mystery of yawning
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Fetal yawning assessed by 3D and 4D sonography
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
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Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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mise à jour du
30 janvier 2011
 
Psychopharmacology (Berl).
2011;215(4):609-20
Behavioral sensitization to cocaine in rats:
evidence for temporal differences
in dopamine D(3) and D (2) receptor sensitivity
Collins GT, Truong YN, Levant B, Chen J, Wang S, Woods JH.
Department of Pharmacology, University of Michigan Medical School,
Ann Arbor, MI, USA

Chat-logomini

Cocaine-induced changes in D(2) receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D(3) receptors is less clear.
 
OBJECTIVES: To characterize the effects of repeated cocaine administration on the sensitivity of rats to D(2)- and D(3)-mediated behaviors, as well as the binding properties of ventral striatal D(2)-like and D(3) receptors.
 
METHODS: Pramipexole was used to assess the sensitivity of rats to D(3)/D(2) agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D(2)-like and D(3) receptors (24 h and 42 days) were also evaluated.
 
RESULTS: Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h-42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose-response curve. Cocaine treatment also decreased B (max) and K (d) for D(2)-like receptors and increased D(3) receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists.
 
CONCLUSIONS: These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D(3) and D(2) receptors, with enhancements of D(3)-mediated behavioral effects observed within 72 h and enhancements of D(2)-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D(3) receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.

Introduction
 
Early studies on the effects of repeated cocaine administration described a common behavioral sequelae in monkeys, dogs, and rats in which the behavioral and physiologic effects of cocaine were observed sooner, and with greater intensity following repeated, intermittent cocaine administration (Downs and Eddy 1932a, b; Post and Rose 1976; Tatum and Seevers 1929), and the progressive and persistent nature of these effects, frequently referred to as behavioral sensitization, are now well established in rodents. Although some important differences exist between effects of experimenter- and self-administered cocaine (Jacobs et al. 2003), a variety of progressive and time-dependent neuropharmacologic and behavioral changes have been shown to correspond to the expression of the sensitized locomotor response to cocaine, including decreases in dopamine transporter (DAT) density and enhancements of cocaine-induced increases in extracellular dopamine, regardless of whether cocaine is experimenter(Heidbreder et al. 1996; Henry and White 1995; Kalivas and Duffi 1993; Pilotte et al. 1994; Wilson et al. 1994), or self-administered (Ahmed and Cador 2006; Ferrano et al. 2005; Hooks et al. 1994; Phillips and Di Ciano 1996; Zapata et al. 2003). The repeated administration of psychostimulants is also known to affect a variety of neurotransmitter systems (e.g., cholinergic, dopaminergic, GABAergic, glutamatergic, opioidergic, and serotonergic), and it is thought that the neuroadaptations that underlie the development and expression of the sensitized behavioral responses are also important for the development of addiction-like behaviors in animals (for reviews, see Kalivas and Stewart 1991; Pierce and Kalivas 1997; Robinson and Berridge 1993; Vanderschuren and Kalivas 2000; Vezina 2004). An important theory of the basis of drug addiction posits that drug-induced behavioral sensitization reflects sensitized brain circuits that, in turn, enhance the incentive value of the drugs and the cues associated with them (Robinson and Berridge 1993). Among the data that support this theory are findings that cocaine-induced sensitization of D2-like (D2, D3, and D4) receptors within the nucleus accumbens plays a role in the increased effectiveness of D2-like agonists in inducing cocaine-directed responding (i.e., drug-seeking) following the cessation of cocaine selfadministration (De Vries et al. 2002; Dias et al. 2004; Edwards et al. 2007). What is not specified in the theory or demonstrated in these data are the respective roles of the D2, D3, and D4 receptors in mediating either the behavioral sensitization or the corresponding neurological changes.
 
There is, nevertheless, growing evidence to suggest that cocaine, either experimenter- or self-administered, has differential effects on the density/availability/expression of D2-like (D2, D3 and D4), with decreases in D2 receptor levels reported in rodents (Bailey et al. 2008; Conrad et al. 2010; Goeders and Kuhar 1987; Maggos et al. 1998), and rhesus monkeys (Nader et al. 2006), and increases in D3 receptor levels observed in human cocaine overdose fatalities (Segal et al. 1997; Staley and Mash 1996), and rats with a history of experimenter- (Le Foll et al. 2005) or self-administered cocaine (Conrad et al. 2010; Neisewander et al. 2004).
 
Despite these apparent differences in the effects of cocaine on D2 and D3 receptor levels, the lack of agonists or antagonists with high degrees of selectivity for the D2 or D3 receptor has made it difficult to parse the relative contributions of these receptor subtypes to the expression of sensitized behavioral responses or addiction-like behaviors. One approach that has been useful in determining the involvement of different dopamine receptor subtypes has been to evaluate the capacity of cocaine to sensitize animals to the selective behavioral effects of DI-like (D1 and D5) or D2-like (D2, D3, and D4) receptor agonists. Accordingly, increases in SKF-3 8393-induced tongue protrusions (Neisewander et al. 1996) have been interpreted as a cocaine-induced sensitization of Dl -like receptors, whereas enhancements of quinpirole-, or quinelorane-induced sniffing, head movements, or locomotor stimulation (De Vries et al. 2002; Dias et al. 2004; Edwards et al. 2007; Ujike et al. 1990) have been attributed to a sensitization of D2 receptors. It should be noted, however, that these latter studies do not permit a discrimination between effects produced through the D2 as opposed to the D3 receptors as the majority of these effects are observed at doses of quinpirole or quinelorane that are 50- to 250-fold higher than those required to induce behaviors that have been attributed to the selective activation of D3 receptors, such as yawning (Collins et al. 2007; Collins et al. 2005), and 5- to 25-fold higher than those required to produce D2-mediated effects, such as hypothermia (Chaperon et al. 2003; Collins et al. 2007).
 
Support for these sub-type-specific roles of the D3 and D2 receptors in the regulation of yawning and hypothermia has been provided by antagonist interaction studies in which D3-selective antagonists have been shown to produce dose-dependent and selective rightward shifts of the ascending limb of the dose-response curve for D2-like agonist-induced yawning, whereas D2-preferring antagonists have been shown to produce selective rightward shifts of the descending limb of the yawning doseresponse curve for D2-like agonist-induced yawning at doses that also inhibit the induction of hypothermia (Baladi et al. 2009; Collins et al. 2008; Collins et al. 2007; Collins et al. 2009; Collins et al. 2005). Based on these differential roles of the D3 (induction) and D2 (inhibition) receptors in the mediation of yawning, we have hypothesized that cocaine-induced increases in D3 receptor density and/or sensitivity would result in leftward shifts of the ascending limb of the yawning dose-response curve, whereas decreases in D2 receptor density would result in rightward shifts of the descending limb of the yawning dose-response curve. Conversely, an increase in the sensitivity of D2 receptors should result in a leftward shift of the descending limb of the yawning doseresponse curve.
 
 
In the current experiments, rats were first given a regimen of once daily cocaine or saline injections prior to assessing the sensitivity of rats to the D3- and D2-mediated behavioral effects of the D3-preferring agonist, pramipexole (and '-30-fold selective for D3 over D2 in vivo; Collins et al. 2007; '-90-fold selective for D3 over D2 in vitro; Millan et al. 2002). Dose-response curves for pramipexoleinduced yawning, locomotor activity, and hypothermia were obtained 24 h, 72 h, 10, 21, and 42 days after the cessation of cocaine or saline administration to allow for evaluation of the development of cocaine-induced changes in D3- and/or D2-mediated behavioral effects. To assess the selectivity of cocaine's effects for dopaminergic systems, dose-response curves for yawning induced by the indirect cholinergic agonist, physostigmine, and the 5-HT2 receptor agonist, 3-trifluoromethylphenylpiperazin (TFMPP), were also obtained after 24-72 h and 41-43 days of cessation from cocaine or saline administration. In parallel, radioligand binding studies were performed to assess the effects of repeated cocaine administration on the binding properties of ventral striatal D2 and D3 receptors 24 h and 42 days after the cessation of cocaine or saline administration.
 
Discussion
 
In agreement with the majority of previous studies, cocainetreated rats displayed an enhanced locomotor response to cocaine 42 days after the cessation of cocaine, suggesting that the current regimen of cocaine administration was sufficient to produce a long-lasting behavioral sensitization to cocaine. In addition, although cocaine treatment failed to alter pramipexole-induced locomotor activity or hypothermia, cocaine-treated rats displayed a progressive and persistent leftward and/or upward shift in the ascending limb of the dose-response curve for pramipexole-induced yawning, as well as a leftward shift in the inhibition of yawning that comprises the descending limb of the doseresponse curve for yawning. The temporal differences in the development of these two effects suggest that increases in the sensitivity of rats to D3-mediated behavioral effects become apparent shortly after the cessation of cocaine with progressive and persistent enhancements observed for up to 42 days, whereas increases in the sensitivity of rats to D2mediated behavioral effects do not emerge until 42 days after the cessation of cocaine.
 
Although it has been well established that repeated, experimenter- or self-administered cocaine results in a progressive and persistent enhancement of the locomotor stimulatory effects of subsequent cocaine challenges (Heidbreder et al. 1996; Henry and White 1995; Kalivas and Duffy 1993), it is important to note that crosssensitization between the locomotor stimulatory effects of cocaine and direct D2-like agonists has been reported with self-administered cocaine (De Vries et al. 2002; Dias et al. 2004; Edwards et al. 2007), but not experimenteradministered cocaine (e.g., Djano and Martin-Iverson 2000). The inability of cocaine to cross-sensitize rats to the locomotor stimulatory effects of pramipexole in the present studies provides further support for this dichotomy between experimenter- and self-administered cocaine. However, it is possible that cross-sensitization was not observed due to the relatively low doses of pramipexole that were used, the relatively short period of time that pramipexole-induced locomotor activity was measured, or some combination thereof (De Vries et al. 2002; Dias et al. 2004; Edwards et al. 2007). Alternatively, it has also been suggested that the development (Henry et al. 1998; Hoflthan and Wise 1993) and expression (Djano and Martin-Iverson 2000; Kiyatkin 1994) of cross-sensitization between the locomotor stimulatory effects of experimenter-administered cocaine and D2like agonists depends upon an activation of both Dr and Dr like receptors, raising the possibility that basal extracellular dopamine levels were insufficient to activate D1-like receptors during the locomotor tests. Nevertheless, when taken together with previous reports of food restrictioninduced enhancements of the locomotor stimulatory effects of pramipexole under identical experimental conditions (Collins et al. 2008), the current fmdings suggest that locomotor assays are insufficient to detect changes in D2 and/or D3 receptor sensitivity following experimenteradministered cocaine in rats.
 
Despite this inability of prior cocaine administrations to alter the locomotor effects of pramipexole, cocaine-treated rats displayed a progressive and persistent leftward and upward shift of the D3-mediated (Collins et al. 2007; Collins et al. 2005), ascending limb of the dose-response curve for pramipexole-induced yawning, as well as an increased sensitivity to the D2-mediated (Collins et al. 2007; Collins et al. 2005) inhibitory effects of pramipexole on yawning when tested after the cessation of cocaine administration. These findings not only suggest that yawning assays are sensitive enough to differentiate between cocaine-induced changes in the D3- and Dr mediated behavioral effects of pramipexole, but also that there are temporal differences in these effects. Progressive enhancements of D3-mediated behaviors emerged shortly after the cessation of cocaine administration ('-72 h) and persisted for at least 42 days, whereas increases in the sensitivity of rats to some D2-mediated behaviors do not become apparent until after a prolonged period of time since the cessation of cocaine administration ('-42 days). Importantly, cocaine treatment failed to alter the induction of yawning by the indirect cholinergic agonist, physostigmine, or the 5-HT2 receptor agonist, TFMPP, suggesting that the cocaine-induced changes in pramipexole-induced yawning represent changes in the sensitivity and/or expression of the D3 and D2 receptors that mediate yawning and not a more general enhancement of the signaling pathways within the paraventricular nucleus that regulate yawning.
 
Although the relatively low levels of D2 and D3 receptor expression and small volume of the paraventricular nucleus precluded the ability to accurately assess changes in the binding properties of D2-like receptors within this brain region, the results of radioligand binding studies performed on ventral striatal tissue provide molecular evidence to support these behavioral changes. Importantly, although 3H-spiperone binds to both the D2 and D3 receptor subtypes, its preferential affinity for D2 compared to D3 receptor ('-80-fold selective for D2 over D3 in rat brain using the current in vitro assay conditions; Levant and DeSouza 1993), combined with the differential levels of expression for the D2 and D3 receptors (D2 expressed at -100-fold higher levels than D3; Levesque et al. 1992), means that the cocaine-induced changes in the Bmw. and Kd obtained with 3H-spiperone in the current studies can be primarily attributed to changes in the binding properties of D2 receptors. Similar to what was observed with pramipexole-induced yawning at the 24 h time-point, cocaine treatment failed to alter the binding properties of D3 or D2-like receptors at this early time-point. Although previous studies in mice, rats, and rhesus monkeys have suggested that cocaine is capable of altering D2-like receptor levels within a few hours of the last cocaine administration (Bailey et al. 2008; Le Foil et al. 2005; Maggos et al. 1998; Nader et al. 2002; Nader et al. 2006; Tsukada et al. 1996), it is important to note that differences in the dosing regimen, route of administration, and length of time since cocaine treatment are all known to affect changes in D2-like receptor density (e.g., Anderson and Pierce 2005). Consistent with the cocaine-induced changes in pramipexole-induced yawning that developed over the course of the study, significant increases in D3 receptor binding, as well as significant decreases in D2-like receptor density and increases in D2-like receptor affinity were observed in the ventral striatum of cocaine-treated rats 42 days after the cessation of cocaine. Not only are these cocaine-induced changes in D3 receptor binding similar to the time-dependent increases in D3 receptor binding and cell surface expression that have been reported following periods of cocaine self-administration in rats (Conrad et al. 2010; Neisewander et al. 2004), but the observed decreases in D2-like receptor density are also similar to recent reports of decreases in D2 receptor expression in rats with a history of cocaine self-administration (Conrad et al. 2010). It should be noted, however, that similar decreases in D2 and increases in D3 receptor densities have also been reported following the repeated administration of high doses of D2-like agonists (Stanwood et al. 2000). Although an interaction between cocaine pretreatment and pramipexole cannot be ruled out, the fact that repeated pramipexole administration failed to alter the binding properties of either D2-like or D3 receptors in the saline-treated group suggests that the observed changes in D2-like and D3 receptor binding resulted from the repeated administration of cocaine, and not pramipexole.
 
Curiously, unlike the rapid sensitization of rats to the D2mediated effects of pramipexole that has been observed with food restriction (Collins et al. 2008), cocaine treatment appeared to have a delayed effect on the D2-mediated effects of pramipexole as no changes in the sensitivity of rats to the inhibition of yawning, induction of hypothermia, and locomotor stimulation were observed throughout the first 21 days after the cessation of cocaine administration. Importantly, however, increases in the sensitivity of rats to the inhibitory effects of pramipexole on yawning corresponded to a significant decrease in Kd for [3H]spiperone at D2-like receptors at 42 days, suggesting that the observed behavioral changes were mediated by an increased affinity of pramipexole at the D2 receptor. Although the current studies were not designed to differentiate between the highand low-affinity states of D2 receptors, it is possible that the increased sensitivity of the cocaine-treated rats to the D2mediated inhibition of pramipexole-induced yawning was also influenced by an increased proportion of D2 receptors in the high-affinity state as has been reported in rats following cocaine self-administration (Bnand et al. 2008) or sensitization to caffeine (Simola et al. 2008) or amphetamine (Seeman 2009). In addition to providing convergent evidence to support a cocaine-induced sensitization of the D2 receptor, the current studies also suggest that increases in D3 receptor binding may underlie the progressive increase in the sensitivity of cocaine-treated rats to the D3-mediated induction of yawning by low doses of pramipexole. However, the limitations of single-point assays make it impossible to determine whether these behavioral changes resulted from an increase in D3 receptor density, D3 receptor affinity, or some combination of the two. Interestingly, Hamilton et al. (2010) have recently reported a similar enhancement of D2-like agonist-induced yawning in male monkeys that were exposed to cocaine in utero. Not only was this effect positively correlated with the maximal daily dose of cocaine received during gestation, but this enhanced yawning response was observed 13 years later, suggesting that cocaine exposure may result in long lasting, if not permanent enhancements of the function and/or sensitivity of D3 receptors.
 
In addition to altering the potency and/or effectiveness of drugs (e.g., psycho stimulants or D2-like agonists) to stimulate locomotor activity or elicit other behavioral effects, the neuroadaptations that underlie behavioral sensitization are also thought to play a crucial role in the development of addiction-like behaviors in animals (e.g., Kalivas and Stewart 1991; Robinson and Berridge 1993; Vezina 2004), such as the increased capacity of cocaine and direct D2-like agonists to increase responding that was previously reinforced by cocaine (De Vries et al. 1998; De Vries et al. 2002; Dias et al. 2004; Edwards et al. 2007). Although these studies suggest that increases in responding are mediated by a sensitization of D2-like receptors in general, there is growing evidence to support a role for the D3 receptor, specifically in the capacity of cocaine-paired cues to reinstate or maintain responding following periods of cocaine self-administration (Cervo et al. 2007; Collins and Woods 2009; Gal and Gyertyan 2006; Gilbert et al. 2005). Given this putative role for the D3 receptor, it is interesting to note that the capacity of these cues to reinstate responding appears to be positively correlated with the duration of abstinence insofar as progressive and persistent increases in responding have been observed over the first 3 months of abstinence (e.g., Grimm et al. 2001; Lu et al. 2004). This effect appears to be similar in magnitude and time course to the increases in D3-mediated yawning observed in the current studies.
 
In summary, these studies provide convergent behavioral and molecular evidence to support a cocaine-induced enhancement of both D3- and D2-mediated elicited behavioral effects in rats. The temporal differences in the development of these effects suggest that increases in the sensitivity of rats to the D3-mediated effects of pramipexole emerge as early as 72 h after the cessation of cocaine administration with progressive and persistent enhancements observed for at least 42 days, whereas increases in the sensitivity of rats to the D2-mediated behavioral effects of pramipexole do not become apparent until after longer periods of time have passed. In addition to suggesting that D2-like agonist-induced yawning may provide a valuable tool for the evaluation of the functional changes in D3 and D2 receptors that occur following cocaine administration, when taken together with previous reports (Conrad et al. 2010; Hamilton et al. 2010; Neisewander et al. 2004), these studies provide further support for the notion that the progressive and persistent increases in the density, function, and/or sensitivity of the D3 receptor that occur during periods of abstinence or withdrawal may contribute to the enduring vulnerability to relapse commonly observed in human drug abusers.
 
 
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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.