A neurobehavioral evaluation of subcutaneously administered amphetamine, WIN55,212–2, 2,5-dimethoxy-4-Iodoamphetamine, and morphine in mice

Abstract

The neurobehavioral effects of certain classes of CNS active compounds (e.g., stimulants, depressants, neuroleptics) have been well characterized in rats. However, relatively less is known about the neurobehavioral effects of other types of CNS active compounds (e.g., cannabinoid receptor and serotonin 2A [5-HT2A] receptor agonists), and even less in mice. Given the increasing interest in development of therapeutics acting upon these targets, characterizing the neurobehavioral effects of these agents is warranted. The objective of this study was to evaluate the potential acute neurobehavioral effects of amphetamine, the cannabinoid CB1/CB2 agonist WIN55,212–2, the 5-HT_2A receptor agonist 2,5-dimethoxy-4-Iodoamphetamine (DOI), and morphine in mice. Amphetamine (10 mg/kg), WIN55–212-2 (10 mg/kg), DOI (10 mg/kg) and morphine (20 mg/kg) were administered via subcutaneous injection to male CD-1 mice (n = 8/group). Neurobehavioral evaluations including assessments of activity, autonomic, excitability, neuromuscular, physiological, and sensorimotor function were conducted in home cage and open field prior to dosing and at 30 min and 24 h postdose. Effects of amphetamine included high arousal, induction of stereotypy, unkempt appearance, piloerection, alterations in pupil response, salivation, hyperthermia, tremors, and increases in rearing counts, handling reactivity, difficulty of removal, body tone, and respiratory rate. Effects of WIN55,212–2 included low arousal, changes in posture/body carriage, analgesia, impairments in gait/mobility, alterations in pupil response, and decreases in rearing, startle response, handling reactivity, body tone, and respiratory rate. Effects of DOI included induction of stereotypy, alterations in pupil response, ptosis/palpebral closure, and decreases in startle response and body tone. Effects of morphine included changes in posture/body carriage, induction of stereotypy, alterations in pupil response, impairments in gait/mobility, hypothermia, analgesia, and decreases in arousal/alertness, rearing counts, difficulty of removal, and handling reactivity. In conclusion, amphetamine, WIN55,212–2, DOI, and morphine produced various neurobehavioral effects consistent with the known, prototypical effects of these drugs in other species, thereby demonstrating the utility of mice as a suitable model to detect drug-induced neurobehavioral changes via divergent mechanisms of action.