Table 1.
Summary of studies using AMPH or L-dopa in animal stroke models.
| Study | Model | Dosing/Rehab | Behavior | Outcomes |
|---|---|---|---|---|
| Adkins and Jones, 2005 | Cortical infarct caused by application of ET-1 to the surface of the rat cortex | 1 mg/kg AMPH every third day starting 10–14 days postop, training given daily, 1–2 h after injection on injection days, on the single pellet reaching test | Single pellet reaching | AMPH rats were robustly better than saline mice while training continued, by 2 months after conclusion of training, AMPH mice had declined and the saline mice improved to the extent that the two experimental groups were similar |
| Alaverdashvili et al., 2007 | Female rats, craniotomy followed by removal of pia mater and surface blood vessels | Oral D-amphetamine 1 mg/kg beginning 24 h poststroke given every 3rd day for 8 doses, half hour before training on their specific reaching task | Either single pellet reaching with trained trip to back of the box between reaches, modified single pellet or tray reaching | AMPH and controls were similar by the end of the experiment on all tasks, controls recovered faster than AMPH animals, having significantly better performance on some days, AMPH animals typically more qualitatively impaired than controls |
| Auriat and Colbourne, 2008 | Collagenase intracerebral hemorrhage model, primarily striatal damage | 2 mg/kg AMPH on days 7, 9, and 11, housed in an enriched environment and training on the tray reaching and beam walking tasks, 30 min after injection | Tested beam walking (non-aversive), a neural deficit score, the Montoya staircase, and the tray task, horizontal ladder | Effect of rehab but not the drug on beam walking and horizontal ladder, no effect on the Montoya staircase or the non-beam portion of the neural deficit score, tray task was not analyzed due to high number of animals which had to be excluded |
| Barbay et al., 2006 | Adult squirrel monkeys, cauterization of surface blood vessels of microelectrode-determined hand representation and ~500 μm into arm representation | Single injection of 0.25 mg/kg AMPH 1 h before hand dexterity training on day 10 postop, training continued for 14 days | Kluver board (skilled reaching) | AMPH and rehab animals were significantly better than rehab alone animals on days 13,14, 17, 18, 19, 20, 21, and 22 poststroke, at 9 weeks postop AMPH was still significantly better than rehab controls |
| Boyeson and Feeney, 1991 | Suction ablation of anterior and neocortical cerebellar cortex in rats | Starting 24 h after ablation 2 mg/kg AMPH, 0.4 mg/kg haloperidol, both or saline injections every 4 days for a total of 6 injections | Beam walking task | Recovery in cerebellum-lesioned rats not as complete as in motor cortex lesioned rats, Saline group recovered the most, haloperidol group recovered the worst, with a marked dip in performance after drug |
| Brown et al., 2004 | Photothrombotic lesion in rats, selecting for highly impaired animals | 2 mg/kg D-AMPH or saline given 1 day poststroke, with or without training on the beam and daily testing, or without daily testing | Beam walking without aversive stimuli | Training and daily testing both improved recovery, while AMPH slowed recovery, although AMPH and experience or training did recover fully by 10 days poststroke |
| Feeney and Hovda, 1983 | Motor cortex ablation followed by packing the wound, in cats | 5 or 8 mg/kg D,L-AMPH on days 4, 9, and 15 | Tactile placing in response to paw stimulation | Placing response is weakly augmented about 3 h after administration on day 4 postop, at day 9 and day 15 saw a much larger restoration of tactile placing which lasts 12–24 h |
| Feeney and Hovda, 1983 | Motor cortex ablation followed by packing the wound, in cats | 5 mg/kg of D-AMPH, L-AMPH, D,L-AMPH or D,L-AMPH followed by haloperidol | Tactile placing in response to paw stimulation | In cats with ablations and no recovery racemic mixture was the most effective, D-AMPH had some effectiveness and L-AMPH had almost no effectiveness, haloperidol at 0.2 mg/kg was able to supress D,L-AMPH, and at 0.4 mg/kg was able to block it. In partially recovered cats but not unlesioned cats haloperidol was able to block tactile reaching |
| Gilmour et al., 2005 | ET-1 stroke in rats | 2 mg/kg AMPH, staring on day 2 postop and continuing every 3rd day until day 26 (8 days administration total) | Paw reach and foot fault, ipsilateral limb was bandaged to prevent use | No benefit of AMPH on the foot fault test, saw a benefit of AMPH on paw reaching 24 h after drug, recovery of AMPH animals still present 6 days after last injection |
| Goldstein, 2009 | Ablation of fore and hindlimb sensorimotor cortex in rats | D-AMPH, haloperidol or saline for 5 days, rats are housed in an enriched environment and some are fitted with casts that prevent use of unimpaired forelimb 24 h before first drug dose | Cylinder test and beam walking (evaluating time to cross the beam) | On the cylinder test, among non-restricted animals AMPH animals performed best and haloperidol animals performed very poorly, restrictive casts offset the deficit in haloperidol animals and increased saline animal's performance to the level of AMPH+ restraint animals, no differences were seen between groups in the beam walking test |
| Goldstein and Davis, 1990b | Suction lesion to the level of the white matter | 2.6 mg/kg D-AMPH | Beam walking with aversive stimulus, began 24 h after surgery and continuing until 48 h postop | Overall faster improvement of AMPH animals in one dose, however see AMPH non-responders and some saline animals spontaneously recovered |
| Goldstein and Davis, 1990c | Suction ablation of the cortex to the level of white matter in rats | 2.6 mg/kg +D-AMPH, training is 6 trials on the beam walking task at 1 h intervals beginning 1 h after injection | Beam walking | At 24 h after injection AMPH+ training had significantly better performance on the beam walking task as compared to all groups, the training alone and AMPH alone groups were better than the saline group, but not significantly |
| Goldstein and Davis, 1990a | Rats, suction ablation of gray matter | 2 mg/kg AMPH | Beam walking with aversive stimulus, given as massed or spaced trials | AMPH helped both massed and spaced trial rats, helped massed trials more early on |
| Hovda and Feeney, 1984 | Cats, motor cortex ablation | 5 mg/kg AMPH with experience, single dose or multiple doses days 10, 14, 18, and 22 after surgery | Beam walking and tactile placing | Fastest recovery with AMPH and experience, slower but complete recovery with AMPH alone (at 60 days post op) Saline group had incomplete recovery, no improvement on tactile placing test |
| Hovda et al., 1987 | Cats, primary visual cortex ablations | 5 mg/kg AMPH on days 10, 14, 18, and 22 postop | Tactile placing (eyes covered, stimulate hairs of dorsal surface) | AMPH cats show recovery within 3 h of first dose, recovery lasts to end of experiment (30 days) |
| Liu et al., 2011 | Transient MCAO, lesions mainly in temporoparietal cortex | 2 mg/kg AMPH every 3rd day for 4 weeks | Turning asymmetry during body swing test | AMPH animals had significantly less asymmetry on body swing, AMPH group had significantly better body posture while suspended on day 12 |
| Papadopoulos et al., 2009 | MCAO in rats, only cortical damage | 2 mg/kg AMPH given on days 2, 5, and 8 postop with or without enriched environment (EE) or focussed activity (starting on day 2 and continuing twice a day for 3 weeks and then once a day for a further 5 weeks) | Forelimb reaching task performed daily, Monday-Friday for 8 weeks, and horizontal ladder performed weekly, behavior testing not done under the drug | AMPH combined with environmental enrichment and focussed activity was significantly better than all other groups on both skilled reaching and the horizontal ladder, show complete recovery on skilled reaching, AMPH and EE and AMPH with EE and focussed activity recovered completely |
| Ramic et al., 2006 | Aspiration lesion of gray matter and some white matter damage | 2 mg/kg D-AMPH on days 2 and 5 post-lesion, rehab under drug's effect, rehab involved a variety of forelimb involving climbing tasks and EE | Ladder walking, pellet reaching | AMPH + rehab group showed significant improvement at 1 week postop, AMPH only at 2 weeks postop on pellet reaching, see significant recovery at 1 week in combo group and 6 weeks in AMPH only on ladder walking, no significant benefit of rehab only |
| Rasmussen et al., 2006 | Injection of autologous macro-clot to the middle cerebral artery in rats | 3.5 mg/kg D-AMPH sulfate given on days 1, 3, 5, and 7 postop, physical therapy consisted of Montoya staircase for 15 min and T-maze for 20 runs on drug days | Montoya staircase | Animals given only therapy performed significantly better than controls and had no asymmetry, AMPH and AMPH + therapy animals still had asymmetry, AMPH + therapy was better than AMPH alone and AMPH alone was better than controls but not significantly so |
| Rasmussen et al., 2011 | Embolic strokes in rats | No AMPH, early AMPH (3.5 mg/kg 10 min after embolization) Late AMPH with training (days 2, 5, 8, and 11 1 mg/kg with Montoya staircase) or both early and late AMPH | Montoya staircase, recovery assessed from days 14–25 poststroke | Acute AMPH group performed better than the control group on the Montoya staircase, the late AMPH and combination AMPH group both performed much worse than the controls |
| Ruscher et al., 2012 | Transient MCAO in male rats | 5 days of either 1, 5 or 20 mg/kg L-dopa (with benserazide) or placebo | Rotating pole test (various speeds), the cylinder test, a composite neuroscore | Significantly better improvement of the 20 mg/kg L-DOPA group as compared to controls on all speeds of the rotating pole test at 7 days post-infarct, the neuroscore at 7 and 14 days poststroke and the cylinder test 14 days poststroke. Significantly better improvement above the controls on the 5rpm speed of the rotating pole at 7 days poststroke and on the cylinder test at 14 days poststroke |
| Schmanke and Barth, 1997 | Male rats with large unilateral electrolytic lesions of the sensorimotor cortex | 24 h after surgery given either 2 mg/kg D-AMPH or saline | Beam walking, foot fault test, bilateral tactile stimulation (adhesive removal) test with neutralization, vibrissae > forelimb placing, forelimb > forelimb placing | Early beam walking recovery improved with AMPH, from 1–6 h post injection. On foot fault test, bilateral tactile stimulation test and vibrissae > forelimb placing and forelimb > forelimb placing there was no difference between the groups |
| Schmanke and Barth, 1997 | Male rats with small unilateral electrolytic lesions in forelimb sensorimotor area | 2 mg/kg D-AMPH at 1, 3, and 5 days postop | Beam walking, foot fault test, bilateral tactile stimulation (adhesive removal) test with neutralization, vibrissae > forelimb placing, forelimb > forelimb placing | AMPH mice showed recovery sooner on the beam walk and were significantly better on days 7, 9 and 15 postop. AMPH mice showed improvement sooner on the vibrissae > forelimb placing and forelimb > forelimb placing, no differences in foot fault test or bilateral tactile stimulation test |
| Schmanke and Barth, 1997 | Male rats with electrolytic lesions of the caudal forelimb representation area. | 2 mg/kg of D-AMPH 1, 3 and 5 days postop with or without forelimb placing training | Vibrissae > forelimb placing and Forelimb > forelimb placing | On vibrissae > forelimb placing AMPH + practice group performed the best starting about 10 days postop, AMPH alone and practice alone both performed better than saline, Forelimb > forelimb placing benefits from AMPH but not significantly, no improvement is observed until 35 days postop |
| Stroemer et al., 1998 | Permanent MCAO in spontaneous hypertensive rats | 2 mg/kg D-AMPH given on day 3, 6, and 13 poststroke and then every 3rd day until day 30, testing done 1 h after injection and again 24 h after injection | Foot fault test with large (6 cm) openings or small (3 cm) openings, Morris water maze (not discussed here), postural reflex test, somatosensory disengage behavior, rearing behavior and grip strength | No differences in postural reflex, somatosensory disengage behavior, rearing behavior, or grip strength. AMPH rats did significantly better than saline rats on the foot fault test from 2 days after surgery onwards on large foot fault test, saw a similar pattern on the small foot fault test |
| Sutton et al., 1989 | Bilateral cortical ablation in cats, varying size of lesions | 5 mg/kg AMPH on days 12, 16, and 20 after surgery | Beam walking with a 10-point scale, started 6 days after lesion | AMPH animals performed better than saline animals, although some AMPH animals were completely non-responsive to treatment and some saline animals display full spontaneous recovery |
| Wolf et al., 2014 | Distal MCAO, affecting primarily the cortex, in rats | 2 mg/kg D-AMPH on 2, 5, and 8 days, focused activity where animals are placed on climbing apparatuses for 20 min beginning 15 min after injection and EE | Skilled reaching test performed daily, horizontal ladder performed once a week | AMPH + rehab performed significantly better than all groups and no longer had a significant difference from the baseline performance on skilled reaching and the horizontal ladder at 8 weeks post infarct |
The table summarizes the study parameters and the outcomes of studies quoted in the main text, which involve administration of AMPH or L-DOPA. For a summary of studies involving other drugs, or intraventricular infusion approaches, please see Feeney et al. (1993).