Behavioral and Molecular Effects of Dopamine D1 Receptor Stimulation during Naloxone-Precipitated Morphine Withdrawal

Abstract

Morphine dependence is characterized by somatic and motivational signs of withdrawal that likely contribute to the maintenance of addictive behavior. The nucleus accumbens (NAc) receives extensive dopaminergic input and is an important substrate for mediating these aversive states. In the NAc, the function of the transcription factor cAMP response element binding protein (CREB) and AMPA glutamate receptor subunit, type 1 (GluR1) can be regulated by dopamine (DA) D 1 receptor-mediated phosphorylation (P-CREB, P-GluR1). However, the roles of D 1 receptors, CREB, and GluR1 in morphine dependence are not well understood. Here, we show that somatic signs of naloxone-precipitated withdrawal were associated with increased P-CREB, but not P-GluR1, in the NAc of morphinedependent rats. The D 1 receptor agonist chloro-APB hydrobromide (SKF 82958) was rewarding in morphine-dependent rats and blocked naloxone-induced place aversions and somatic signs of withdrawal. Surprisingly, SKF 82958 increased P-GluR1, but not P-CREB, in the NAc, and naloxone reduced SKF 82958-mediated P-GluR1 induction specifically in morphine-dependent rats. Together, these results confirm that aversive treatments can increase CREB function in the NAc. Furthermore, they suggest a dependence-associated shift in the molecular mechanisms that regulate the consequences of D 1 receptor stimulation, favoring activation of GluR1 rather than CREB. These data raise the possibility that the rewarding effects of SKF 82958 in morphine-dependent rats involve increased P-GluR1 in the NAc, although the involvement of other brain regions cannot be ruled out. Regardless, these findings suggest for the first time that D 1 agonists might be useful for the treatment of withdrawal symptoms that contribute to the maintenance of opiate addiction in humans.Key words: nucleus accumbens; CREB; GluR1; AMPA; place conditioning; SKF 82958 IntroductionOpiate withdrawal causes somatic abstinence signs as well as a motivational syndrome characterized by dysphoria and depression (Koob and Le Moal, 1997;De Vries and Shippenberg, 2002) in humans. These negative affective states are thought to contribute to addictive behaviors (Koob and Le Moal, 1997;Markou et al., 1998). The nucleus accumbens (NAc), which receives extensive dopaminergic input, plays a key role in opiate reward (Wise, 1989) as well as the motivational and somatic signs of opiate withdrawal (Koob et al., 1992;Harris and Aston-Jones, 1994). The opioid receptor antagonist naloxone precipitates physical withdrawal signs in morphine-dependent rats and produces behaviors, such as conditioned place aversions, that reflect aversive states mediated within the NAc (Stinus et al., 1990).Acute morphine decreases formation of cAMP (Childers, 1991), whereas chronic morphine causes super-sensitivity of cAMP pathways in areas including the NAc (Nestler and Aghajanian, 1997). Precipitated opiate withdrawal unmasks upregulated cAMP pathways, which likely contribute to aversive states. Hypothetically, activation of dopamine (DA) D 1 rece...

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

“…Previous work from our laboratory and others (Harris and Aston-Jones, 1994;Chartoff et al, 2006;Chartoff et al, 2009;Radke et al, 2011) has demonstrated that dopamine receptor agonists attenuate withdrawal behaviors. The current experiments used two subtype-specific dopamine receptor agonists, SKF82958 and quinpirole, to examine the individual contributions of D1-and D2-like dopamine receptors, respectively, to this effect.…”

“…Decreased dopaminergic activity has been shown to contribute to the production of negative emotional states (Stinus et al, 1990;Liu et al, 2008;Nestler and Carlezon, 2006) and manipulation of dopaminergic signaling attenuates conditioned place aversion (Bechara et al, 1995;Laviolette et al, 2002;Chartoff et al, 2006;but see Caillé et al, 2003) and other signs of opiate withdrawal (Harris and Aston-Jones, 1994;Rodríguez-Arias et al, 1999). Importantly, the initial increase in NAc dopamine release following acute exposure to 10 mg/kg of morphine would have largely dissipated at the time at which spontaneous withdrawal-potentiated startle is observed (Di Chiara and Imperato, 1988;Rothwell et al, 2009).…”

“…Treatments that attenuate withdrawal behaviors have been shown to reverse this decrease in dopaminergic signaling, while treatments that exacerbate withdrawal potentiate it (Spanagel et al, 1994;Georges and Aston-Jones, 2003). Finally, studies examining the role dopamine plays in opiate withdrawal behaviors (Bechara et al, 1995;Laviolette et al, 2002;Chartoff et al, 2006Chartoff et al, , 2009Radke et al, 2011) have found that dopaminergic signaling contributes to increased aversion, aggression, and anxiety during withdrawal (but see, Caillé et al, 2003).…”

Orexin Mediates the Expression of Precipitated Morphine Withdrawal and Concurrent Activation of the Nucleus Accumbens Shell

“…While acute morphine administration results in an increase in accumbal extracellular DA, microdialysis studies have shown that in response to chronic morphine, DA outflow is normal until withdrawal where there is a reduction (8)(9)(10). Systemic administration of the DA agonist SKF 82958 reduces somatic signs of morphine withdrawal while increasing phosphorylation of GluR1 in the Acb of morphine dependent rats treated with naloxone (18). Furthermore, in response to morphine withdrawal, there is a reduction in spine density that is specific to the dendrites of medium spiny neurons located in the AcbSh.…”

“…For instance, direct administration of opioid antagonists in the amygdala of morphine-dependent animals is associated with moderate somatic withdrawal (13). Furthermore, systemic DA agonist administration attenuates both conditioned place aversions and somatic withdrawal symptoms in morphinedependent animals treated with naloxone, while increasing phosphorylation of GluR1 in the Acb (18), indirectly implicating the Acb in both withdrawal components. Altogether, these findings suggest a role for limbic structures in both somatic and motivational withdrawal.…”