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16 férvier 2007
J Pharmacol Exp Ther
2007;320(3):1216-1223
Insulin replacement restores the behavioral effects
of quinpirole and raclopride
in streptozotocin-treated rat
Sevak RJ, Koek W, Galli A, France CP 
The University of Texas Health Science Center at San Antonio.USA
 
Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning. Serafine KM

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Streptozotocin (STZ)-induced diabetes can modulate dopamine (DA) neurotransmission and, thereby, modify the behavioral effects of drugs acting on DA systems. Insulin replacement, and in some conditions repeated treatment with amphetamine, can partially restore sensitivity of STZ-treated rats to dopaminergic drugs. The present study sought to characterize the role of insulin and amphetamine in modulating the behavioral effects of drugs that selectively act on D2/D3 receptors. In control rats, quinpirole and quinelorane produced yawning while raclopride and GHB produced catalepsy. Raclopride antagonized quinpirole- and quinelorane-induced yawning with similar potency. STZ treatment increased blood glucose concentration, decreased body weight, and markedly reduced sensitivity to quinpirole-induced yawning, quinelorane-induced yawning, as well as to raclopride-induced catalepsy, while enhancing sensitivity to GHB-induced catalepsy. Repeated treatment with amphetamine partially restored sensitivity of STZ-treated rats to amphetamine-stimulated locomotion and also produced CPP, without affecting blood glucose and body weight changes. However, amphetamine treatment did not restore sensitivity to the behavioral effects of quinpirole, raclopride or GHB, suggesting differential regulation of DAT activity and sensitivity of D2 receptors in hypoinsulinemic rats. Insulin replacement in STZ-treated rats normalized blood glucose and body weight changes and fully restored sensitivity to quinpirole-induced yawning as well as to raclopride-induced catalepsy, while reducing sensitivity to GHB-induced catalepsy. Overall, these data indicate that changes in insulin status markedly affect sensitivity to the behavioral effects of dopaminergic drugs. The results underscore the importance of insulin in modulating DA neurotransmission; these effects might be especially relevant to understanding the co-morbidity of eating disorders and substance abuse.
 
INTRODUCTION
 
Several drugs of abuse (e.g., amphetamine, cocaine) and some drugs that are used in the clinic (e.g., haloperidol, bromocriptine) are believed to act predominantly on dopamine (DA) systems. Activity at DA D2 receptors can modulate DA neurotransmission by affecting DA synthesis, release, uptake, or neuronal activity (Zahniser and Doolen, 2001). Importantly, insulin has been shown to regulate DA signaling in the brain (e.g., Figlewicz et al., 1994; 1996). Insulin can cross the blood-brain barrier and act on receptors (i.e., insulin receptors, insulin-like growth factor-1 receptors) that are densely concentrated in the basal ganglia, a region richly expressing D2/D3 receptors and DA transporters (DAT) (Larson and Ariano 1995; Ciliax et al., 1995; Schulingkamp et al., 2000; Figlewicz et al., 2003). The close proximity of insulin and DA systems appears to have functional consequences. For example, rats with decreased circulating insulin showed decreased coupling of DA D2 receptors to Gi/o proteins (Abbracchio et al., 1989) and reduced DAT activity (Owens et al., 2005) in the striatum. Food deprived (i.e., hypoinsulinemic) rats also showed reduced DAT mRNA in the ventral tegmental area/substantia nigra and decreased DAT activity in the striatum (Patterson et al., 1998). Moreover, drug (alloxan or streptozotocin [STZ])-induced hypoinsulinemia can alter (increase [Lozovsky et al., 1981; Trulson and Himmel, 1983; Serri et al., 1985] or decrease [Rowland et al., 1985]) the density of striatal D2 receptors and impair D2 receptor-coupled signal-transduction (Abbracchio et al., 1989). Finally, hypoinsulinemic rats showed decreased synthesis (Kono and Takada, 1994), uptake (Owens et al., 2005), and turnover (Kwok and Juorio, 1986; Lim et al., 1994) of DA in the striatum. Thus, it is clear that changes in plasma insulin and glucose can have profound effects on DA neurotransmission.
 
Changes in insulin status also can modify the behavioral effects of dopaminergic drugs. For example, STZ-treated rats were less sensitive to the effects of apomorphine (a direct-acting DA agonist) and amphetamine (an indirect-acting DA agonist) on locomotor activity and also to the positive reinforcing effects of amphetamine (Marshall, 1978; Rowland et al., 1985; Galici et al., 2003). Moreover, the cataleptic effects of the DA receptor antagonist haloperidol were markedly reduced in STZ-treated rats (Sevak et al., 2005). Food restriction, a condition that can alter insulin and glucose status, can enhance oral as well as i.v. drug intake (Carroll et al., 1981; Carroll and Stotz, 1983) and potentiate amphetamine-induced hyperactivity (Campbell and Fibiger, 1971). Thus, changes in plasma insulin that modulate DA neurotransmission can also modify the behavioral effects of drugs acting on DA systems.
 
Despite a growing literature on the role of insulin signaling in regulating DA neurotransmission, little is known regarding the effects of altered insulin status on the behavioral effects of direct-acting DA D2/D3 receptor agonists and antagonists. It is well established that direct-acting DA receptor agonists can produce yawning (Kurashima et al., 1995; Collins et al., 2005) and direct-acting DA receptor antagonists can produce catalepsy (Kanes et al., 1993; Sevak et al., 2004). These two behavioral endpoints were used to examine changes in sensitivity to the behavioral actions of direct-acting DA drugs and also in drug combination studies with raclopride to confirm the role of DA receptors in the yawning produced by quinpirole and quinelorane. The pharmacological selectivity of changes in sensitivity to the behavioral effects of direct-acting DA drugs was examined by comparing those effects to the effects obtained with an indirect-acting DA agonist (amphetamine on locomotion and conditioned place preference) and to the effects obtained with a drug (£^-hydroxybutyric acid [GHB]) that exerts cataleptic effects through a non-DA (GABAB receptors) mechanism (Carter et al., 2005). It was hypothesized that decreased circulating insulin (after STZ) would decrease sensitivity to the behavioral effects of drugs acting directly on DA receptors and that insulin replacement would restore sensitivity to those drugs. DAT activity can affect DA D2 receptor function (Jones et al., 1999). For example, activation of D2/D3 receptors by quinpirole can reduce DA synthesis, release and neuronal firing, and mice lacking DAT are less sensitive to the effects of quinpirole (Jones et al., 1999). Because repeated treatment with amphetamine can normalize DAT activity in STZ-treated rats (Owens et al., 2005), the present study also examined whether repeated treatment with amphetamine restores sensitivity of STZ-treated rats to the behavioral effects of drugs acting directly at DA receptors.
 
DISCUSSION
Data from this study show that changes in circulating insulin and glucose can markedlyimpact the behavioral effects of drugs acting on DA receptors. The data also suggest that activity of DAT and D2/D3 receptors are differentially affected by hypoinsulinemia(hyperglycemia) in rats, because amphetamine treatment that restored DAT activity in STZtreated rats (Owens et al., 2005) did not restore sensitivity to the behavioral effects of drugs acting on D2/D3 receptors. Quinpirole and quinelorane are agonists at D2-like (i.e., D2, D3, and D4) receptors, and each agonist shows similar affinity for D2 and D3 receptors (Kebabian et al., 1997).
 
In agreement with others (Kurashima et al., 1995; Collins et al., 2005), the present results show that quinpirole and quinelorane produced yawning, with dose-response curves being inverted Ushaped. Collins et al. (2005) suggested that the biphasic nature of dose-response curves for quinpirole and quinelorane involve two distinct DA receptor mechanisms: D3 receptors mediating the emergence of yawning (i.e., the ascending portion of the dose-response curve) and D2 receptors mediating the disappearance of yawning (i.e., the descending portion of the doseresponse curve). Results of the current study showed that raclopride shifted both the ascending and the descending limbs of the quinpirole and quinelorane dose-response curves to the right in a parallel manner. Moreover, the Schild regressions for the ascending and descending portions of the dose-response curves for quinpirole and quinelorane could be fitted adequately with a single line with a common slope and a common pA2 value, indicating that raclopride antagonized the effects of quinpirole and quinelorane with similar potency, consistent with the involvement of the same D2/D3 receptors in their effects.
 
Increased blood glucose concentration and decreased body weight in STZ-treated rats confirm that STZ eliminates insulin-secreting pancreatic beta-islet cells (Galici et al., 2003), resulting in hypoinsulinemia (Carr 1996). An important finding of this study is that STZ decreased quinpirole-and quinelorane-induced yawning as well as raclopride-induced catalepsy. Reduced sensitivity of STZ-treated rats to the behavioral effects of drugs acting on D2/D3 receptors parallels changes that can occur in DA receptors (e.g., receptor density and signaling)in hypoinsulinemic rats (Lozovsky et al., 1981, Rowland et al., 1985; Abbracchio et al., 1989).
 
To the extent that activity at different DA receptors accounts for the ascending (D3) and descending (D2) portions of the dose-response curve for yawning (Collins et al., 2005), the near absence of yawning observed in STZ-treated rats could indicate a decreased sensitivity of D3 receptors to quinpirole and quinelorane, an increased sensitivity of D2 receptors to quinpirole and quinelorane, or to changes in sensitivity at both receptor types. What ever the underlyingmechanism(s), insulin replacement restored quinpirole-induced yawning, raclopride-induced catalepsy, blood glucose concentration, and body weight in STZ-treated rats. Thus, attenuation of the behavioral effects of drugs acting on D2/D3 receptors in STZ treated rats appears to be a confirmation of marked changes in dopaminergic systems that can occur under conditions where insulin and glucose concentrations are perturbed. The pharmacologic selectivity of decreased sensitivity to the behavioral effects of drugs acting on D2/D3 receptors was evident by the finding that STZ-treated rats were more sensitive to the cataleptic effect of GHB, a drug that does not act at DA receptors. The mechanism by which GHB induces catalepsy is not known, although emerging evidence suggests that this effect involves agonist activity at GABAB receptors (e.g., Carter et al., 2005). Evidence that different mechanisms contribute to the cataleptic effects of raclopride and GHB was provided by an earlier study in which the same dose of the N-methyl-D-aspartate (glutamate) receptor antagonist dizocilpine attenuated catalepsy produced by the D2 receptor antagonist haloperidol, while enhancing catalepsy produced by GHB (Sevak et al., 2004). Thus, changes in insulin and glucose status do not affect all drugs in a similar manner, although it remains to be determined whether the effects of drugs acting on other receptors and neurochemical systems (e.g., other monoamines) also change as a function of insulin and glucose status. Repeated treatment with amphetamine can normalize DAT activity in STZ-treated rats (Owens et al., 2005) and under some conditions DAT activity co-varies with changes in D2 receptor function (Jones et al., 1999; Fauchey et al., 2000). While amphetamine increased locomotion and produced CPP in control and in STZ-treated rats, the same treatment that restored DAT activity (Owens et al., 2005) failed to restore sensitivity to quinpirole-induced yawning or raclopride-induced catalepsy in STZ-treated rats. That amphetamine treatment did not restore sensitivity of STZ-treated rats to drugs acting directly at DA receptors indicates that DAT activity and sensitivity of DA receptors are differentially affected by altered insulin status and by amphetamine treatment.
 
In summary, this study shows that changes in insulin and glucose status affect sensitivity of rats to the behavioral effects of drugs acting directly at D2/D3 receptors. It remains to be seen whether these changes reflect altered sensitivity at D2, D3 or both D2 and D3 receptors. STZ treatment can also affect norepinephrine neurotransmission (e.g., Figlewicz et al., 1996), and amphetamine can modulate norepinephrine uptake (e.g., Kuczenski and Segal, 2001); thus, mechanisms in addition to DA might underlie these differences in sensitivity to amphetamine and other drugs observed in STZ-treated rats. Ongoing studies are evaluating whether less dramatic changes in glucose and insulin status (e.g., produced by modest food restriction) also 24 modify sensitivity to indirect-acting and direct-acting DA receptoragonists. Several reports indicate that eating disorders, where plasma insulin levels markedly fluctuate, show high comorbidity with substance abuse (Holderness et al., 1994; Krahn 1991). Because dopaminergic mechanisms are presumed to account for the positive reinforcing effects of many drugs of abuse and insulin can regulate DA neurotransmission, understanding the functional relationships among insulin status, glucose status, and the behavioral effects of dopaminergic drugs could facilitate the development of treatments for substance abuse and eatingdisorders.
 
-Sevak RJ, Koek W, Galli A, France CP Insulin replacement restores the behavioral effects of quinpirole and raclopride in streptozotocin-treated rats. J Pharmacol Exp Ther. 2007;320(3):1216-1223