Dopamine D3 receptors (DRD3) are implicated in relapse to drugs. The current study investigated the role of DRD3 in cue-induced reinstatement of nicotine-seeking in rats. Rats were trained to lever-press for intravenous infusions of nicotine, associated with the illumination of a cue-light, under a fixed-ratio schedule of reinforcement. Following extinction of the behaviour, where lever pressing had no consequences, reinstatement testing was performed by reintroduction of the cues after systemic or local administration (into discrete brain areas) of the DRD3 selective antagonist SB277011-A. Systemic antagonism of DRD3 significantly attenuated cue-induced reinstatement of nicotine-seeking. The same effect was observed upon infusions of SB277011-A into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens. The current findings implicate DRD3 in cue-induced reinstatement of nicotine, delineate some of the neural substrates underlying this role and support a potential for using selective DRD3 antagonists for the prevention of relapse to smoking.

Dopamine D3 receptors (DRD3) are implicated in relapse to drugs. The current study investigated the role of DRD3 in cue-induced reinstatement of nicotine-seeking in rats. Rats were trained to lever-press for intravenous infusions of nicotine, associated with the illumination of a cue-light, under a fixed-ratio schedule of reinforcement. Following extinction of the behaviour, where lever pressing had no consequences, reinstatement testing was performed by reintroduction of the cues after systemic or local administration (into discrete brain areas) of the DRD3 selective antagonist SB277011-A. Systemic antagonism of DRD3 significantly attenuated cue-induced reinstatement of nicotine-seeking. The same effect was observed upon infusions of SB277011-A into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens. The current findings implicate DRD3 in cue-induced reinstatement of nicotine, delineate some of the neural substrates underlying this role and support a potential for using selective DRD3 antagonists for the prevention of relapse to smoking.

Dopamine D3 receptors (D3Rs) have been implicated in mediating behavioural sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. Neil Richtand proposed a role for D3Rs in the modulation of sensitization by acting as an inhibitor of D1/D2 receptor-mediated behaviours, and several reports suggest D3Rs up-regulate in response to chronic drugs of abuse. In separate experiments, we examined EtOH sensitization in D3R knockout (KO) as well as in D1R and D2R KO mice. We also examined amphetamine sensitization in D3R KOs compared to wild type mice. We challenged C57Bl/6 and DBA/2 mice with a D3R agonist (PD128907) and antagonist (U99194A) to examine how acute and chronic D3R activation and inactivation may affect the induction and expression of EtOH sensitization. We investigated D1/D3R interactions in sensitized and control mice and examined whether EtOH sensitization leads to changes in D3R binding using [125I]-7-OH-PIPAT autoradiography. Results showed that D3R KOs, were resistant to EtOH but not to amphetamine sensitization. Chronic but not acute D3R blockade with U99194A inhibited the induction, whereas acute D3R activation with PD128907 attenuated the expression of EtOH sensitization. In our D1/D3R interaction study we observed that although PD128907 attenuated D1 agonist-induced hyperactivity with SKF81297, this effect was the same in sensitized and control animals, even though sensitized mice were more responsive to PD128907 than controls. This enhanced response, which suggests a functional up-regulation of D3Rs, was not accompanied by changes in D3R binding as indicated by autoradiography, and could mean that functional changes in the D3R associated with EtOH sensitization occur elsewhere than at the level of the membrane-bound receptor. Taken together, these results suggest a modulatory role for the D3R in EtOH but not amphetamine sensitization, where D3R activation attenuates the expression and D3R blockade prevents the induction of EtOH sensitization. These results are important because a better understanding of the role of the D3R in EtOH sensitization may help not only to identify some of the underlying neural mechanisms of sensitization, but also help in the identification of treatment strategies for patients that may be susceptible to alcohol abuse.

Dopamine D3 receptors (D3Rs) have been implicated in mediating behavioural sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. Neil Richtand proposed a role for D3Rs in the modulation of sensitization by acting as an inhibitor of D1/D2 receptor-mediated behaviours, and several reports suggest D3Rs up-regulate in response to chronic drugs of abuse. In separate experiments, we examined EtOH sensitization in D3R knockout (KO) as well as in D1R and D2R KO mice. We also examined amphetamine sensitization in D3R KOs compared to wild type mice. We challenged C57Bl/6 and DBA/2 mice with a D3R agonist (PD128907) and antagonist (U99194A) to examine how acute and chronic D3R activation and inactivation may affect the induction and expression of EtOH sensitization. We investigated D1/D3R interactions in sensitized and control mice and examined whether EtOH sensitization leads to changes in D3R binding using [125I]-7-OH-PIPAT autoradiography. Results showed that D3R KOs, were resistant to EtOH but not to amphetamine sensitization. Chronic but not acute D3R blockade with U99194A inhibited the induction, whereas acute D3R activation with PD128907 attenuated the expression of EtOH sensitization. In our D1/D3R interaction study we observed that although PD128907 attenuated D1 agonist-induced hyperactivity with SKF81297, this effect was the same in sensitized and control animals, even though sensitized mice were more responsive to PD128907 than controls. This enhanced response, which suggests a functional up-regulation of D3Rs, was not accompanied by changes in D3R binding as indicated by autoradiography, and could mean that functional changes in the D3R associated with EtOH sensitization occur elsewhere than at the level of the membrane-bound receptor. Taken together, these results suggest a modulatory role for the D3R in EtOH but not amphetamine sensitization, where D3R activation attenuates the expression and D3R blockade prevents the induction of EtOH sensitization. These results are important because a better understanding of the role of the D3R in EtOH sensitization may help not only to identify some of the underlying neural mechanisms of sensitization, but also help in the identification of treatment strategies for patients that may be susceptible to alcohol abuse.