Kappa-Opioid Agonist U69593 Potentiates Locomotor Sensitization to the D2/D3 Agonist Quinpirole: Pre- and Postsynaptic Mechanisms

Abstract

To assess whether the development and expression of behavioral sensitization to the dopamine D2/D3 agonist quinpirole (QNP) is influenced by coadministration of the kappa opioid receptor agonist U69593, rats received every 3-4 days for a total of 10 treatments an injection of U69593 (0.3 mg/kg) together with an injection of either a postsynaptic (0.5 mg/kg) or a presynaptic dose of QNP (0.05 mg/ kg); locomotor activity was measured after each treatment. Control rats were injected as appropriate with QNP, U69593, and vehicle/ saline. Following chronic treatment, dose-response profiles to QNP were obtained to assess the expression of sensitization; the effect of U69593 on locomotor activity in animals already sensitized to QNP was also assessed. Results showed that cotreatment of U69593 with a postsynaptic dose of QNP doubled the speed and magnitude of sensitization to QNP, while U69593 cotreatment with a presynaptic dose of QNP switched the effects of QNP from locomotor depression to locomotor sensitization. However, U69593 cotreatment with a presynaptic dose of QNP changed a different set of measures of sensitization than did cotreatment with a postsynaptic dose of the dopamine agonist. Together, findings suggest that sensitization to QNP is not a unitary phenomenon but has components that are relatively independent, mediated by distinct pre-and postsynaptic mechanisms and modulated by kappa receptor activity.

Immunolocalization of kappa opioid receptors in the axon initial segment of a group of embryonic mesencephalic dopamine neurons

“…Accordingly, we found high labeling of KOR in fibers similar to axons. As we previously reported ( Escobar et al, 2017 ), we found that KOR was also in MSN colocalizing with D2R, giving an anatomical substrate for the potentiated locomotion found in rats after the repeated co-activation of KOR and D2R ( Perreault et al, 2006 ).…”

Immunolocalization of kappa opioid receptors in the axon initial segment of a group of embryonic mesencephalic dopamine neurons

“…Accordingly, we found high labeling of KOR in fibers similar to axons. As we previously reported ( Escobar et al, 2017 ), we found that KOR was also in MSN colocalizing with D2R, giving an anatomical substrate for the potentiated locomotion found in rats after the repeated co-activation of KOR and D2R ( Perreault et al, 2006 ).…”

Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder

“…Figure 1 shows that the distance travelled by quinpirole-treated rats increased as a function of repeated quinpirole injections, confirming the presence of the expected locomotor Dvorkin -12 sensitization to quinpirole [16,20]. As shown in Table 1, the fitted asymmetric sigmoid curve suggests that the half-maximum response was reached after 4.1 (+ 0.3) quinpirole injections, that the maximum response was more than 6-fold of the acute response, and that the slope of the curve was 3.4 (+ 0.6), values that are within the range of those found in previous studies [14,16,20].…”

Drug withdrawal conceptualized as a stressor

“…Acute administration of salvA causes long-lasting (~2 h) decreases in dopamine levels in the extracellular NAc (Carlezon et al ., 2006; Ebner et al ., 2010), which likely initiates compensatory changes in dopamine signaling (Acri et al ., 2001; Chefer et al ., 2005). Consistent with this, repeated treatment of rats with the KOR agonist U69593 potentiates locomotor sensitization to a D2 receptor agonist (Perreault et al ., 2005), and the D2 receptor number is significantly increased after withdrawal from repeated U69593 administration (Izenwasser et al ., 1998). We have shown that prior, repeated salvA treatment potentiates the locomotor response to a D1 receptor agonist (Chartoff et al ., 2008).…”

Immunolocalization of kappa opioid receptors in the axon initial segment of a group of embryonic mesencephalic dopamine neurons

“…Accordingly, we found high labeling of KOR in fibers similar to axons. As we previously reported ( Escobar et al, 2017 ), we found that KOR was also in MSN colocalizing with D2R, giving an anatomical substrate for the potentiated locomotion found in rats after the repeated co-activation of KOR and D2R ( Perreault et al, 2006 ).…”

Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder

“…Figure 1 shows that the distance travelled by quinpirole-treated rats increased as a function of repeated quinpirole injections, confirming the presence of the expected locomotor Dvorkin -12 sensitization to quinpirole [16,20]. As shown in Table 1, the fitted asymmetric sigmoid curve suggests that the half-maximum response was reached after 4.1 (+ 0.3) quinpirole injections, that the maximum response was more than 6-fold of the acute response, and that the slope of the curve was 3.4 (+ 0.6), values that are within the range of those found in previous studies [14,16,20].…”

Drug withdrawal conceptualized as a stressor

“…Acute administration of salvA causes long-lasting (~2 h) decreases in dopamine levels in the extracellular NAc (Carlezon et al ., 2006; Ebner et al ., 2010), which likely initiates compensatory changes in dopamine signaling (Acri et al ., 2001; Chefer et al ., 2005). Consistent with this, repeated treatment of rats with the KOR agonist U69593 potentiates locomotor sensitization to a D2 receptor agonist (Perreault et al ., 2005), and the D2 receptor number is significantly increased after withdrawal from repeated U69593 administration (Izenwasser et al ., 1998). We have shown that prior, repeated salvA treatment potentiates the locomotor response to a D1 receptor agonist (Chartoff et al ., 2008).…”

Immunolocalization of kappa opioid receptors in the axon initial segment of a group of embryonic mesencephalic dopamine neurons

“…Accordingly, we found high labeling of KOR in fibers similar to axons. As we previously reported ( Escobar et al, 2017 ), we found that KOR was also in MSN colocalizing with D2R, giving an anatomical substrate for the potentiated locomotion found in rats after the repeated co-activation of KOR and D2R ( Perreault et al, 2006 ).…”

Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive-compulsive disorder

“…Figure 1 shows that the distance travelled by quinpirole-treated rats increased as a function of repeated quinpirole injections, confirming the presence of the expected locomotor Dvorkin -12 sensitization to quinpirole [16,20]. As shown in Table 1, the fitted asymmetric sigmoid curve suggests that the half-maximum response was reached after 4.1 (+ 0.3) quinpirole injections, that the maximum response was more than 6-fold of the acute response, and that the slope of the curve was 3.4 (+ 0.6), values that are within the range of those found in previous studies [14,16,20].…”

Drug withdrawal conceptualized as a stressor

“…Acute administration of salvA causes long-lasting (~2 h) decreases in dopamine levels in the extracellular NAc (Carlezon et al ., 2006; Ebner et al ., 2010), which likely initiates compensatory changes in dopamine signaling (Acri et al ., 2001; Chefer et al ., 2005). Consistent with this, repeated treatment of rats with the KOR agonist U69593 potentiates locomotor sensitization to a D2 receptor agonist (Perreault et al ., 2005), and the D2 receptor number is significantly increased after withdrawal from repeated U69593 administration (Izenwasser et al ., 1998). We have shown that prior, repeated salvA treatment potentiates the locomotor response to a D1 receptor agonist (Chartoff et al ., 2008).…”