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Identification
and validation of molecular targets for pharmacological treatment
of alcohol dependence
Objective: Proposal aim is to identify novel targets for pharmacological
treatment of alcoholism. In an integrative approach, complementary
expertise of 5 laboratories is applied. Pharmacologically validated
animal models are adapted for generation of tissue from key brain
regions. RNA is purified, and gene expression profiles established
using Affymetrix methodology. An expression database is constructed,
and mining the database identifies candidate genes differentially
expressed in the functional models. Candidates are prioritised on
the basis of available knowledge and availability of pharmacological
tools, and confirmed using real time PCR and in situ hybridisation.
Confirmed targets are fed back into the functional models, where pharmacological
and molecular manipulations of targets are evaluated for their ability
to block alcohol drinking and reinstatement. Validated targets are
patented and provide seeds for drug development.
Start Date: 2002-10-01
End Date: 2005-09-30 |
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Role
for the endogenous cannabinoid system in ethanol and nicotine addiction:
Implications for the treatment of drug abuse
Objective: This proposal is aimed to explore the role of the endogenous
cannabinoid system(ECS) on the development of ethanol and nicotine
tolerance, rewarding effects and physical dependence. The studies
will be done in normal mice and rats as well as in CB1 knockout mice
and Sardinian Alcohol Preferring rats. We will characterize the changes
induced by acute or chronic ethanol/nicotine administration on the
ECS, (Enzymes for synthesis and metabolism of end cannabinoids and
cannabinoidCB1 receptors and its transduction systems), as well as
the activity of drugs acting at the ECS in drug ethanol/nicotine self
administration and withdrawal. The final goal is to investigate the
utility of drugs targeting the ECS for the treatment of alcoholism
and tobacco addiction.
Start Date: 2002-01-01
End Date: 2005-01-01
Project Reference: QLG4-CT-2001-01691 |
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Differential
genetic makeup and MRNA expression profiles of Sardinian alcohol preferring
rat line by use of DNA microarrays genechip technology
Objective: Technology development is an essential part of modern genetic
research. With the existing techniques it is possible to test only
one single gene each time; as a consequence, a lot of time it is spent
by the scientists on the gene expression experiments. Using the Gene-Chip
technology we can test at the same time on single slide the expression
of all genes known in specific tissues or mutations in patient samples
quickly in parallel. It will be used "Gene Chip" on two
particular families of laboratory rats, the Sardinian alcohol -preferring
and the Sardinian alcohol-non-preferring.
They constitute a suitable animal model for searching for gene expression
patterns in the identification of effective molecules for alcoholism.
Neuroscience and AAT decided to carry out this project together because
a remarkable added value can come out from this partnership (combination
between knowledge and technology). This would prove to be the most
cost-effective way to reach the final goal of knowledge on the function
of all genes. The expected results will be exploit mainly by Neuroscience
with the pharmaceutics companies and by AAT with the biotechnology
enterprises.
Start Date: 2001-12-17
End Date: 2002-04-16
Project Reference: QLG1-CT-2001-42329 |
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The
Dopamine D3 Receptor in Drug Addiction and Withdrawal : Development
of a Novel Therapeutic Approach
Objective: To perform anatomical localisation studies in rat and human
brains to provide information about the systems involved in D3 dopamine
receptor (D3R)-drug interactions.
To assess the biological activity of D3R agents in behavioural animal
models measuring various aspects of drug addiction and dependence.
To design and synthesise new D3R agonists and antagonists with increased
selectivity, biological activity and oral bioavailability and to assess
their safety in toxicological studies in animals and in Phase I clinical
study.
To seek for genetic association of the D3R gene and alcoholism and
drug addiction.
General Information: It is well established that abused drugs (alcohol,
heroin and cocaine) share the property to affect dopamine systems
in selected brain areas. Pharmacological modulation of the activity
of dopaminoceptive neurons may be a novel therapeutic approach to
drug addiction. However, this approach could not be envisaged before
the recent discovery of the dopamine D3 receptor. Thus, neuroleptics,
the only dopamine receptor blocking compounds presently available
for clinical use, all are D2R-preferring agents, which have profound
motor and cognitive side-effects that preclude their use in the treatment
of drug addiction. In contrast, the D3R is expressed in restricted
brain areas that neurochemical studies have identified as anatomical
substrates for the actions of drugs of abuse, and the first partially
selective D3R antagonists, available at a preclinical stage, have
no cataleptogenic or akinetic properties in animals. In addition,
D3R agonists reduce cocaine self-administration in rats, whereas they
are not self-administered. This observation strikingly demonstrates
the implication of the D3R in mechanisms by which drugs produce pleasure
and reward and also suggests that D3R agents may constitute novel
therapeutical agents for treating drug-seeking behaviour and withdrawal
symptoms.
In this context, our general objectives are i) to understand the D3R
function in drug addiction by combining pharmacological, anatomical
and genetic approaches ii) to design, develop and assess the therapeutic
efficacy of novel D3R agents in drug intake and dependence. To this
aim, behavioural studies will be performed in animal models measuring
various aspects of drug addiction (sensitisation, reward, craving
and anhedonia), with partially selective D3R agonists and antagonists.
Localisation studies in rat and human post-mortem brain tissues will
provide information about the systems involved. Ligands for Positron
Emission Tomography studies will also be developed to measure D3R
level and occupation. New D3R agonists and antagonists with increased
selectivity, biological activity and oral bioavailability, will be
rationally designed using structure-activity relationship and molecular
modelling, synthesised, and screened in binding studies with recombinant
receptors already available, or to be cloned during this program.
Pharmaceutical development of selected molecules will be made by a
SME, which will be in charge of pilot synthesis, toxicological studies
and phase I clinical trials. A genetic association study will be performed
in alcoholics to assess the role of D3R gene in the susceptibility
to drug dependence, and possibly provide a marker for high-risk populations.
Start Date: 1996-07-01
End Date: 1998-12-31
Project Reference: BMH4960203 |
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Study
of the influence of alcohol consumption and alcoholism as an external
factor in occupational accidents and the design of an education and
prevention programme within the enterprise
Objective: Starting from the established fact that the workplace is
a suitable environment in which to counter the adverse effect of this
human factor on the safety of persons and plant, the project aims
to assess the effect of alcohol consumption on accidents at work by
analysing accident causes and the behaviour of the workers concerned
with a view to designing and implementing an in-house education and
prevention programme intended to reduce levels of alcohol-related
accidents and absenteeism and to improve safety standards.
General Information: The causes of occupational accidents will be
investigated with particular reference to accidents in connection
with jobs which involve a particular risk to the men directly engaged
in them or to others. To this end, a database will be set up to allow
the causes investigated to be related to the factors associated with
human behaviour at work: compliance with safety standards, accident-proneness,
absenteeism, productivity and accident rates, job attitudes and aptitude,
etc.
A programme, which is largely practical in content, will then be designed
for the education, the prevention and the treatment of alcoholism
aimed at all workers but including special measures for those who
have problems of alcohol abuse. Confidentiality in access to, and
processing of, the information will be ensured by using persons whose
professional code affords the necessary guarantees.
Achievements: In the present research work the dimensions and characteristics
of the alcohol problem in our enterprise have been studied.
We have analysed its consequences in accidentally, poliaccidentality
and absenteeism. There are some conclusions:
1) The percentage of injured workers is bigger when there is
an alcohol problem
2) The mean of worker's accidents shows the tendency to increase
as the alcohol problem increases its gravity
3) The poliaccidentally is significantly bigger in the group
of workers with alcohol dependence
4) The alcohol problem with its dimensions of excessive consumption,
abuse and alcohol dependence are variables that increase significantly
the absenteeism.
Finally, we offer the development of our Plan for Prevention and Treatment
of Alcoholism adaptable to other enterprises.
Start Date: 1990-01-01
End Date: 1993-12-31
Project Reference: 7262-01/242/14
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