing of unpleasant stimuli in the amygdala has been associated with a functional polymorphism (val158-met) in the catechol-O-methyltransferase (COMT) gene and independently with a functional polymorphism in the regulatory region of the serotonin transporter (5-HTT) gene. 5-HTT function may also be affected by a recently detected A/G exchange in the long allele (insertion) of the 5-HTT regulatory region. In individuals with more COMT met158 alleles and with more s or lG alleles of the 5-HTT regulatory region, aversive stimuli elicited greater neuronal activity in the bilateral amygdalae and hippocampi. These genotype effects were additive on amygdala and hippocampus activation by aversive versus neutral stimuli, indicating that COMT val158 -met and 5-HTT genotype were additively associated with increased processing of aversive stimuli in the amygdalae. Such genotype effects in healthy volunteers may be augmented in alcohol dependence and major depression, where reductions in thalamic 5-HTT availability was recently observed in patients matched with healthy controls for genotype, gender and smoking effects.