A role for D2 but not D1 dopamine receptors in the cross-sensitization between amphetamine and salt appetite

Abstract

A history of sodium depletions has been found to potentiate the psychomotor as well as the rewarding effects of amphetamine, an indirect dopamine agonist. The present experiments were conducted to further define the role of dopamine receptor subtypes in this cross-sensitization effect. Rats with a history of sodium depletions were found to display psychomotor sensitization to a D2 but not a D1 direct agonist. Cross-sensitization between salt appetite and amphetamine was found to be blocked by a D2 but not a D1 antagonist. Together, these results implicate D2 but not D1 receptor function in the cross-sensitization seen after sodium depletions.

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.