The effect of memantine on behavioural sensitisation to methamphetamine in mice

Abstract

After repeated administration the psychostimulant methamphetamine (Met) produces a substantial increase in behavioural responses, which is termed behavioural sensitisation. Many studies have reported that N-methyl-d-aspartate (NMDA) receptors play an important role in the development and expression of behavioural sensitisation. Memantine (Mem) is used particularly for the treatment of Alzheimer’s disease and acts as a non-competitive NMDA glutamate receptor antagonist, possessing a variety of psychotropic effects. For example, there are studies indicating that memantine prevents the expression of withdrawal symptoms in mice and causes reversal of opioid dependence. Although not all pharmacological mechanisms of memantine have been clarified yet, it is known that memantine inhibits NMDA receptor inward currents. Thus, the present study was designed to assess whether memantine would influence behavioural sensitisation to the stimulatory effects of methamphetamine on mouse locomotion. Mice were randomly allocated into four groups. They were given vehicle on Day 1of the experiment and after five days without application they were administered seven drug daily doses (i.p.) from Day 7 to Day 13 of the study, as follows: (a) n_{1, 2}: 2.5 mg/kg/day of Met; (b) n₃: combination Met + Mem at the doses of 2.5 mg/kg/day and 5 mg/kg/day, respectively; (c) n₄: Mem at the dose of 5 mg/kg/day. On Day 14 mice were given the first “challenge treatment” (a) n₁: Met, (b) n₂: Met + Mem, (c) n₃: Met, (d) n₄: Mem. The second “challenge treatment” was given after a six day wash-out period on Day 21: (a) n₁: Met, (b) n₂: Met + Mem, (c) n₃: Met, (d) n₄: Mem. Changes in locomotion were measured for a period of 3 min in the Open field on Days 1, 7, 14 and 21 to assess the sensitising phenomenon. Met pre-treatment significantly sensitised to the effects of the challenge doses (n₁). Mem given alone did not change the measured behavioural parameters after the acute dose but it significantly decreased locomotion after its repeated administration (n₄). Repeated pre-treatment with the Met + Mem combination (n₃) did not produce sensitisation after Met challenge doses and similarly, repeated pre-treatment with Met did not induce sensitisation after the challenge dose of Met + Mem (n₂). Thus, our results suggest that the role of the NMDA receptor antagonist memantine in the development and expression of behavioural sensitisation to Met seems to be an inhibitory one.