Modulation of Psychostimulant Induced Sensitization by KOR Ligands Role of the Mesoprefrontal and Mesolimbic DA Systems

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The systemic administration of KOR agonists with cocaine prevents the sensitization that develops to the locomotor activating and conditioned reinforcing effects of this psychostimulant (113-116). KOR agonists also prevent changes in basal and cocaine-evoked DA levels in the NAc that are associated with the induction and long-term expression of sensitization (117,118). As discussed above, quantitative dialysis studies have shown that repeated administration of KOR agonists produces changes in DA neurotransmission that are opposite to that produced by cocaine. Abstinence from repeated cocaine use is associated with a transient increase in DA uptake and release in the NAc core, whereas abstinence from repeated KOR agonist treatment produces decreases in these parameters (84). In animals that received a 5-d cocaine treatment regimen with the selective KOR agonist, U-69593, DA uptake was not different from controls. Thus, repeated activation of KORs during cocaine administration may prevent cocaine-induced alterations in NAc DA neurotransmission by producing changes in basal DA uptake and release that are opposite to those produced by cocaine.

In the mPFC, the early phase of abstinence from cocaine is associated with an elevation of basal DA uptake and a blunted response of mesocortical DA neurons to a subse quent cocaine challenge (34). This reduction in cocaine-evoked levels of DA in mPFC can be an important element in the mechanism of behavioral sensitization, since disinhibition of EAA neurons in mPFC leads to increased excitatory drive on VTA neurons (32). The co-administration of a selective KOR agonist with cocaine prevents these changes in mPFC DA neurotransmission as well as the sensitized behavioral response (34), possibly by decreasing basal DA uptake and increasing drug-evoked DA release in the mPFC. This, in turn, would oppose and normalize changes in mPFC DA neurotransmission induced by repeated cocaine administration.

Interestingly, although KOR agonist treatment, by itself, does not modify basal DA uptake in the mPFC, the co-administration of a KOR agonist with cocaine is effective in preventing increases in DA uptake, which occur in this brain region during early abstinence. Taken together, these data indicate that repeated activation of KOR profoundly affects the function of the DA transporter in terminal areas of the mesolimbic DA system. At present the mechanism by which KOR activation regulates DA transporter function is unknown. However, KORs are collocalized with DA transporters in the NAc (A. Svingos, personal communication), and their activation modulates protein kinase C and other intracellular cascades that has been implicated in both phosphorylation and internalization of the transporter (119-121). Therefore, activation of these cascades and resulting changes in transporter trafficking may underlie the KOR agonist-induced changes in transporter function that occur in the absence of changes in transporter protein expression.

Anatomical mapping studies provide some insights regarding the localization of KOR that mediate the prevention of sensitization produced by systemic agonists. Infusions of a KOR agonist into the NAc suppressed behavioral sensitization to cocaine and prevented cocaine-induced increases in basal and drug-evoked levels in the NAc (Fig. 2), while activation of KOR in the mPFC potentiated the expression of behavioral sensitization and increased cocaine-evoked DA levels (122). The exact mechanisms mediating these opposing effects of KOR activation in the two projections fields of DA neurons are unclear. However, KOR agonists decrease DA release in vitro (75) and in vivo (123,124), and downregulate D2 autoreceptors (125,126). Inhibition of DA release and D2 receptor downregulation in the mPFC would, through D2-mediated changes in GABA release (127) or disinhibition pyramidal cell firing, increase glutamatergic drive on VTA DA neurons, and enhance the behavioral and neurochemical effects produced by the repeated administration of cocaine. In contrast, a decrease in DA release and downregulation of D2 autoreceptors within the NAc would oppose the effects of cocaine and attenuate behavioral sensitization.

Recent studies in our laboratory have shown that the selective blockade of KORs in the NAc with the selective KOR antagonist norbinaltorphinine (nor-BNI), does not affect the development of behavioral sensitization to cocaine, but significantly exacerbates the locomotor response to a subsequent cocaine challenge in cocaine naive animals (Fig. 3; Chefer and Shippenberg, unpublished). This fact is consistent with the hypothesis that NAc KOR plays an important role in inhibiting those processes leading to behavioral sensitization. It is also consistent with the notion that changes in DA neurotransmission in axon terminal fields such as the NAc are critical for the expression of sensitization, while the somatodendritic region of VTA is critical for its initiation (128). These findings are particular noteworthy, because selective and irreversible

Fig. 2. Influence of intra-NAc infusions of a KOR agonist on alterations in behavior and DA dynamics in the NAc that occur during abstinence from repeated cocaine administration. Rats received once-daily injections of cocaine (20 mg/kg, ip) or saline for 5 d. They received bilateral intra-NAc infusions of the KOR agonist U-69593 (1.0 ag) or vehicle on d 3-5 of the 5-d treatment regimen. Behavioral and microdialysis studies were conducted 3 d after the cessation of the various treatments. Upper panel: Sagittal diagram of the rat brain with localization of cannulae and the microdialysis probe in the NAc. Lower panel: (A,D) The behavioral response to a cocaine challenge (20 mg/kg, ip) in rats previously treated with U-69593 (U69) or its vehicle (VEH) in combination with cocaine (COC) or saline (SAL). (B,E) Basal levels of DA in the NAc for each of the pretreatment groups (SAL-VEH, SAL-U69, COC-VEH, COC-U69). (C,F) cocaine-evoked DA levels in the NAc for each of the pretreatment groups. *Significant difference between control and cocaine pretreated animals. "Significant difference between vehicle and U-69593-pretreated animals.

Fig. 2. Influence of intra-NAc infusions of a KOR agonist on alterations in behavior and DA dynamics in the NAc that occur during abstinence from repeated cocaine administration. Rats received once-daily injections of cocaine (20 mg/kg, ip) or saline for 5 d. They received bilateral intra-NAc infusions of the KOR agonist U-69593 (1.0 ag) or vehicle on d 3-5 of the 5-d treatment regimen. Behavioral and microdialysis studies were conducted 3 d after the cessation of the various treatments. Upper panel: Sagittal diagram of the rat brain with localization of cannulae and the microdialysis probe in the NAc. Lower panel: (A,D) The behavioral response to a cocaine challenge (20 mg/kg, ip) in rats previously treated with U-69593 (U69) or its vehicle (VEH) in combination with cocaine (COC) or saline (SAL). (B,E) Basal levels of DA in the NAc for each of the pretreatment groups (SAL-VEH, SAL-U69, COC-VEH, COC-U69). (C,F) cocaine-evoked DA levels in the NAc for each of the pretreatment groups. *Significant difference between control and cocaine pretreated animals. "Significant difference between vehicle and U-69593-pretreated animals.

Fig. 3. Influence of intra-NAc infusion of the selective KOR antagonist, nor-BNI, on basal and cocaine-induced DA levels in the NAc. Animals received bilateral intra-NAc infusions of nor-BNI 24 h prior to the commencement of once-daily injections of saline or cocaine (20 mg/kg, ip) for 5 d. Studies were conducted 3 d later. (A,B) Time course of basal and cocaine-evoked DA neurotransmission for saline (vehicle-saline, nor-BNI-saline) and cocaine (vehicle-cocaine, nor-BNI-cocaine) pretreated animals, respectively. (C,D) Bar graphs of area under the curve (AUC) values expressed as mean ± SEM for saline (vehicle-saline, nor-BNI-saline) and cocaine (vehicle-cocaine, nor-BNI-cocaine)-pretreated animals, respectively. *Significant difference between control and cocaine-pretreated animals.

Fig. 3. Influence of intra-NAc infusion of the selective KOR antagonist, nor-BNI, on basal and cocaine-induced DA levels in the NAc. Animals received bilateral intra-NAc infusions of nor-BNI 24 h prior to the commencement of once-daily injections of saline or cocaine (20 mg/kg, ip) for 5 d. Studies were conducted 3 d later. (A,B) Time course of basal and cocaine-evoked DA neurotransmission for saline (vehicle-saline, nor-BNI-saline) and cocaine (vehicle-cocaine, nor-BNI-cocaine) pretreated animals, respectively. (C,D) Bar graphs of area under the curve (AUC) values expressed as mean ± SEM for saline (vehicle-saline, nor-BNI-saline) and cocaine (vehicle-cocaine, nor-BNI-cocaine)-pretreated animals, respectively. *Significant difference between control and cocaine-pretreated animals.

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