Effects of clonidine and α-adrenoceptor antagonists on motor activity in DSP4-treated mice I: Dose-, time- and parameter-dependency

Abstract

In three experiments the acute effects of clonidine administration upon locomotor and rearing behaviour of mice pretreated with the selective noradrenaline (NA) neurotoxin, DSP4 (1 x 75 mg/kg, i.p.) 10-12 days previously, were studied. Clonidine (0.01, 0.05, 0.25, 1.25 and 3.0 mg/kg, i.p.) induced a dose-dependent reduction of motor activity during the initial 30min of testing in both DSP4-treated and control mice; this effect was attenuated by DSP4 treatment in the 0.01, 0.05, 0.25 and 3.0 mg/kg dose groups. By the third 30-min period of testing (60-90 min), each clonidine dose group, except the highest (3.0 mg/kg) dose for locomotion and the two highest (1.25 and 3.0 rag/ kg) doses for rearing, induced increases in motor activity in the control mice. In DSP4-treated mice, a large increase in locomotor counts was produced by the 0.05 mg/kg dose of clonidine with lesser increases induced by the 0.01mg/kg dose group, whereas a lesser effect of the 0.05 mg/kg group (30-60 min) was obtained for rearing but a larger effect of the 0.25 mg/ kg group (60-90min). Yohimbine (0.5mg/kg, i.p., 15 min before clonidine) attenuated the suppressive effects of clonidine (0.01 and 0.05 mg/kg) during the initial 30min of testing and markedly increased locomotor and rearing counts, both by itself and in combination with each dose of clonidine, in both DSP4-treated and control mice over the following 90 min of testing. Yohimbine treatment attenuated the large increase in locomotor counts induced by the 0.05 mg/kg dose of clonidine in the NA-denervated mice. Dihydroergotamine (0.5 mg/kg, i.p., 15 min before clonidine) did not antagonise either the initial suppressive effect or the later supersensitivity effect of the 0.05mg/kg dose of clonidine. DSP4 treatment by itself reduced motor activity. The effects of clonidine, dose-and time-dependently, by itself or in coadministration with ~e-adrenoceptor antagonists, in DSP4-treated or control mice displayed denervationinduced supersensitivity that appear to reflect mainly postsynaptic ~2-adrenoceptor mediation.

Effects of Spinal α2-Adrenoceptor and I1-Imidazoline Receptor Activation on Hindlimb Movement Induction in Spinal Cord-Injured Mice

“…In addition, we can not exclude the possibility of differential effects in other conditions as suggested by the time-and dose-dependent results reported elsewhere in DSP4-treated mice (Archer and Fredriksson, 2000). However, taken together, results from Tx cats showing prolocomotor effects at Chau et al, 1998) and data from Tx mice (lack of prolocomotor effects up to 50 min postinjection; Guertin et al, 2002) suggest no significant dose-dependent (i.e., prolocomotor effects at high doses) or time-dependent effects (i.e., prolocomotor effects at 30 or 45 min postinjection) induced by clonidine after spinal cord transection.…”

“…Intraperitoneal administration of 0.25, 0.5, 1.0, 2.5, or 5.0 mg/kg clonidine (2,6-dichloro-N-2-midazolidinylidenebenzenamine; Tocris Cookson Inc., Ellisville, MO) was performed once a week for four consecutive weeks or, alternatively, at 41 days in nonpreviously treated animals. This range of doses was chosen based upon the prolocomotor effects (i.e., brain-mediated) reported elsewhere in DSP4-treated mice (Archer and Fredriksson, 2000).…”

Effects of α-adrenoceptor agonists in chronic morphine administered DSP4-treated rats: Evidence for functional cross-sensitization

“…Archer and Fredriksson, 2000) in both DSP4 and control rats is demonstrated. It appears that the acute effect of naloxone, immediately after the 0-60 test period, was to enhance the cross-sensitization effects, particularly in DSP4-treated rats.…”

“…The initial hypoactivity (0-30 min but not 30-60 min) induced by both clonidine (0.04mg/kg) and guanfacine (0.08 mg/kg) was enhanced in the DSP4-treated rats (see Figures 2, 3, 4 and 5; sal-clon and sal-guan groups in the control and DSP4 conditions, respectively) once again demonstrating denervation-induced behavioural supersensitivity (cf. Archer and Fredriksson, 2000). (3) During the 60-90 min test period, clonidine potentiated the elevated levels of motor activity shown by morphine-treated rats; this effect was enhanced for locomotion, but reduced for rearing, by DSP4 pretreatment.…”

“…Clonidine by itself, 0.04mg/kg, increased both locomotion and rearing, compared both to the sal-sal group and itself at 0-30 min, in the DSP4-treated rats, as demonstrated previously with the 0.05 mg/kg dose in DSP4-treated mice (cf. Archer and Fredriksson, 2000). (4) Administration of naloxone potentiated markedly the clonidine-induced elevations of motor activity in morphine administered control rats; in the DSP4-treated rats, these effects were dramatically potentiated (except in the case of rearing, Figure4, although this maybe a "ceiling effect").…”