1 Biochemistry
1.1 Craving for alcohol and psycho-stimulants: Role of individual variations in the make-up of the brain
University of Nijmegen Department of Psychoneurofarmacology
Drs. M.A. Gingras & prof.dr. A.R. Cools.
Startdate: January 1993. Duration: 4 years.
Description / Goal:
This project analyses to what extent differences in the make-up of the brain of two pharmacogenetically selected rat lines produces differences in response to the administration of ethanol and amphetamine.
Research questions:
- What is the relationship between susceptibility to stress and intake of ethanol?
- What is the relationship between susceptibility to reinforcing effects of central dopamine and ethanol preference?
- What is the relationship between susceptibility to aversive effects of peripheral and/or central noradrenaline and ethanol preference?
- What is the relationship between susceptibility to self-administration of amphetamine, circulating glucocorticoids and ethanol intake?
- What is the relationship between ethanol preference and learning strategies?
Results:
APO-SUS line (greatest susceptibility to stress, dopamine, etc.) is more susceptible to excessive effects of ethanol intake and preference than the APO-UNSUS line (mirror image of APO-SUS). APO-SUS line shows enhanced locomotor response followed by a reduced locomotor response to ethanol, whereas the APO-UNSUS line only shows sedation.
APO-SUS rats are far more susceptible to amphetamine than APO-UNSUS rats.
1.2 Animal research on drug addiction
Rudolf Magnus Institute for Neurosciences
Prof.dr. J.M. van Ree & dr. M.A.F.M. Gerrits.
Startdate: 1971. Duration:
Description / Goal:
To establish the external and internal factors involved in the initiation, maintenance and relapse in drug addiction, using the validated animal model of self-administration.
Research questions:
- What pathways in the brain (endorphins, dopamine) are implicated in experimental drug addiction?
- What external (e.g. stress) and internal (e.g. altered brain activity) factors contribute tot the initiation of self-administration?
- Which factors experienced in the past (e.g. in utero) facilitate the initiation of drug addiction?
- Can the initiation of self-administration be diminished by intervention therapies (chemicals, environmental changes)?
Results:
The results of the last year have revealed the importance of the endogenous opioid system for experimental drug addiction. These systems are not only implicated in the self-administration of heroin, but also in that of cocaine and in alcohol drinking. These data support the hypothesis that endogenous opioid systems in the brain are important for drug addiction in general, which may have consequences for treatment of addiction.
1.3 Long-lasting neuroadaptive changes in reward-related brain regions underlying drug-seeking behaviour and relapse
Department of Farmacology Free University Amsterdam
Dr. A.N.M. Schoffelmeer, dr. T.J. De Vries, dr., L.J.M.J. Vanderschuren, & dr. A.B. Smit.
Startdate: January 1994. Duration: At least 5 years.
Description / Goal:
To identify the long-lasting (weeks/months) effects of opiate, psychostimulant and alcohol (self)administration on neurotransmission processes in mesocorticolimbic rat brain regions and the role of these neuroadaptations in the acquisition and maintenance of addiction behaviour. This preclinical research may open new vistas for intervention strategies to readjust neuronal functioning in the brain of addicts.
Research questions:
- Which neuronal genes display spatio-temporal changes in expression levels long (until 1 month) after intravenous heroine/amphetamine or cocaine self-administration and following voluntary alcohol drinking?
- What is the nature of drug- and alcohol-induced neuroadaptive changes in rat brain?
- Which pharmacological and molecular biological intervention strategies adequately prevent the acquisition of drug and alcohol self-administration in rats?
- Which interventions attenuate craving and relapse to self-administration behaviour in detoxified rats?
Results:
Prior exposure to psychostimulants, opiates and alcohol was shown to cause an increase in the responsiveness of dopaminergic and cholinergic neurons to depolarization in the nucleus accumbens and caudate/putamen of rat striatum until at least 1 month after drug administration. Dopamine D1 receptor induced cyclic AMP formation and cyclic AMP-dependent preprodynorphin gene expression in dopamine-sensitive gamma-aminobutyric acid (GABA) neurons as well as the responsiveness of these neurons to the stress hormone corticosterone was also enhanced long after drug administration. These enduring neuroadaptive changes were associated with behavioural sensitization, i.e. enhanced acquisition of self-administration behaviour and drug-induced psychomotor effects.
The recent behavioural studies on craving and relapse showed that a single forced injection of cocaine, amphetamine or heroine causes reinstatement of drug-seeking behaviour 1 month after extinction of intravenous drug self-administration. Moreover, 1-2 weeks of withdrawal from ethanol exposure (free choice between water and 10% ethanol, leading to consumption of about 1 g/kg ethanol/day) appeared to cause an about 3-fold increase in alcohol drinking behaviour, indicating the occurrence of an enhanced motivation to drink alcohol.