Amphetamine behavioral sensitization: An inquiry into the effects of dose, scheduling of injections, and antagonism by sodium valproate

The invention of the force-plate actometer (Fowler et al. 2001), allows us to quantify with high spatial and temporal resolution the behavioral changes that accompany sensitization to central nervous system (CNS) stimulants. An increased behavioral stimulation and appearance of stereotyped behaviors with repeated, intermittent exposure to moderate doses of amphetamine (2.5 to 5.0 mg/kg) characterize amphetamine sensitization. We first demonstrated that 5 mg/kg amphetamine produced greater intensity, longer duration, and shorter latency to onset of focused stereotypy than 2.5 mg/kg. We also discovered that the frequency (8--13Hz) of the dominant focused stereotypy behavior (head-bobbing/head-weaving) undergoes changes both within the session and across-sessions. This may be indicative of a concurrent sensitization and tolerance phenomenon within the same behavior, and if so, would be the first documentation of such an event occurring within a single behavioral aspect of CNS-stimulant-induced sensitization. We studied the effects of conditioning of amphetamine-induced behavior to environmental cues and found no direct evidence for conditioning effects for focused stereotypes. Utilizing the antiepileptic drug sodium valproate (50, 100, and 200 mg/kg) given either before or after amphetamine, we attempted to attenuate the sensitization process to 2.5 mg/kg amphetamine. Dosing 50 and 100 mg/kg sodium valproate two hours after amphetamine and on non-amphetamine days decreased the intensity and duration of focal stereotyped behaviors while increasing the distance traveled and onset time to the appearance of stereotypies. In contrast, acute dosing of 200 mg/kg sodium valproate one hour prior to each amphetamine exposure did not affect sensitization. The major findings of these studies were that (1) sensitization was affected by dose level but not environmental conditioning, (2) the dominant rhythm of focused stereotypy undergoes within-session increases and across-session decreases which may be related to the sensitization process, and (3) sodium valproate can partially antagonize the behavioral effects of amphetamine sensitization under a chronic dosing schedule. As CNS-stimulant abuse has been theoretically linked to the process of sensitization, this research raises the possibility of sodium valproate as a potential treatment of CNS-stimulant abuse.