Synergistic behavioural effects of dopamine D1 and D2 receptor agonists are determined by circadian rhythms

European Journal of Pharmacology, 215 (1992) 119-125

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© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00

EJP 52425

Synergistic behavioural effects of dopamine D 1 and D 2 receptor agonists are determined by circadian rhythms M a t h e w T. M a r t i n - I v e r s o n

and Naoto Yamada

Neurochemical Research Unit, Department of Psychiatry, Unil~ersity of Alberta, Edmonton, Alberta T6G 2B7, Canada Received 18 July 1991, revised MS received 4 February 1992, accepted 18 February 1992

The effects of continuous subcutaneous infusions of rats for 336 h with vehicle, SKF 38393 (a dopamine Dr receptor agonist), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a dopamine D, receptor agonist) or both D~ and D 2 receptor agonists, on locomotor activity werc investigated. Rats were maintained under constant lighting conditions, either continuous dark (dark : dark) or continuous light (light :light), before and during drug treatments in order to determine the influence of free-running circadian rhythms on drug responses. The D, receptor agonist initially increased locomotion in rats kept under d a r k : d a r k during both subjcctive night (period of maximum locomotion) and day (period of minimum locomotion), but had no effect in rats maintained in light:light throughout the 336 h of treatment. The motor stimulant effects of the D 2 receptor agonist on rats kept in d a r k : d a r k increased during the course of treatment during subjective night (sensitization), but decreased during the rats' subjective day (tolerance). The D i receptor agonist, SKF 38393, had no effect on its own regardless of the lighting conditions and the duration of treatment. However, the D~ receptor agonist interacted synergistically with the D~ receptor agonist in rats maintained under light:light, depending on the duration of treatment. Synergistic effects were also observed on initiation of treatment in rats under d a r k : d a r k but only during subjective day. Tolerance to the synergistic effects of the receptor agonists occurred as a function of treatment duration, but only during subjective day. The D I receptor agonist blocked the effects of the D 2 receptor agonist during the rats' subjective night after 100 h of treatment, but not after 25 or 325 h. It is concluded that the motor stimulant effects of a D~ receptor agonist, behavioural D I / D 2 dopamine receptor interactions, and the development of sensitization and tolerance to the locomotor effects of a D, receptor agonist are determined by endogenous free-running circadian rhythms, lighting conditions and duration of treatment. Circadian rhythms; Dopamine; Dopamine D~ receptors; Dopamine D z receptors; Locomotion; Sensitization; Tolerance; PHNO (( + )-4-propyl-9-hydroxynaphthoxazine); SKF 38393

1. Introduction R e s e a r c h of the last 15 y e a r s on the b e h a v i o u r a l effects o f p s y c h o m o t o r s t i m u l a n t s has u n c o v e r e d two p h e n o m e n a that have r e c e i v e d m u c h a t t e n t i o n . O n e of t h e s e p h e n o m e n a is that m a n y of the b e h a v i o u r a l effects o f p s y c h o m o t o r s t i m u l a n t s once t h o u g h t to be m e d i a t e d by direct or i n d i r e c t actions on d o p a m i n e D 2 r e c e p t o r s a r e actually a function of a synergistic interaction of e n d o g e n o u s d o p a m i n e a n d / o r e x o g e n o u s rec e p t o r agonists acting on b o t h D 1 a n d D z d o p a m i n e r e c e p t o r s (see C l a r k a n d W h i t e , 1987; W a d d i n g t o n a n d O ' B o y l e , 1987, 1989 for reviews). This is in c o n t r a s t to the b i o c h e m i c a l i n t e r a c t i o n of t h e s e r e c e p t o r s u b t y p e s on a d e n y l a t e cyclase, the D~ r e c e p t o r i n c r e a s i n g a n d

Correspondence to: M.T. Martin-Iverson, Neurochemical Research Unit, D e p a r t m e n t of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2B7, Canada.

the D 2 r e c e p t o r d e c r e a s i n g o r having no effect on activity of this s e c o n d m e s s e n g e r system ( K e b a b i a n a n d Calne, 1979). T h e s e c o n d p h e n o m e n o n is that of b e h a v i o u r a l sensitization, a g r a d u a l a u g m e n t a t i o n of the b e h a v i o u r a l effects of s t i m u l a n t s with r e p e a t e d injections, t h o u g h t by m a n y investigators to be a likely c a n d i d a t e as a neurochemical mechanism underlying stimulant-ind u c e d psychosis ( R o b i n s o n a n d B e c k e t , 1986). Sensitiz a t i o n has b e e n f o u n d to be a function of t r e a t m e n t r e g i m e n ; s p a c e d injections (e.g. daily injections) p r o duce sensitization, while c o n t i n u o u s s u b c u t a n e o u s (s.c.) infusions result in tolerance, a progressive d e c r e a s e in the b e h a v i o u r a l effects of p s y c h o m o t o r s t i m u l a n t s (Post, 1980). R e c e n t r e s e a r c h has shown t h a t b o t h sensitization a n d t o l e r a n c e to the b e h a v i o u r a l effects of continuously infused d o p a m i n e D 2 r e c e p t o r agonists occur, d e p e n d i n g on w h e t h e r o r not the rats are t e s t e d d u r i n g the d a r k or light p h a s e o f a 12-h l i g h t : d a r k cycle ( M a r t i n - I v e r s o n et al., 1988b). S i m i l a r effects have b e e n

120 found with continuous infusions of ( + ) - a m p h e t a m i n e , an agent that increases the release of dopamine from central neurons (Martin-Iverson and Iversen, 1989). Nocturnal sensitization and daytime tolerance appear to be dependent on D J D 2 receptor interactions, possibly involving circadian patterns of endogenous dopamine release (Martin-Iverson et al., 1988a), and can be reversed by reversal of the lighting schedule (Martin-Iverson et al., 1988b). In addition, the change from one state to another (sensitization to tolerance, and vice versa) occurs rapidly, within 1 h after the lights come on or go off (Martin-Iverson et aI., 1987a). This observation indicates that traditional accounts of sensitization and tolerance in terms of supersensitive and subsensitive receptors are unable to completely explain behavioural sensitization and tolerance, since the behavioural effects alter far more rapidly than is possible for changes in receptor density. The present experiment addressed two issues. Is the differential development of nocturnal sensitization and daytime tolerance to the behavioural effects of motor stimulants determined by the lighting schedule per se, or is it due to free-running circadian patterns of motor activity which correlate with the lighting schedule? Secondly, how are synergistic behavioural interactions between D~ and D 2 receptors affected by rats' freerunning circadian rhythms of motor activity? These issues were investigated by measuring the locomotor activity of rats previously adapted to constant lighting conditions, either constant dark (dark: dark) or constant light (light:light), during continuous administration with a D 2 receptor agonist, a D~ receptor agonist, or both drugs for 336 h.

2. Materials and methods

2.1. Anima& Male S p r a g u e - D a w l e y rats weighing 200-250 g at the beginning of the experiment were adapted to constant lighting conditions, constant light (overhead fullspectrum fluorescent lighting of 55 lux intensity), or constant dark (overhead infrared fluorescent illumination extending into the visible red spectrum with an intensity of 2 lux) for 21 days before drug treatments. Rats were housed singly in locomotor testing boxes made of stainless steel with one Plexiglas wall and a steel mesh floor. The dimensions of these boxes were 25 (width)× 25 ( h e i g h t ) × 30 (length) cm, with two photocells and parallel infrared light emitters placed 3 cm from the floor on the side walls, spaced 14 cm apart, equidistant from the end walls (Acadia Instruments Ltd). Photobeam interruptions were recorded in 1 h blocks by a C o m m o d o r e 64 computer. Rats had ad libitum access to fresh food (Wayne Rodent Blox) and

water (changed 3 times a week). T e m p e r a t u r e (21°C) was kept constant. 2.2. Drugs Drugs were vehicle (distilled water containing 40% dimethyl sulfoxide), (+)-l-phenyl-2,3,4,5-tetrahydro (1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393), a D~ receptor agonist purchased from Research Biochemicals Incorporated, and ( + )-4-propyl-9hydroxynaphthoxazine hydrochtoride (PHNO), a D 2 receptor agonist graciously provided by Merck Sharp and D o h m e Ltd. Drugs were given using Alzet osmotic minipumps (Model 2ML2) purchased from A L Z A Ltd. The pumps infused solutions at a rate of 5.6 / z l / h for at least 336 h, according to information supplied by ALZA. 2.3. Procedure After 21 days of habituation to the lighting schedule and the test boxes, rats (12 rats per drug group) were implanted with Alzet osmotic minipumps in the s.c. midscapular region under methoxyfluorane anaesthesia, as described previously (Martin-Iverson et al., 1988a). The pumps contained vehicle, SKF 38393 in a concentration such that the pumps would deliver 336 # g h ~ (all drug weights expressed as salts) according to the pump rate specified by ALZA, P H N O (5 txg h ~) or both SKF 38393 (336 # g h i) and P H N O (5 /xg h l). The dose of P H N O was chosen on the basis of previous work with this drug (Martin-Iverson et al., 1988a,b). The dose of SKF 38393 was chosen on the basis of previous work showing that a similar dose injected daily for 3 days produced synergistic actions with PHNO, but had no effect on its own (Martin-Iverson et al., 1988a). Locomotor activity was assessed in hourly blocks throughout the adaptation and drug treatment phases. Analysis of variance (ANOVA) was used to determine the statistical significance of differences among groups, with two independent factors (vehicle or P H N O and vehicle or SKF 38393) and one repeated factor (treatment duration). The F-test for planned comparisons was used to compare between groups, using the MSERRO R term from the A N O V A (Kiess, 1989).

3. Results

The flee-running circadian activity rhythm of rats is usually longer than 24 h (Yamada and Martin-Iverson, 1990). Least-squares determinations of the length of each daily cycle (period) of each rat in the present experiment indicated that the average day length for all 96 rats was 25 h. Therefore, daily cycles were

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divided into 25 l-h blocks. Locomotor activity counts from the 3 h of peak activity counts were averaged across rats within a drug group to give the mean peak activity for each cycle. Similarly, activity counts from the nadir (3 h of the least activity) were averaged across rats within a group to give the mean nadir activity for each 25h cycle. These values were taken to represent the subjective 'night' and subjective 'day', respectively, and this was confirmed by visual inspection of actograms for each rat. Results from the first, fourth and thirteenth 25 h cycle were included as representing the effects of initial, intermediate and long-term treatment durations. As rats are nocturnal animals, they are most active during their subjective 'night' and least active (usually asleep) during their subjective 'day' (fig. 1). Control (vehicle-treated) rats in the light :light condition exhibited similar levels of peak locomotion (subjective night) as control rats in the d a r k : d a r k condition. However, control rats in the light :light condition exhibit higher levels of locomotion during their subjective day (nadir) than equivalently treated rats in the d a r k : d a r k condition (fig. 1). P H N O , the D 2 receptor agonist increased locomotion as a function of presence or absence of the D. receptor agonist, subjective day and night, duration of treatment and lighting condition as shown by analysis of variance (interaction term for P H N O × SKF 38393 x subjective n i g h t / d a y × treatment duration: F(2,176)

LOCOMOTION

250

200 \

150

O 100

50

0 DD PEAK

LL PEAK

DD NADIR

LL NADIR

Fig. 1. Locomotion ( + S.E.M.), as measured by infrared photobeam interruptions, in vehicle-treated rats kept under constant dark (dark : dark) or constant light (light : light) conditions. Measurements were taken for 3 h of peak locomotion (subjective night) and for 3 h of nadir (minimum) levels of locomotion (subjective day) on the first (left hatched bars.), fourth (right hatched bars) and thirteenth (crosshatched bars) 25-h free-running cycle.

300 •

LOCOMOTION % CONTROL *1

250

200

150

100

50

0 SKF

PHNO

SKF + PHNO

Fig. 2. Effects of a dopamine D 1 agonist, SKF 38393 (SKF; 0.336 mg h l), a D 2 agonist, PHNO (5 /xg h i), or both agonists combined ( S K F + P H N O ) given with s.c. osmotic minipumps on mean peak locomotion 4__S.E.M. (subjective night) in rats maintained in constant dark (dark:dark). Measurements are taken for 3 h of maximum locomotion and are expressed as percent of the vehicle group on the first (left hatched bars), fourth (right hatched bars) and thirteenth (cross-hatched bars) 25-h free-running cycle. * Significantly different from control, P < 0.05. + Significantly different from the equivalent treatment group on 'night' 1. P < 0.05.

= 395, P < 0.05; interaction term for P H N O × lighting condition × subjective n i g h t / d a y × treatment duration: (F(2,176) = 6.28, P < 0.005). Significant differences between drug-treated and vehicle-treated groups are displayed in the figures. P H N O , when given alone, initially increased the locomotion of rats kept in d a r k : d a r k during both subjective night (peak: fig. 2) and subjective day (nadir: fig. 4). P H N O did not significantly increase locomotion in rats kept in light:light regardless of the duration of treatment or subjective night or day (figs. 3 and 5). After 13 25-h cycles, the effect of P H N O on dark : dark rats was increased (sensitization) during the subjective night (fig. 2), but was decreased (tolerance) during the subjective day (fig. 4). The D~ receptor agonist, SKF 38393, had no effect on locomotion in dark : dark or light : light groups when given on its own, except for an increase in locomotion during the subjective day on the first cycle of treatment for rats maintained under d a r k : d a r k conditions. This effect decreased on later cycles (fig. 4). SKF 38393 significantly influenced the effects of the D 2 receptor agonist, P H N O . The D 1 and D 2 receptor agonists had synergistic effects on increasing locomotion in light : light rats on the first and last subjective nights of treatment (fig. 3), at least when synergism is defined as occurring when two drugs without significant effect on their bwn produce a statistically significant effect when

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LOCOMOTION % CONTROL

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t

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LOCOMOTION % CONTROL 700 -]-

[

I 600 t

250

I 500 200

400

00, v

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50

100

sk~

PH'NO

SKF +' PHNO

Fig. 3. Effects of a dopamine D~ agonist, SKF 38393 (SKF; 0.336 mg h l), a D z agonist, PHNO (5 p,g h i), or both agonists combined ( S K F + P H N O ) given with s.c. osmotic minipumps on mean peak locomotion + S.E.M. (subjective night) in rats maintained in constant light (light:light). Measurements are taken for 3 h of maximum locomotion and are expressed as percent of the vehicle group on the first (left hatched bars), fourth (right hatched bars) and thirteenth (cross-hatched bars) 25-h free-running cycle. * Significantly different from control, P < 0.05. + Significantly different from the equivalent treatment group on 'night' 1, P < 0.05.

700~

LOCOMOTION % CONTROL i

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/

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PHNO

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Fig. 5. Effects of a dopamine D~ agonist, SKF 38393 (SKF; 0.336 mg h t), a D 2 agonist, PHNO (5 /xg h i), or both agonists combined ( S K F + P H N O ) given with s.c. osmotic minipumps on mean nadir locomotion _+S.E.M. (subjective day) in rats maintained in constant light (light:light). Measurements are taken for 3 h of minimum locomotion and are expressed as percent of the vehicle group on the first (left hatched bars), fourth (right hatched bars) and thirteenth (cross-hatched bars) 25-h free-running cycle. * Significantly different from control, P < 0.05. ** Significantly different from PHNO and SKF alone, first cycle, P < 0.05.

combined. A similar synergistic effect of the two receptor agonists was apparent on the first subjective day of treatment of d a r k : d a r k rats (fig. 4), and on both the first and fourth subjective day of treatment of light: light rats (fig. 5). The synergistic effects of the dopamine receptor agonists developed tolerance in both d a r k : d a r k and light:light rats by subjective day 13. Neither tolerance nor sensitization to the interaction effects occurred during subjective night (fig. 3). However, SKF 38393 blocked PHNO-induced locomotion after 4 nights of treatment (fig. 3).

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4. Discussion

200

100

0

SKF

PHNO

SKF + PHNO

Fig. 4. Effects of a dopamine Dt agonist, SKF 38393 (SKF; 0.336 mg h 1), a D 2 agonist, PHNO (5 p g h - l ) , or both agonists combined ( S K F + P H N O ) given with s.c. osmotic minipumps on mean nadir locomotion+ S.E.M. (subjective day) in rats maintained in constant dark (dark:dark). Measurements are taken for 3 h of minimum locomotion and are expressed as percent of the vehicle group on the first (left hatched bars), fourth (right hatched bars) and thirteenth (cross-hatched bars) 25-h free-running cycle. * Significantly different from control, P < 0.05. ** Significantly different from PHNO and SKF alone, first cycle, P < 0.05.

Rats were maintained under constant lighting conditions, either continuous light (light:light) or continuous dark (dark:dark) in order to determine their freerunning circadian rhythms in locomotion. Different groups were given continuous infusions of a D~ receptor agonist (SKF 38393), or a D 2 receptor agonist (PHNO), or both of these drugs together. It was observed that the motor stimulant effects of a selective dopamine D 2 receptor agonist are attenuated in light:light rats. The light:light-induced attenuation of the effects of the D 2 receptor agonist was found to be reversed by coadministration of a D~ receptor agonist at a dose that is without effect when given alone. In

123 contrast, the effects of the D 2 receptor agonist during subjective night in dark:dark rats are increased (sensitization), while tolerance to the same effects in the same animals develops during their subjective day. It can be difficult to attribute changes in stimulant-induced locomotion to tolerance or sensitization because increasing doses of stimulants can lead to focussed stereotypies in one location, accompanied by decreases in locomotion. However, it has previously been demonstrated that nocturnal increases and diurnal decreases in the locomotor response to P H N O and to the combination of P H N O and SKF 38393 are a function of sensitization and tolerance, and not to the decrease or emergence of competing stereotyped behaviours (Martin-Iverson, 1991). Furthermore, video records of the rats in the present study support the current interpretation (unpublished observations). Synergistic effects of D t and D 2 receptor agonists on locomotor activity did not occur during the subjective night of dark:dark rats. While the possibility that the lack of synergistic action after the thirteenth cycle is due to a 'ceiling' effect cannot be ruled out, two observations argue against this interpretation. Firstly, the variability of the response (see fig. 2) indicates that a ceiling was not reached since a ceiling effect should exhibit very little variability. Secondly, in no other case was a synergistic action of the two agonists on locomotor activity appal"ent after 13 cycles; rather, synergistic actions were only clearly present on the first cycle. In fact, rather than synergistic actions between the drugs on locomotor activity during the 'subjective night', the D~ receptor agonist blocked the locomotor effects of a D 2 receptor agonist during subjective night after 4 days of continuous treatment in both d a r k : d a r k and light : light rats. The mechanism by which constant light blocked the effects of a D 2 receptor agonist is not known. That the blockade can be reversed by coadministration of a D~ receptor agonist suggests that the effects of constant light are a function of loss of activation of D 1 receptors. This conclusion is supported by the findings that temporary depletions of dopamine block the locomotor stimulant effect of D 2 receptor agonists, and this blockade is reversed by coadministration with a D 1 receptor agonist (Dreher and Jackson, 1989; Jackson and Hashisume, 1986; Jackson and Jenkins, 1985; Jackson et al., 1988a,b; White et al., 1988). In addition, S p r a g u e - D a w l e y rats maintained under constant light exhibit an attenuation or loss of circadian rhythmic patterns of activity (Yamada and Martin-Iverson, 1990), and it may be that the effects of D 2 receptor agonists require the presence of this rhythmicity. Sensitization of the motor effects of psychomotor stimulants has been proposed to be a possible mechanism underlying stimulant-induced psychosis and schizophrenia (Robinson and Becker, 1986). It is

blocked by infusion of a dopamine D 1 antagonist directly into the ventral tegmental area (Stewart and Vezina, 1989), the site of dopamine-containing cell bodies, axons of which terminate in the mesolimbic and mesocortical areas and which are responsible for the locomotor stimulant (Kelly and iversen, 1976) and euphoric effects of psychomotor stimulants (Roberts et al., 1980). Both tolerance and sensitization were previously shown to occur to the stimulant effects of PHNO, depending on the light:dark schedule (Martin-Iverson et al., 1988b). Tolerance was shown to be reversed by acute coadministration of a DI receptor agonist (Martin-lverson et al., 1988a). This tolerance to the effects of a D 2 receptor agonist can also be reversed by application of arousing or stressful stimuli, and the reversal of tolerance was blocked by a D I antagonist (Martin-lverson et al., 1987b, 1988a). It is perhaps relevant that psychotic episodes in schizophrenics and stimulant-abusers can be precipitated by stress (Robinson and Becker, 1986). The present data indicate that the dual development of tolerance and sensitization is a function of the free-running circadian rhythms in locomotor activity, and not due directly to the lighting schedule itself. One finding which is difficult to account for is the blockade of the effects of P H N O by the D~ receptor agonist after 4 subjective nights of infusions. Relevant to this finding are the observations that the locomotor effects of P H N O (Martin-Iverson et al., 1988b), ( + ) amphetamine (Martin-lverson and Iversen, 1989), or dopamine infused directly into the nucleus accumbens (Costall et al., 1982), in rats on a 12-h light:dark cycle exhibit a biphasic pattern, with decreases after 4 - 7 days of treatment followed by increases to (or surpassing) initial levels. Thus, a decrease in locomotion during chronic treatment of rats with drugs that influence (directly or indirectly) both D1 and D e receptors between 4 - 7 days of treatment appears to be a rather general phenomenon. However, the mechanism of this effect is not understood. The occurrence of synergistic or antagonistic interactions between D 1 and D 2 receptor agonists are clearly a function of endogenous free-running activity rhythms. This has direct consequences for the development of behavioural sensitization and tolerance, and may play an important role in stimulant-induced psychosis. For example, 98% of 74 patients with Parkinson's disease who had psychotic reactions to treatment with the precursor to dopamine ( L - D O P A ) reported sleep disturbances usually prior to the appearance of the levodopa psychosis (Nausieda et al., 1982), which is likely associated with alterations in circadian rhythms of sleep-wakefulness. Furthermore, both never-medicated and medicated schizophrenics exhibit a loss of normal circadian rhythms in plasma levels of the dopamine metabolite homovanillic acid (Doran et al., 1985). Thus,

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there is evidence that psychosis is associated with disturbances of normal circadian rhythms. An understanding of how circadian rhythms alter the effects of psychomotor stimulants and selective D] and D 2 receptor agonists is essential for the understanding of behavioural sensitization and D i / D 2 interactions, phenomena that may underlie human psychoses. It is also clear that an understanding of the influence of circadian rhythms on dopaminergic systems is necessary for the rational therapy of Parkinson's disease with direct dopamine receptor agonists. For example, patients with this disorder treated with sustainedrelease formulations of ( + )-PHNO develop a relatively rapid tolerance to the therapeutic effects of this drug (Cedarbaum et al., 1990). On the other hand, those given 12-h daily infusions with lisuride, another dopamine D 2 receptor agonist, appear not to develop tolerance and have a much reduced potential for developing psychiatric side effects than those given continuous infusions of lisuride (Ruggieri et al., 1989). An awareness of the importance of circadian rhythms in determining drug effects is growing rapidly. For example, chemotherapy of certain cancers can be markedly improved by delivering drugs following a circadian infusion pattern (Von Roemeling and Hrushesky, 1989). Circadian rhythms are an important feature with treatment implications in cardiovascular disease (Coy et al., 1990; Valle and Lemberg, 1990). The toxic effects of many drugs are dependent upon circadian rhythms (Motohashi et al., 1990), and can be reduced by administering drugs following a circadian infusion pattern (Von Roemeling and Hrushesky, 1989). The present data indicate that responses to chronic treatment with dopamine receptor agonists are determined largely by circadian rhythms and environmental lighting. These results suggest that circadian rhythms should be taken into account in the rational therapy of at least some neurological (e.g. Parkinson's disease) and psychiatric (e.g. psychoses) conditions. In conclusion, the results indicate that (1) the motor stimulant effects of a selective dopamine D= receptor agonist are attenuated by exposing rats to constant light (light : light); (2) the light : light-induced attenuation of the effects of the D 2 receptor agonist is reversed by coadministration of a D~ receptor agonist at a dose that is without effect when given alone; (3) the effects of the D 2 receptor agonist during subjective night are increased (sensitization), while tolerance to the same effects in the same animals develops during their subjective day; (4) synergistic effects of D~ and D 2 receptor agonists on locomotor activity do not occur during the subjective night of rats kept in constant dark (dark:dark); (5) the D l receptor agonist blocks the locomotor effects of a D 2 receptor agonist during subjective night after 4 days of continuous treatment.

Acknowledgements This research was funded by the Medical Research Council of Canada and the Alberta Mental Health Fund. M . T . M . - I . is supported by an Alberta Heritage Foundation for Medical Research Scholarship. We thank G.B. Baker and A.J. Greenshaw for the critical reading of this manuscript.

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