Long-term development of excessive and inflexible nicotine taking by rats, effects of a novel treatment approach.

RATIONALE: Addiction is characterized by inflexible drug consumption: unpleasant consequences are accepted. Rat studies with several drugs proved that long-term voluntary intake induced abstinence-outlasting excessive and inflexible consumption. OBJECTIVE: Establishing a long-term model of oral self-administration of nicotine in rats with outlasting consequences for flexibility; testing a novel approach to restore flexibility by increasing neuroplasticity for memory reorganization via glucocorticoids. METHODS: 2 test groups of male Wistar rats were given continuous free choice between water and 8, 16, 32mg/l nicotine solutions for 48 weeks. Two other groups received water or 4mg/l nicotine as sole drinking fluid. After 10 weeks abstinence, all rats were given nicotine choice in a retest. Nicotine solutions were then adulterated with bitter-tasting quinine to test flexibility. In two treatment sessions (3 weeks, each), half of the rats received placebo, the other ones 250mg/l corticosterone, corticosterone plus 4mg/l nicotine and finally 4mg/l nicotine (1 week per phase). RESULTS: Voluntary intake groups developed a flexible, moderate consumption revealed by reversible influences of social conditions. Intake was individually stable but varied among subjects. In the retest, all rats from water and forced groups showed moderate, flexible intake whereas several rats from the choice groups were excessive, inflexible consumers. The treatment was effective in selectively reducing inflexible, excessive consumption. CONCLUSION: Long-term voluntary intake of nicotine, but not forced one, induces abstinence-enduring loss of flexibility in part of the rats. The tested treatment approach seems suitable to degrade an established addiction memory in rats.

An animal model of compulsive food-taking behaviour.

The increase in the incidence of obesity and eating disorders has promoted research aimed at understanding the aetiology of abnormal eating behaviours. Apart from metabolic factors, obesity is caused by overeating. Clinical reports have led to the suggestion that some individuals may develop addictive-like behaviours when consuming palatable foods, and compulsive eating plays a similar dominant role in obesity as compulsive drug taking does in drug addiction. The progress made in the development of treatment strategies for obesity is limited, in part, because the physiological and neurological causes and consequences of compulsive eating behaviour are not clearly understood and cannot readily be studied in human subjects. We have developed experimental approaches that reflect the functioning of the components of eating control, including compulsive food taking in rats. Rats that are given free choice between standard chow and a palatable, chocolate-containing 'Cafeteria Diet' (CD) develop distinct signs of compulsive food taking that appear at an early stage. These include the inability to adapt intake behaviour in periods of limited or bitter-tasting CD access, continued food intake during resting phases and changes in fine structure of feeding (duration, distribution and recurrence of feeding bouts). The model will help examine the neurobiological underpinnings of compulsive food seeking and food taking and provides a possibility to study the effects of novel anti-obesity compounds on compulsive eating and other components of food-taking behaviour in detail. For future use of genetic models, the possibility of a transfer to a mouse was discussed.

Loss of flexibility in alcohol-taking rats: promoting factors.

Alcohol consumption in humans can move from a flexible pattern of intake to an inflexible (addictive) one. Several endogenous and exogenous factors are discussed to be involved in this transition. The purpose of this study was to examine factors that might promote the development of inflexibility. Over a period of 52 weeks (long-term) rats had continuously free choice between differently concentrated alcohol solutions and tap water (four-bottle paradigm). After 4 months of alcohol deprivation, a retest with free choice of alcohol was performed. Bitter-taste conditions were used to test the flexibility of alcohol taking. In the retest alcohol-experienced rats revealed a much higher alcohol intake than previously alcohol-naive ones. Part of the alcohol-experienced animals showed impairment of flexibility in alcohol taking. During long-term choice, some groups were submitted to experimental interventions that might affect addiction development (stress, withdrawal, limited access, adverse consequences). Rats with limited access to alcohol at the end of the long-term choice period took more alcohol and were less flexible in the retest than any other group. It is suggested that an unsatisfied urge for alcohol leads to impairment of control over alcohol drinking.

Long-term voluntary consumption of MDMA and THC in rats is modified by individual and situational factors.

Factors influencing long-term voluntary intake of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) and Delta9-tetrahydrocannabinol (THC; cannabis) were studied in a rat model. Sixty-four male Wistar rats were given free choice for 49 weeks between (1) water and MDMA solution, (2) water and THC solution or (3) water, MDMA solution and THC solution. After the first experiences with the drugs, animals of both monodrug and polydrug group developed an individually stable pattern of MDMA consumption, whereas the individual predictability of THC consumption remained poor. While THC consumption was maintained for the whole experimental period, MDMA consumption decreased with time and was nearly ceased after 3-7 months. Intake of both drugs was adapted to social changes, with THC consumption being more sensitive to social changes than MDMA consumption. In the re-test after 4 months of abstinence, all animals ceased drug consumption when the drug solutions were adulterated with bitter tasting quinine. The results show that the rats had maintained a flexible mode of drug consumption and had not become addicted. Response to novelty of the rats in test trials before the start of drug supply correlated with later MDMA intake. In conclusion, although very low amounts of MDMA and/or THC were consumed, the findings that drug-experienced animals responded differentially to a stressor and that housing conditions influenced drug intake suggests that MDMA and THC can induce psychopharmacological effects in our long-term voluntary consumption paradigm.

Long-term voluntary D-amphetamine consumption and behavioral predictors for subsequent D-amphetamine addiction in rats.

Flexibility of drug taking is characteristic for "controlled" drug consumption whereas addiction is reflected by inflexibility and persistent high risk to relapse. Male Wistar rats (N = 12) that were given a continuous free choice between water and D-amphetamine solutions for 16 weeks, revealed a moderate and flexible pattern of D-amphetamine intake when tested again after 36 weeks of drug deprivation. A second group of rats had the same choice between water and D-amphetamine for 42 weeks. In the retest after abstinence, six out of 12 rats showed a moderate and flexible pattern of intake whereas the other animals revealed an excessively high and inflexible D-amphetamine consumption. They took high doses despite an adverse bitter taste of the drug solutions caused by addition of quinine. After 39 weeks of moderate D-amphetamine intake in the long-term period exactly the same animals had spontaneously and suddenly increased their D-amphetamine consumption. In a retrospective view, the later inflexible D-amphetamine consumers had already shown differences to their flexible conspecifics before their first drug access. During "tetradic" encounter tests the later "inflexible" animals were more interested in non-social stimuli than the later "flexible" ones. The results are discussed in respect to predisposition factors that might facilitate or inhibit the development of loss of control over drug intake.