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mise à jour du
16 mars 2008
JEPT
2008;325:691-697
Food restriction alters pramipexole-induced yawning, hypothermia, and locomotor activity in rats: Evidence for sensitization of dopamine D2 receptor-mediated effects
Gregory T. Collins, Diane M. Calinski, Amy Hauck Newman, Peter Grundt and James H. Woods
Department of Pharmacology University of Michigan Medical School Ann Arbor

Chat-logomini

Abstract:
 
Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggests that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor, however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of pramipexole to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexoleinduced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restrictioninduced enhancement of D2 receptor activity as the D2 antagonist, L-741,626, recovered pramipexole-induced yawning to free-fed levels, while yawning and PE were suppressed following pretreatment with the D3 antagonist, PG01037. The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole.
 
Introduction:
 
Food restriction affects the function of a variety of neurotransmitter systems including dopaminergic (Carlson et al., 1988; Carr et al., 2003), serotonergic (Gur et al., 2003; Jahng et al., 2007), and cholinergic (Persinger et al., 2002) systems, and is known to alter the effects of drugs with diverse mechanisms of action. For instance, food restriction has been shown to enhance the reinforcing properties of opiates (Carroll et al., 1979), ethanol (Meisch and Thompson, 1973), nicotine (Donny et al., 1998), and psychostimulants (Carroll et al., 1981; Macenski and Meisch, 1999), elevate extracellular dopamine levels in the nucleus accumbens core in response to psychostimulants (Cadoni et al., 2003), and enhance the locomotor stimulatory effects of both direct- (Carr et al., 2001; 2003), and indirect-dopamine agonists (Deroche et al., 1993; Cadoni et al., 2003). A growing literature supports the notion that the sensitized behavioral responses to D2/D3 agonists, such as quinpirole, observed in foodrestricted rats result from an enhancement of the functional coupling of Gi G-proteins to D2 receptors, and not an increase in D2 receptor expression (Pothos et al., 1995; Carr et al., 2003). Alternatively, changes in D3 receptor expression and/or function could also explain the behavioral sensitivity observed in food-restricted animals, however, little is known about how food restriction affects D3 receptors.
 
For example, previous studies suggest that the enhancement of quinpirole-induced locomotor activity observed in food-restricted rats results from an enhanced functional activity of the D2 receptor (Carr et al., 2003). However, this effect could also be explained by a tolerance, or down-regulation of the D3 receptor as the inhibition of locomotor activity by D2/D3 agonists has been hypothesized to be mediated by the D3 receptor (Svensson et al., 1994). Interpretation of changes in D2/D3 agonist-induced locomotor activity is further complicated by the fact that D2like antagonists often alter locomotor activity on their own. In addition to their effects on locomotor activity, D2/D3 agonists are known to possess a variety of other behavioral effects including the induction of yawning (Yamada et al., 1986), penile erection (PE) (Melis et al., 1987), and hypothermia (Faunt and Crocker., 1987). While post-synaptic D2/D3 receptors within the mesolimbic dopaminergic pathway are thought to mediate the locomotor effects of D2-like agonists (Levant, 1997), the induction of yawning and PE by D2-like agonists is thought to be mediated by postsynaptic D2-like receptors on oxytocinergic neurons in the paraventricular nucleus (Argiolas and Melis, 1998).
 
Recently, D3-selective antagonists have been shown to produce selective rightward shifts of the ascending limbs, while D2-selective antagonists shifted only the descending limbs of the dose-response curves for D2-like agonistinduced yawning and PE (Collins et al., 2005; 2007; submitted) suggesting that the induction of yawning and PE by D2/D3 agonists is mediated by a selective activation of the D3 receptor while the inhibition of yawning and PE observed at higher doses is mediated by agonist activity at the D2 receptor. D2 receptors have also been reported to mediate the hypothermic effects of D2-like (Boulay et al., 1999; Chaperon et al., 2003; Collins et al., 2007). Interestingly, food restriction has been shown to suppress apomorphine-induced yawning (Nasello et al., 1995), an effect that is suggestive of a decrease in D3 receptor expression and/or function. However, based on the findings that yawning is differentially mediated by the D3 (induction) and D2 (inhibition) receptors, the suppression of D2/D3 agonist-induced yawning observed during food restriction could also result from an enhanced or sensitized D2 response.
 
 
The present studies were aimed at determining the effects of food restriction on D2 and D3 receptor function in rats. Thus, the capacity of pramipexole to induce yawning, PE, hypothermia, and locomotor activity was first assessed in free-fed rats, assessed in the same rats following 10 days of food restriction, and then reassessed following 7 days of free feeding. Additionally, antagonists selective for the D2 and D3 receptors were assessed for their capacity to alter the induction of yawning and FE in both free-fed and food-restricted rats to determine whether changes in D2 and/or D3 receptor function and/or sensitivity could be observed. Finally, as yawning can be induced by a variety of mechanisms, the capacity of the cholinesterase inhibitor, physostigmine, and the 5-HT2 receptor agonist, TFMPP, to induce yawning was assessed in free-fed and food-restricted rats. Results from the study of the effects of food restriction on the behavioral effects of pramipexole alone, and in combination with antagonists suggest that food restriction effectively sensitized rats to the D2-mediated effects of pramipexole while not altering the function and/or sensitivity of the D3 receptor.
 
Food restriction has been shown to enhance and/or sensitize the D2-mediated behavioral and molecular effects of dopaminergic agonists (Deroche et al., 1993; Candoni et al., 2003; Carr et al., 2001; 2003), however, the effects of food restriction on the function and/or sensitivity of D3 receptors is not well understood. The current studies were aimed at characterizing the effects of food restriction on the induction of putative D3- (yawning and PE), and D2-mediated (hypothermia and locomotor activity) effects by the D3-preferring agonist, pramipexole (90-fold selective for D3 over D2 receptors in vitro; Millan et al., 2002). Food restriction differentially affected the D3-mediated effects of pramipexole, suppressing pramipexole-induced yawning while not altering pramipexole-induced PE. Food restriction had similar effects on the D2mediated effects of pramipexole, enhancing and/or sensitizing rats to the hypothermic and locomotor stimulatory effects of pramipexole. While food restriction altered both D2- and D3mediated behavioral effects of pramipexole, convergent evidence from the effects of pramipexole alone, and in combination with D2- and D3-selective antagonists suggests that food restriction sensitized rats to the D2-mediated effects of pramipexole while not altering the function and/or sensitivity of D3 receptors.
 
Similar to previous reports in free-fed rats (Collins et al., 2005; 2007; submitted), pramipexole induced yawning and PE over low doses with inhibition of both behaviors occurring at higher doses that also corresponded to the induction of hypothermia, suggestive of a selective activation of D3 receptors at low doses, and a concomitant D2 receptor activation at higher doses. Food restriction affected pramipexole-induced yawning, locomotor activity, and hypothermia, but did not alter pramipexole-induced PE. While the enhanced and/or sensitized locomotor stimulatory and hypothermic effects of pramipexole suggest that food restriction enhanced the function and/or sensitivity of D2 receptors in the mesolimbic pathway (Ouagazzal and Creese, 2000) and anterior hypothalamus/preoptic area (Lin et al., 1982), respectively, the effects of food restriction on pramipexole-induced yawning and PE are less clear. Previous studies (Melis et al., 1987; Collins et al., submitted) suggest that D2-like agonist-induced yawning and PE are similarly mediated by D3 (induction) and D2 (inhibition) receptors within the paraventricular nucleus of the hypothalamus, yet food restriction differentially affected pramipexole-induced yawing and PE, suppressing yawning while not affecting the induction of PE. While it is possible that these effects represent a decreased function and/or sensitivity of only some D3 receptors, the effects of food restriction on pramipexole's D2-mediated effects, as well as a comparison of the effects of D3- and D2-selective antagonists on pramipexole-induced yawning and PE suggest that the food restriction-induced suppression of yawning resulted from changes in the function and/or sensitivity of D2, but not D3 receptors.
 
Unlike the hypothermic effects of D2-like agonists which have been shown to be mediated by D2, but not D3 receptors (Boulay et al., 1999; Chaperon et al., 2003; Collins et al., 2007), the induction of yawning by D2-like agonists has been shown to be mediated by the D3 receptor, with the subsequent inhibition of yawning resulting from a concomitant D2 receptor activation (Collins et al., 2005; 2007; submitted). Therefore, although decreases in D3 receptor function could explain the suppressed yawning response in food-restricted rats, increases in D2 receptor function and/or sensitivity would also be expected to suppress pramipexole-induced yawning. Support for the notion that food restriction-induced changes in D2, but not D3 receptor function and/or sensitivity was provided by the effects of the D3-selective, PGO1 037 (-133-fold selective for D3 over D2 receptors in vitro; Grundt et al., 2005; 2007), and D2-selective, L-741,626 (13fold selective for D2 over D3 receptors in vitro; Millan et al., 2000) antagonists on pramipexoleinduced yawning.
 
Similar to previous reports (Collins et al., 2005; 2007; submitted), pretreatment with the D3selective antagonist, PGO1 037, inhibited pramipexole-induced yawning and PE in both the freefed and food-restricted conditions, regardless of whether the responses were affected by food restriction. These data not only support a role for the D3 receptor in the induction of PE by pramipexole, but also suggest that food restriction does not alter, at least some of, the D3mediated behavioral effects of pramipexole. Likewise, the D2-selective antagonist, L-741,626, had similar effects in both free-fed and food-restricted rats, reversing the inhibition of yawning and PE observed at higher doses while not altering their induction at lower doses of pramipexole. However, while L-741,626 increased the low levels of yawning observed at higher doses in both free-fed and food-restricted rats, this effect was observed at a lower dose of pramipexole in the food-restricted (0.1 mg/kg) compared to free-fed condition (0.32 mg/kg), suggestive of a leftward shift in the D2-mediated effects of pramipexole when food was restricted. Moreover, comparison of the effects of L-741,626 on pramipexole-induced yawning in food-restricted and free-fed rats suggests that the D2-selective antagonist was not only effective at reversing the D2-mediated inhibition of yawning in both conditions, but also that it was capable of unmasking pramipexole's D3-mediated effects, effectively restoring the food restricted yawning dose-response curve to that of free fed levels. When taken together with the enhanced hypothermic and locomotor stimulatory effects of pramipexole, these data strongly suggest that food restriction enhanced the function and/or sensitivity of D2 receptors in mesolimbic (locomotor activity) and hypothalamic (hypothermia and yawning) brain regions, while not altering the function and/or sensitivity of D3 receptors.
 
Interestingly, dopaminergic, cholinergic, and serotonergic systems within the corticostriatal and hypothalamic regions have been implicated in a variety of aspects of feeding behavior including, motor control, motivation to obtain food, food intake, and satiation (e.g., Leibowitz and Alexander, 1998; Kelley et al., 2005). Thus, food restriction-induced increases in the function and/or sensitivity of mesolimbic and/or hypothalamic D2 receptors may be beneficial for several reasons. First, increased D2 receptor activity within the nucleus accumbens may serve to increase the motivational aspects of food or the orientation towards food-related stimuli (e.g., Robinson and Berridge, 1993; Kelley et al., 2005), while changes in D2 receptor activity affecting the integration of accumbal and hypothalamic dopamine systems may also alter motor control, food intake, and feeding duration (Kelley et al., 2005; Meguid et al., 2000). Moreover, dopaminergic neurons within the hypothalamus are known to interact with other neurotransmitters and neurohormones (i.e., serotonin and orexin) and thus changes in the function and/or sensitivity of hypothalamic D2 receptors may indirectly influence a variety of behaviors including arousal, food preference (i.e., carbohydrate vs. protein / palatable vs. nonpalatable), and satiety (Leibowitz et al., 1990; Meguid et al., 2000; Isaac and Berridge, 2003; Alberto et al., 2006; Palmiter et al., 2007).
 
Unlike the effects of food restriction on pramipexole-induced behaviors which generally returned to baseline levels following 7 days of re-feeding, decrements in physostigmine- and TFMPPinduced yawning were still evident following 7 days of unrestricted access to food suggesting a prolonged effect of food restriction on cholinergic and serotonergic function. Interestingly, as both cholinergic and serotonergic systems have been strongly implicated in satiety mechanisms (e.g., Leibowitz et al., 1990; Meguid et al., 2000; Kelley et al., 2005), it is possible that a persistent decrease in cholinergic and serotonergic function may allow for increased levels of food intake once food is available. Thus, while these studies were not primarily aimed at the effects of food restriction on cholinergic and serotonergic function they do suggest that food restriction induced a prolonged decrease in cholinergic and serotonergic receptor function and/or sensitivity.
 
To summarize, evidence was provided in support of the notion that food restriction sensitized rats to the D2-mediated effects of pramipexole while not altering their sensitivity to the D3mediated effects of pramipexole. Food restriction suppressed pramipexole-induced yawning while resulting in a sensitization and/or enhancement of the hypothermic and locomotor stimulatory effects of pramipexole; all of which suggest an increased function and/or sensitivity of the D2 receptor. This notion is further supported by the finding that the effects of food restriction on pramipexole-induced yawning were reversed by the D2 antagonist, L-741,626, and when combined with the finding that food restriction did not alter pramipexole-induced PE, these data strongly suggest that food restriction altered the D2-, but not D3-mediated effects of pramipexole. Importantly, while food restriction suppressed dopaminergic-, cholinergic-, and serotonergic-mediated behaviors, differences in the duration of these effects were observed and may be reflective of differential roles for dopamine, acetylcholine, and serotonin in feeding behaviors. For instance, while food restriction-induced changes in dopaminergic function may serve to increase the motivation to obtain food when food is unavailable, sensitization of D2 receptors would serve little purpose once food is readily available. Conversely, prolonged decreases in cholinergic and serotonergic sensitivity may allow for a sustained increase in meal frequency and size following extended periods of food deprivation. Moreover, while food restriction altered a variety of D2-mediated behaviors, food restriction failed to alter the proerectile effects of pramipexole suggesting that food restriction-induced changes in D2 receptors may serve a more general purpose to increase arousal and/or enhance dopamine-mediated reward (or prediction of reward), while allowing for other behaviors (reproduction) to be maintained. In conclusion, these studies suggest that food restriction enhanced the function and/or sensitivity of D2 receptors while having no effect on the function and/or sensitivity of D3 receptors.
 
-Collins C, Truccone A et al. Pro-erectile Effects of Dopamine D2-like Agonists are Mediated by the D3 Receptor in Rats and Mice. J J Pharmacol Exp Ther 2009
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-Canales JJ, Iversen SD Dynamic dopamine receptor interactions in the core and shell of nucleus accumbens differentially coordinate the expression of unconditioned motor behaviors Synapse 2000; 36; 297-306
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-Collins GT, Newman AH,Woods JH et al.Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists. Psychopharmacology (Berl). 2007;193(2):159-170
-Collins GT. et al. Food restriction alters pramipexole-induced yawning, hypothermia, and locomotor activity in rats: Evidence for sensitization of dopamine D2 receptor-mediated effects. JEPT 2008;325:691-697
-Collins GT et al. Narrowing in on compulsions: dopamine receptor functions Exp Clin Psychopharmacol 2008,16(4):498,502
-Chen J, Gregory T. Collins, et al. Design, Synthesis, and Evaluation of Potent and Selective Ligands for the Dopamine 3 (D3) Receptor with a Novel in Vivo Behavioral Profile. J Med. Chem., 2008;51(19):5905&endash;5908
-Collins GT, Truong YN, et al. Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D(3) and D (2) receptor sensitivity. Psychopharmacology (Berl). 2011;215(4):609-20.
Li SM, Collins GT et al. Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rat. Behav Pharmacol. 2010; 21(3): 171&endash;181.
 
Distribution of dopamine D3 receptor expressing neurons in the human forebrain:
comparison with D2 receptor expressing neurons
Gurevich EV, Joyce JN.
Neuropsychopharmacology 1999;20(1):60-80
Based on studies in the rat, Sokoloff et al. have made the valuable suggestion that the D3 receptor is a particularly important target for antipsychotics in the mesolimbic DA system. These study in the human demonstrates that the distribution of D3 receptors and D3 mRNA-bearing neurons is consistent with relative segregation of the D3 subtype to the limbic striatum as well as it primary and secondary targets and many sources of its afferents.