Opioid-environment interaction: Contrasting effects of morphine administered in a novel versus familiar environment on acute and repeated morphine induced behavioral effects and on acute morphine ERK activation in reward associated brain areas.

We report that environmental context can have a major impact on morphine locomotor behavior and ERK effects. We manipulated environmental context in terms of an environmental novelty/ familiarity dimension and measured morphine behavioral effects in both acute and chronic morphine treatment protocols. Wistar rats (n=7 per group) were injected with morphine 10 mg/kg or vehicle (s.c.), and immediately placed into an arena for 5 min, and locomotor activity was measured after one or 5 days. The morphine treatments were initiated either when the environment was novel or began after the rats had been familiarized with the arena by being given 5 daily nondrug tests in the arena. The results showed that acute and chronic morphine effects were strongly modified by whether the environment was novel or familiar. Acute morphine administered in a novel environment increased ERK activity more substantially in several brain areas, particularly in reward-associated areas such as the VTA in comparison to when morphine was given in a familiar environment. Repeated morphine treatments initiated in a novel environment induced a strong locomotor sensitization, whereas repeated morphine treatments initiated in a familiar environment did not induce a locomotor stimulant effect but rather a drug discriminative stimulus dis-habituation effect. The marked differential effects of environmental novelty/familiarity and ongoing dopamine activity on acute and chronic morphine treatments may be of potential clinical relevance for opioid drug addiction.

Opposite effects of low versus high dose haloperidol treatments on spontaneous and apomorphine induced motor behavior: evidence that at a very low dose haloperidol acts as an indirect dopamine agonist.

Anti-psychotic drugs are antagonists at the dopamine D2 receptors and repeated administration can lead to the development of dopamine receptor supersensitivity. In two experiments, separate groups of rats were administered 10 daily low or high doses of the typical anti-psychotic drug haloperidol (0.03 or 1.0 mg/kg). The high dose decreased locomotion whereas, the low dose increased locomotion. After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on 5 successive days. The apomorphine treatments given to the vehicle group generated a progressive locomotion sensitization effect and this effect was potentiated by pre-exposure to 0.03 mg/kg haloperidol. Initially, the prior high dose of haloperidol exaggerated the apomorphine locomotor stimulant effect but with repeated apomorphine treatments desensitization developed. Following a 5-day withdrawal period an apomorphine challenge test was conducted and apomorphine sensitization was absent in the haloperidol high dose pre-exposure group but potentiated in the low dose pre-exposure group. In the second replication experiment a conditioning test instead of a sensitization challenge test was conducted 5 days after completion of the 5-day apomorphine treatment protocol. The repeated apomorphine treatments induced conditioned hyper- locomotion and this conditioned effect was prevented by the prior high dose haloperidol pre-exposure but enhanced by the prior low dose haloperidol pre-exposure. Two new key findings are (a) that a low dose haloperidol regimen can function as a dopamine agonist and these effects persist after withdrawal and (b) that repeated apomorphine treatments can desensitize D2 receptors previously sensitized by a high dose haloperidol treatment regimen.