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BEHAVIORAL PHARMACOLOGY
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (G.T.C., D.M.C., J.H.W.); and Medicinal Chemistry Section, National Institutes on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, Maryland (A.H.N., P.G.)
Received for publication
October 17, 2007
Accepted
February 25, 2008.
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; 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 body of literature supports the notion that the sensitized behavioral responses to D2/D3 agonists, such as quinpirole, observed in food-restricted rats result from an enhanced 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 the 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 because 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 D2-like 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). Although postsynaptic 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). In recent studies, D3-selective antagonists have been shown to produce selective rightward shifts of the ascending limbs, whereas D2-selective antagonists shifted only the descending limbs of the dose-response curves for D2-like agonist-induced yawning and PE (Collins et al., 2005, 2007; G. T. Collins, R. K. Sunahara, F. Haii-Abdi, A. Truccone, A. H. Newman, P. Grundt, K. C. Rice, S. M. Husbands, B. M. Greedy, C. Enguehard-Gueiffier, et al., submitted for publication). These data suggest that the induction of yawning and PE by D2/D3 agonists is mediated by a selective activation of the D3 receptor, whereas 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 agonists (Boulay et al., 1999; Chaperon et al., 2003; Collins et al., 2007). It is interesting to note that food restriction has been shown to suppress apomorphine-induced yawning (Nasello et al., 1995), an effect that is suggestive of a decrease in the 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 after 10 days of food restriction, and then reassessed after 7 days of free feeding. In addition, antagonists selective for the D2 and D3 receptors were assessed for their capacity to alter the induction of yawning and PE in both free-fed and food-restricted rats to determine whether changes in the D2 and/or D3 receptor function and/or sensitivity could be observed. Finally, because yawning can be induced by a variety of mechanisms, the capacity of the cholinesterase inhibitor, physostigmine, and the serotonin 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.
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), as adopted and promulgated by the National Institutes of Health, and all experimental procedures were approved by the University of Michigan Committee on the Use and Care of Animals. Surgical Implantation of Temperature and Locomotor Probes. Rats were anesthetized with ketamine (90 mg/kg i.p.) and xylazine (10 mg/kg i.p.), and their abdominal area was shaved and cleaned with Betadine swabs and alcohol before implantation of the radio-telemetric probes (E-4000 E-Mitter; Mini-Mitter, Bend, OR). A small rostral-caudal incision was made in the abdominal wall to allow for the insertion of the probe. The abdominal wall was closed with absorbable, 5.0 chromic gut sutures, and the skin was closed with 5.0 Ethilon sutures. Rats were allowed to recover for at least 1 week before experiments began.
Behavioral Observations. On the day of testing, rats were weighed and transferred from their home cage to a test cage (48 x 23 x 20 cm, clear rodent cage with cob bedding). Dose-response curves for agonist-induced yawning, PE, and hypothermia were generated using a multiple-dosing procedure. In brief, after a 30-min habituation period, rats were administered either vehicle or antagonist 30 min before the first dose of agonist, with each successive dose of agonist separated by 35 min. Behavioral observations began immediately after each injection, and the total number of yawns and PE were recorded for 25 min thereafter. Yawning was defined as a prolonged (
1 s), wide opening of the mouth followed by a rapid closure, whereas PE was defined by an upright posture, repeated pelvic thrusts, and an emerging, engorged penis that was typically followed by genital grooming. All experiments were conducted between 12:00 PM and 6:00 PM.
Dietary Conditions. Rats had free access to standard Purina rodent chow during free-fed conditions, and they were maintained at 85% of their free-feeding weight with 20 g of Purina rodent chow per day during food-restricted conditions; water was always freely available. Rats were fed at 6:00 PM each day during the food-restricted condition, and they remained on the restricted diet for a period of 10 days before experimental sessions. After the generation of dose-response curves in the food-restricted condition, all rats were returned to the free-fed condition for a period of 7 days before re-establishing the free-fed dose-response curves. Rats were subsequently returned to the food-restricted condition for a period of 10 days before antagonist studies.
Pramipexole-, Physostigmine-, and TFMPP-Induced Yawning and Penile Erection. The effect of food restriction on yawning and PE induced by the D3-preferring agonist (pramipexole), the cholinesterase inhibitor (physostigmine), and the nonselective serotonin agonist (TFMPP) were assessed using a multiple-dosing procedure as described above. Doses of pramipexole (vehicle, 0.01, 0.032, 0.1, 0.32, and 1.0 mg/kg s.c.), physostigmine (vehicle, 0.032, 0.1, and 0.32 mg/kg i.p.), and TFMPP (vehicle, 1.0, 3.2, and 10.0 mg/kg s.c.) were administered at 35-min intervals with observations occurring for 25 min immediately after each injection. Doses for the multiple-dosing procedure were based on doses that induced yawning in single-dosing procedures (Collins et al., 2005). Dose-response curves for the free-fed, food-restricted, and free-fed conditions were generated in separate groups of rats (n = 8) on the last day of each dietary condition (day 7 of free-fed and day 10 of food-restricted).
Effects of D3- and D2-Selective Antagonists on Pramipexole-Induced Yawning and Penile Erection in Free-Fed and Food-Restricted Rats. The ability of the D3 antagonist PG01037 and the D2 antagonist L741,626 to alter the induction of yawning and PE induced by pramipexole was assessed in free-fed and food-restricted rats using the multiple-dosing procedures described above with either PG01037 (32.0 mg/kg s.c.), L741,626 (1.0 mg/kg s.c.), or vehicle administered 30 min before the first dose of pramipexole. The food-restricted rats were the same group of rats that had previously been used to assess the effects of food restriction and refeeding, whereas the free-fed rats were experimentally naive. After 10 days of food restriction, dose-response curves were generated for each rat with antagonists and vehicle administered in random order. Experimental sessions were separated by at least 72 h to allow for a drug washout period.
Effects of D2-Selective Antagonists on Physostigmine- and TFMPP-Induced Yawning and Penile Erection during Food Restriction. The ability of the D2 antagonist L741,626 to alter the induction of yawning and PE by physostigmine or TFMPP during food restriction was assessed using the multiple-dosing procedure described above with L741,626 (1.0 mg/kg s.c.) or vehicle administered, in random order, 30 min before the first dose of each agonist. Experimental sessions were separated by at least 72 h to allow for a drug washout period.
Pramipexole-Induced Hypothermia and Locomotor Activity. The effects of food restriction on pramipexole-induced hypothermia and locomotor activity were assessed using the same multiple-dosing procedure as described for the yawning and PE studies. On the day of testing, rats were weighed and returned to their home cages that were placed onto a receiving pad (ER-4000 Receiver; Mini-mitter) to allow for the real-time detection and recording of core body temperature and ambulatory locomotor activity. Temperature and locomotor activity measurements were taken every minute with at least 45 min of baseline data recorded before vehicle injection. Doses of pramipexole (vehicle, 0.01, 0.032, 0.1, 0.32, and 1.0 mg/kg s.c.) were administered every 35 min, and rats were removed from the receivers for a period of 5 min to allow for injections to be administered but were otherwise uninterrupted. Dose-response curves for pramipexole-induced hypothermia and locomotor activity were generated in the free-fed, food-restricted, and free-fed conditions using the same experimental timeline as described above. All experiments were carried out between the hours of 9:00 AM and 3:00 PM.
Drugs. Pramipexole was generously provided by Drs. Shaomeng Wang and Jianyong Chen (University of Michigan, Ann Arbor, MI), and PG01037 was provided by Drs. Amy H. Newman and Peter Grundt (Medicinal Chemistry Section-National Institute on Drug Abuse, Baltimore, MD). L741,626 was obtained from Tocris Cookson Inc. (Ellisville, MO), and physostigmine and TFMPP were obtained from Sigma-Aldrich (St. Louis, MO). All drugs were dissolved in sterile water, with the exception of L741,626 that was dissolved in 5% ethanol with 1 M HCl and PG01037 that was dissolved in 10% β-cyclodextrin. All drugs were administered in a volume of 1 ml/kg s.c., with the exception of physostigmine that was delivered i.p.
Data Analysis. Dose-response curves for agonist-induced yawning, PE, hypothermia, and locomotor activity were generated with eight rats per drug. Yawning and PE are expressed as the mean number of yawns or PE during the 25-min observation period ±S.E.M. Change in core body temperature is expressed as the mean ± S.E.M. difference in core body temperature as measured 30 min after each injection compared to the core body temperature measured 1 min before the vehicle injection. Locomotor activity is expressed as the mean ± S.E.M. of the total number of ambulatory locomotor activity counts during the 30-min period between each injection. A one-way, repeated measures analysis of variance (ANOVA) with post hoc Dunnett's tests were used to determine significant differences in agonist-induced yawning, hypothermia, and locomotor activity compared with vehicle (GraphPad Prism; GraphPad Software Inc., San Diego, CA). A two-way, repeated measures ANOVA with post hoc Bonferroni tests were used to determine significant differences in agonist-induced yawning, hypothermia, and locomotor activity between the three dietary conditions (free-fed 1, food-restricted, and free-fed 2) as well as between yawning in vehicle- and antagonist-pretreated rats. Friedman tests with post hoc Dunn's tests were used to determine significant levels of agonist-induced PE compared with vehicle as well as the effects of dietary condition and antagonist pretreatment on agonist-induced PE.
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, 2007; G. T. Collins, R. K. Sunahara, F. Haji-Abdi, A. Truccone, A. H. Newman, P. Grundt, K. C. Rice, S. M. Husbands, B. M. Greedy, C. Enguehard-Gueiffier, et al., submitted for publication); however, slight differences in the magnitude of the yawning and PE response were observed.
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), physostigmine and TFMPP induced dose-dependent increases in yawning behavior, with inhibition of yawning observed at higher doses, resulting in an inverted U-shaped dose-response curve during the initial free-fed condition (Fig. 1, C and E). Although significant increases in yawning were observed at doses of 0.1 mg/kg physostigmine (p < 0.01) and 3.2 mg/kg TFMPP (p < 0.01) during the free-fed condition, physostigmine and TFMPP both failed to induce significant levels of yawning at any dose tested during the food-restricted condition. As with pramipexole, food restriction significantly suppressed physostigmine- and TFMPP-induced yawning, with significant inhibition of yawning observed at doses of 0.1 (p < 0.001) and 0.32 mg/kg (p < 0.01) physostigmine and 1.0 (p < 0.05) and 3.2 mg/kg (p < 0.001) TFMPP. Refeeding partially recovered physostigmine-induced yawning; however, TFMPP-induced yawning remained suppressed, even after 7 days of unrestricted access to food. No significant increases in PE were observed at any dose of physostigmine or TFMPP tested (Fig. 1, D and F).
Food Restriction on Pramipexole-Induced Hypothermia and Locomotor Activity. The effects of food restriction on pramipexole-induced changes in core body temperature and locomotor activity are shown in Fig. 2. Food restriction had a significant effect on both the hypothermic and locomotor stimulatory effects of pramipexole. Significant decreases in core body temperature were observed in all dietary conditions, with doses of 0.32 and 1.0 mg/kg pramipexole (p < 0.01 for both) resulting in significant decreases in core body temperature during both free-fed conditions and doses of 0.1 (p < 0.05), 0.32 (p < 0.01), and 1.0 (p < 0.01) mg/kg pramipexole resulting in significant decreases in core body temperature during the food-restricted condition. Whereas the dose-response curve for pramipexole-induced hypothermia was shifted to the left, significant differences between the hypothermic responses in the food-restricted and free-fed conditions were only observed at a dose of 1.0 mg/kg pramipexole; an effect that persisted even after rats were returned to the free-fed condition (Fig. 2A). As with pramipexole-induced yawning and hypothermia, food restriction significantly altered the locomotor-stimulatory effects of pramipexole (Fig. 2B). Although there were no significant effects of pramipexole on locomotor activity in either free-fed condition, a significant increase in locomotor activity was observed after a dose of 0.32 mg/kg pramipexole (p < 0.01) during the food-restricted condition; locomotor activity returned to baseline levels after return to the free-fed condition. It is noteworthy that the dose-response curves for pramipexole-induced hypothermia obtained in the current studies using the multiple-dose procedure are similar to those obtained using single-dose procedures (Collins et al., 2007).
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D2- and D3-Selective Antagonism of Pramipexole-Induced Yawning and Penile Erection in Free-Fed and Food-Restricted Rats. The effects of the D2-selective antagonist L741,626 and the D3-selective antagonist PG01037 on pramipexole-induced yawning and PE induced are shown in Fig. 3. Similar to previous reports using single-dosing procedures (Collins et al., 2005, 2007; G. T. Collins, R. K. Sunahara, F. Haji-Abdi, A. Truccone, A. H. Newman, P. Grundt, K. C. Rice, S. M. Husbands, B. M. Greedy, C. Enguehard-Gueiffier, et al., submitted for publication), in free-fed rats, pretreatment with the D3-selective antagonist resulted in a selective rightward shift of the ascending limbs of the yawning and PE dose-response curves with significant reductions in the levels of yawning and PE observed after a dose of 0.1 mg/kg pramipexole (p < 0.05 for both). Pretreatment with the D2 antagonist L741,626 resulted in a reversal of the inhibition of yawning and PE by higher doses while having no effect on yawning or PE induced by lower doses of pramipexole (Fig. 3, A and B). Similar to the effects of the antagonists in free-fed rats, pretreatment of food-restricted rats with the PG01037 resulted in a significant inhibition of pramipexole-induced yawning and PE with significant reductions in the levels of yawning and PE observed after doses of 0.032 (p < 0.05) and 0.1 mg/kg pramipexole (p < 0.01), respectively (Fig. 3, C and D). However, unlike in the free-fed condition in which the effects of L741,626 were only observed at a dose of 0.32 mg/kg pramipexole, pretreatment of food-restricted rats with L741,626 effectively restored the capacity of pramipexole to induce yawning, with the resulting dose-response curve (Fig. 3C) very similar to that observed in free-fed rats (Fig. 1). Pretreatment with L741,626 also significantly altered pramipexole-induced PE with a significant increase in the number of PEs observed after a dose of 0.32 mg/kg pramipexole (Fig. 3D).
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D2-Selective Antagonism of Physostigmine- and TFMPP-Induced Yawning and Penile Erection during Food Restriction. Similar to the effects of food restriction on pramipexole-induced yawning, food restriction also suppressed physostigmine- and TFMPP-induced yawning. However, unlike with pramipexole-induced yawning and PE, the inhibition of physostigmine- and TFMPP-induced yawning resulting from food restriction was not reversed by pretreatment with L741,626 (Table 1), although a nonsignificant increase in the number of yawns observed after a dose of 0.1 mg/kg physostigmine from 1.4 ± 0.6 yawns to 4.8 ± 2.3 yawns was observed.
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; Cadoni 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 D2-mediated effects of pramipexole, enhancing and/or sensitizing rats to the hypothermic and locomotor stimulatory effects of pramipexole. Although food restriction altered both D2- and D3-mediated behavioral effects of pramipexole, convergent evidence from the effects of pramipexole alone and in combination with D2- and D3-selective antagonists suggest 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; G. T. Collins, R. K. Sunahara, F. Haji-Abdi, A. Trucone, A. H. Newman, P. Grundt, K. C. Rice, S. M. Husbands, B. M. Greedy, C. Enguehard-Gueiffier, et al., submitted for publication), 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 it did not alter pramipexole-induced PE. Although 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., 2005, 2007; G. T. Collins, R. K. Sunahara, F. Haji-Abdi, A. Truccone, A. H. Newman, P. Grundt, K. C. Rice, S. M. Husbands, B. M. Greedy, C. Enguehard-Gueiffier, et al., submitted for publication) 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. Although it is possible that these effects represent a decreased function and/or sensitivity of only some D3 receptors, the effects of food restriction on the D2-mediated effects of pramipexole 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 that 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; G. T. Collins, R. K. Sunahara, F. Haji-Abdi, A. Truccone, A. H. Newman, P. Grundt, K. C. Rice, S. M. Husbands, B. M. Greedy, C. Enguehard-Gueiffier, et al., submitted for publication). 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 the D2 but not D3 receptor function and/or sensitivity was provided by the effects of the D3-selective PG01037 (133-fold selective for D3 over D2 receptors in vitro; Grundt et al., 2005, 2007) and D2-selective L741,626 (13-fold selective for D2 over D3 receptors in vitro; Millan et al., 2000) antagonists on pramipexole-induced yawning.
Similar to previous reports (Collins et al., 2005, 2007; G. T. Collins, R. K. Sunahara, F. Haji-Abdi, A. Truccone, A. H. Newman, P. Grundt, K. C. Rice, S. M. Husbands, B. M. Greedy, C. Enguehard-Gueiffier, et al., submitted for publication), pretreatment with the D3-selective antagonist PG01037 inhibited pramipexole-induced yawning and PE in both the free-fed 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 they also suggest that food restriction does not alter at least some of the D3-mediated behavioral effects of pramipexole. Likewise, the D2-selective antagonist L741,626 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, whereas L741,626 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 with free-fed condition (0.32 mg/kg), suggesting a leftward shift in the D2-mediated effects of pramipexole when food was restricted. Moreover, comparison of the effects of L741,626 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 the D3-mediated effects of pramipexole, 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.
It is interesting to note that 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 toward food-related stimuli (e.g., Robinson and Berridge, 1993; Kelley et al., 2005), whereas 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 versus protein/palatable versus nonpalatable), and satiety (Leibowitz et al., 1990; Meguid et al., 2000; Isaac and Berridge, 2003; Alberto et al., 2006; Palmiter, 2007).
Unlike the effects of food restriction on pramipexole-induced behaviors that generally returned to baseline levels after 7 days of refeeding, decrements in physostigmine- and TFMPP-induced yawning were still evident after 7 days of unrestricted access to food, suggesting a prolonged effect of food restriction on cholinergic and serotonergic function. It is interesting to note that because 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, although 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 D3-mediated 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 L741,626, 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. It is noteworthy that whereas 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, although 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. In contrast, prolonged decreases in cholinergic and serotonergic sensitivity may allow for a sustained increase in meal frequency and size after extended periods of food deprivation. Moreover, whereas 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.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: PE, penile erection; TFMPP, N-[3-(trifluoromethyl)phenyl]piperazine hydrochloride; PG01037, N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride; physostigmine, (3aS)-cis-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate hemisulfate; pramipexole, N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride; L741,626, 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole; ANOVA, analysis of variance.
Address correspondence to: Dr. James H. Woods, Department of Pharmacology, 1301 Medical Science Research Building III, 1150 W. Medical Center Drive, University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: jhwoods{at}umich.edu
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