A role for D2 but not D1 dopamine receptors in the cross-sensitization between amphetamine and salt appetite
Introduction
Behavioral sensitization is defined as a persistent increase in the response to a drug with repeated exposure (Stewart and Badiani, 1993). The administration of psychostimulants such as cocaine and amphetamine has been shown to promote an enduring potentiation in the locomotor and rewarding effects of these drugs as well as drug-induced plasticity in the mesolimbic dopamine system (Robinson and Kolb, 2004). In addition to the activational and motivational effects of drugs of abuse this system is thought to be critical to behaviors related to natural rewards such as food, sex and salt in the sodium-depleted rat (Kelley and Berridge, 2002). The discovery that drugs of abuse may target and induce plasticity in the same system responsive to natural rewarding stimuli has led to questions concerning shared mechanisms and the potential influence of previous experience on responses to drugs.
To address the potential relationship between these types of reward, induction of salt appetite was used as a model of a natural reward system. Sodium depletion is a strong homeostatic challenge that produces a salt appetite. Rats depleted of sodium will seek out, work for and consume concentrated NaCl solutions they would otherwise avoid (McCutcheon and Levy, 1971). Interestingly, there are some properties of this model that resemble the features of psychostimulant administration. First, like drugs of abuse and other natural rewards, NaCl intake in the sodium-depleted rat is associated with dopamine release in nucleus accumbens (Frankmann et al., 1994). Second, multiple sodium depletions give rise to salt appetite sensitization, characterized by an increase in NaCl intake in animals with a previous depletion (Sakai et al., 1987). Third, this sensitization is associated with alterations in dendritic morphology in nucleus accumbens, similar to that shown after repeated drug administration (Roitman et al., 2002, Robinson and Kolb, 1997). Finally, a history of sodium depletion leads to a potentiation in the behavioral response to amphetamine, or cross-sensitization.
Cross-sensitization, a process whereby one treatment may facilitate the response to another, has been demonstrated to occur between drug classes (Vanderschuren et al., 1999, Robinson and Berridge, 1993) and between drugs of abuse and natural rewards (Fiorino and Phillips, 1999, Nocjar and Panksepp, 2002, Vitale et al., 2003). We have previously demonstrated the presence of reciprocal cross-sensitization between salt appetite and amphetamine (Clark and Bernstein, 2004a). A history of sodium depletion promotes a potentiation of the rewarding and locomotor effects of the drug and, conversely, repeated amphetamine administration produces a sensitized salt appetite similar to that produced by prior sodium depletions. The underlying mechanism of this cross-sensitization effect remains unknown and is the focus of the present studies.
Altered dopamine function has been implicated in drug sensitization as well as cross-sensitization between drugs of abuse and natural rewards (Fiorino and Phillips, 1999, Pierce and Kalivas, 1997, Vanderschuren et al., 1999). The aim of the present experiments was to define the role of dopamine in the cross-sensitization between salt appetite and amphetamine by administering dopamine agonists and antagonists to animals with and without a history of sodium depletion. In addition, because the striatum is made up of separate populations of medium spiny neurons expressing either D1-like or D2-like dopamine receptors, selective agonists and antagonists were used to define the selective involvement of these receptor subtypes.
Section snippets
Subjects
Male Long–Evans rats weighing between 300 and 350 g, housed individually in hanging metal cages, were used for all experiments. Animals were maintained on a 12 h light/dark cycle; lights off at 7:00 PM, with free access to Teklad Rodent chow (Madison, WI) and water unless otherwise noted. All procedures were done in accordance with the Institutional Animal Care and Use Committee at the University of Washington.
Sodium depletion
To induce salt appetite, rats were depleted of sodium with procedures modified from
Experiment 1
Rats with a history of sodium depletion show behavioral cross-sensitization to amphetamine, an indirect dopamine agonist, as evidenced by an increase in locomotor activity relative to animals with no such history. The underlying mechanism responsible for this potentiation in the behavioral response remains unknown. One possibility is that this treatment leads to enduring increases in dopamine receptor activity in the striatum. The purpose of this experiment was to examine the contribution of
Experiment 2
The results of Experiment 1 indicate that, in addition to amphetamine, a history of sodium depletions produces behavioral cross-sensitization to a D2, but not a D1, direct dopamine agonist. This suggests that an alteration in dopamine function may play a role in cross-sensitization and that D2 receptors may be selectively involved. Another way to address this possibility is to administer dopamine antagonists in conjunction with amphetamine. The purpose of Experiment 2 was to evaluate the
Discussion
Multiple sodium depletions produce salt appetite sensitization as well as behavioral cross-sensitization to amphetamine. The results of this study confirm behavioral cross-sensitization between salt appetite sensitization and amphetamine and support our previous demonstration that this protocol produces potentiation of general locomotor activity in addition to rearing (Clark and Bernstein, 2004b). The results of Experiment 1 indicate that a history of sodium depletion also leads to a
References (33)
Augmentation of drug reward by chronic food restriction: behavioral evidence and underlying mechanisms
Physiol Behav
(2002)- et al.
Reciprocal cross-sensitization between amphetamine and salt appetite
Pharmacol Biochem Behav
(2004) - et al.
Quinpirole-induced behavioral sensitization is enhanced by prior scheduled exposure to sucrose: a multi-variable examination of locomotor activity
Behav Brain Res
(2006) - et al.
Differential changes in central monoaminergic metabolism during first and multiple sodium depletions in rats
Pharmacol Biochem Behav
(1994) - et al.
Dopamine receptor antagonists block amphetamine and phencyclidine-induced motor stimulation in rats
Pharmacol Biochem Behav
(1994) - et al.
Previous exposure to amphetamine increases incentive to obtain the drug: long-lasting effects revealed by the progressive ratio schedule
Behav Brain Res
(2000) - et al.
Chronic intermittent amphetamine pretreatment enhances future appetitive behavior for drug- and natural-reward: interaction with environmental variables
Behav Brain Res
(2002) - et al.
The neural basis of drug craving
Brain Res Brain Res Rev
(1993) - et al.
Structural plasticity associated with exposure to drugs of abuse
Neuropharmacology
(2004) Regulation of drug-taking and-seeking behaviors by neuroadaptations in the mesolimbic dopamine system
Neuropharmacology
(2004)
Chronic access to sucrose solution enhances the development of conditioned place preferences for fentanyl and amphetamine in male Long–Evans rats
Pharmacol Biochem Behav
Rewarding and locomotor-activating effects of direct dopamine receptor agonists are augmented by chronic food restriction in rats
Psychopharmacology
Sodium depletion is necessary but not sufficient for behavioral cross-sensitization to amphetamine
Sensitization of salt appetite is associated with increased “wanting” but not “liking” of a salt reward in the sodium deplete rat
Behav Neurosci
Infusion of a D-1 receptor agonist into the nucleus accumbens enhances cocaine-induced behavioural sensitization
Neuroreport
Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration
Psychopharmacology
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2011, Pharmacology Biochemistry and BehaviorCitation Excerpt :In a series of studies Bernstein and colleagues established the relationship between the sensitization of salt appetite motivated by repeated sodium depletions and psychomotor sensitization induced by amphetamine (Clark and Bernstein, 2004, 2006b; Roitman et al., 2002). These studies explored whether repeated sodium depletion increases salt appetite by sensitizing motivational mechanisms underlying sodium seeking and intake behaviors just as psychomotor stimulants sensitize the motivational mechanisms underlying drug consumption (Bernstein, 2003; Clark and Bernstein, 2004, 2006a, 2006b; Roitman et al., 2002). In addition, members of the Bernstein laboratory demonstrated that sodium depletion-induced salt appetite reciprocally cross-sensitized with an amphetamine-induced psychomotor response (Clark and Bernstein, 2004; Roitman et al., 2002).
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2009, Physiology and BehaviorCitation Excerpt :The mechanism of enhancement is incompletely understood. It is not due to long-term changes in plasma levels of angiotensin II, aldosterone, sodium, or hematocrit [39], but in brain, after repeated sodium depletions, dopamine D2 receptors are sensitized, dendritic spines and branches in the shell of the nucleus accumbens are more prolific [6,36], and FOS immunoreactivity is enhanced in the subfornical organ and basolateral amygdala, loci implicated in mediation of sodium appetite [32]. The proposed rationale for the phenomenon is that the enhanced palatability of sodium in animals previously sodium depleted is an allostatic response, an evolutionary strategy, whereby the past crisis engenders a proactive, preventive strategy of permanently prioritized sodium seeking and increased sodium intake, as a hedge against recurrence [13,15,30,40].
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