Date of Award
Doctor of Philosophy
Lisa Baker, Ph.D.
Alan Poling, Ph.D.
Ron Van Houten, Ph.D.
Scott Rawls, Ph.D.
Behavioral, drug discrimination, kratom, locomotor activity, mitragynine, radial arm maze
Mitragyna speciosa (kratom) is a medicinal plant indigenous to Southeast Asia and Africa with a long history of use for a variety of ailments, including diarrhea, pain relief, cough suppression, and amelioration of opiate withdrawal symptoms. Despite its status as an herbal remedy, kratom is banned in some countries due to a myriad of negative health risks. Preclinical psychopharmacology studies of mitragynine (MG), the main alkaloid of kratom, indicate it has opioid-like effects at higher doses and psychostimulant-like effects at lower doses. The current study utilized three rodent behavioral paradigms to evaluate the putative psychostimulant effects of MG. The specific aims of the current study were to 1) determine if repeated MG exposure produced locomotor sensitization, 2) assess the effects of subchronic MG treatment on the acquisition of a spatial memory task, and 3) evaluate the role of noradrenergic mechanisms in the discriminative stimulus effects of MG. In experiment one, male and female Wistar-Han rats were injected every other day for five days and locomotor activity was recorded in an open field for one hour immediately before and one hour immediately after injections. Activity measures analyzed were total distance traveled, stereotypy counts, and time in center. For experiment two, the same rats were assessed one week later for spatial memory acquisition in an eight-arm radial maze while injections continued daily after each learning trial for eight days. Maze acquisition was quantified by reductions in latency to complete each trial and repeat arm entries from trial one to trial eight. In experiment three, female Sprague Dawley rats were trained to discriminate 10 mg/kg (N=6) or 15 mg/kg (N=4) MG from vehicle and noradrenergic antagonists with varying receptor selectivity were tested in combination with a range of MG doses (2.5-15 mg/kg). In experiment one, both MG doses produced stronger psychomotor stimulant effects in females compared to males, though neither dose produced locomotor sensitization in either sex. In experiment two, RAM acquisition was unaffected by mitragynine treatment in either sex. In experiment three, stimulus control was established in the eight of 10 rats, but reliably maintained in only five rats. The alpha-1 adrenergic antagonist, prazosin and the nonselective beta antagonist, propranolol partially attenuated MG-lever responding at some doses, while the alpha-2 antagonist, yohimbine fully blocked discrimination of 10 mg/kg MG, with minimal effects on other doses. The lack of evidence for behavioral sensitization in the current study indicates MG is dissimilar from stimulant drugs, which typically produce locomotor sensitization with repeated intermittent exposure. Nonsignificant effects on RAM acquisition in the current study are inconsistent with at least one previous published report that MG impairs spatial memory in rodents. Finally, low MG doses (10-15 mg/kg) do not reliably maintain adequate stimulus control in female rats, and the current results with noradrenergic antagonists should be interpreted with caution. Whereas the only published drug discrimination studies of MG utilized higher training doses (15-32 mg/kg) in male rats, future investigations are warranted to determine the optimal training dose to evaluate the contribution of monoaminergic receptors to the discriminative stimulus effects of this substance in both male and female rats.
Burroughs, Rachel, "Preclinical Behavioral Assessments of Mitraginyne, The Main Psychoactive Alkaloid in Kratom" (2022). Dissertations. 3903.