Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK-801 (dizocilpine)

Rationale: It has been inferred from indirect tests that MK-801, an NMDA re ceptor antagonist, blocks sensitization to amphetamine and to morphine. The se inferences were made from studies where behavioral scores were not recor ded after each drug treatment in the sensitization protocol. Objectives: We reinvestigated the role of NMDA receptors in sensitization to amphetamine or morphine more directly by taking locomotor and stereotypy scores after e ach of several treatments with MK-801 and amphetamine or morphine. Methods: Each male Long Evans rat was administered intraperitoneal injections of MK -801 (0.1 or 0.25 mg/kg) or saline followed 30 minutes later by amphetamine (0.75 mg/kg), morphine (1.25 mg/kg) or saline and placed immediately in a photocell chamber. Locomotion and stereotypy were measured simultaneously b y photobeam breaks and direct observation, respectively. This procedure was repeated on days 1, 2, 3, 4, 5, 8, 11 and 27 for rats receiving amphetamin e or saline as the second injection and on days 1-10, 13, 16 and 32 for rat s receiving morphine or saline as their second injection (with no testing o r treatment on intervening days). Results: The animals treated in the amphe tamine condition and animals treated in the morphine condition all showed p rogressively greater locomotion and stereotypy over the first 5 (amphetamin e) or 10 (morphine) test days; the sensitized response was seen regardless of whether the animals were pretreated with saline or with MK-801. Thus MK- 801 failed to block the development of psychomotor sensitization seen with these treatment regimens. When, following initial sensitization, amphetamin e or morphine was given in the absence of MK-801 (days 8 and 13 for ampheta mine and morphine rats, respectively), there was no expression of the sensi tized response; the sensitized response of animals previously treated in th e MK-801 drug state was expressed only when the animal was tested in the MK -801 drug state. The sensitized response was still expressed, in animals te sted in the appropriate drug condition, after a 2-week period in which no d rugs were given, confirming that the changes underlying this form of sensit ization were long-lasting and thus probably a consequence of some form of s ynaptic plasticity Conclusions: Our data provide evidence that behavioral s ensitization to amphetamine and to morphine can occur despite the presence of NMDA receptor blockade. These and previous findings suggest that the fai lure of expression of sensitization seen when MK-801 is withdrawn from a gi ven psychomotor stimulant treatment regimen reflects, at least in part, the dependency of sensitization on the various conditions of training rather t han dependency on some essential function of NMDA receptor activation.