Anatomically dissociable effects of dopamine D1 receptor agonists on reward and relief of withdrawal in morphine-dependent rats

Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, MRC 218, 115 Mill Street, Belmont, MA 02478, USA.
Psychopharmacology (Impact Factor: 3.88). 02/2009; 204(2):227-39. DOI: 10.1007/s00213-008-1454-7
Source: PubMed


Chronic opiate administration induces neuroadaptations within the nucleus accumbens (NAc) and ventral tegmental area (VTA) that can contribute to dependence. We have shown that morphine dependence shifts the behavioral consequences of D1 dopamine (DA) receptor signaling: systemic administration of a D1 receptor agonist is rewarding and blocks naloxone-precipitated withdrawal signs in morphine-dependent rats, but has minimal effects in nondependent rats. These data suggest that D1 receptors acquire the ability to regulate reward and withdrawal in morphine-dependent rats. The brain regions involved in these effects are not known.
Studies were designed to test the hypothesis that the nucleus accumbens shell (NASh) and the ventral tegmental area (VTA) are important sites for mediating the behavioral effects of D1 receptor activation in morphine-dependent rats.
The effects of microinjecting the D1 receptor agonist SKF 82958 into the NASh or the VTA on place conditioning and somatic withdrawal signs were studied in morphine-dependent and nondependent rats.
Intra-NASh microinjection of SKF 82958 (1 microg/side) established conditioned place preferences in morphine-dependent but not nondependent rats, but had no effect on naloxone-induced place aversions or somatic withdrawal signs. Intra-VTA microinjection of SKF 82958 (2 microg) did not establish place preferences under any conditions, but blocked naloxone-induced place aversions without effects on somatic withdrawal signs.
There is an anatomical dissociation between D1 receptor-mediated reward and relief of withdrawal in morphine-dependent rats. When combined, the individual effects of D1 receptor activation in the NASh and VTA on the affective signs of precipitated morphine withdrawal resemble those seen with systemic administration.

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    • "Taken together, increased VTA-NAc DA neuronal activity may contribute to the morphine challenge-induced CPP behavior during withdrawal. Increased stimulation of D 1 receptors in the NAc contributes to the enhanced strength in response to morphine reward (Chartoff et al. 2009) and counteracts negative affective states during morphine withdrawal (Chartoff et al. 2003), moreover D 1 receptor antagonism blocked the potentiation of morphine reward (Koo et al. 2012). The behavioral transition pattern observed in the present study was paralleled by a switch in mesoaccumbens DA signaling, indicating that mesoaccumbens DA signaling may underlie the behavioral transition in the rewarding properties of morphine from early to prolonged withdrawal. "
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    ABSTRACT: Although the firing activity of dopamine (DA) neurons in the ventral tegmental area (VTA) and the behavioral response to morphine rewarding properties alter as opiate withdrawal, little is known about the dynamic changes in DA signal pathway from the VTA to the nucleus accumbens (NAc) during prolonged withdrawal, and whether the changes are indicative of vulnerability to relapse of drug abuse. Here we report that morphine spontaneously withdrawn (SW) rats are incapable of responding to small dose of morphine-induced conditioned place preference (CPP) from 24h-SW to 30d-SW, but recover response at 45d-SW. Interestingly, mesoaccumbens DA signaling, including the firing of DA neurons in the VTA, contents of DA and its metabolic ratio, and the membrane level of dopamine D1 receptor in the NAc elicited by morphine challenge, display a similar pattern of time-dependent changes during morphine withdrawal. Moreover, blockade of D1 receptor abolishes this behavioral transition. In addition, a strong correlation was found between % change in CPP score and membrane D1 receptor level induced by morphine challenge. These results indicate a time-dependent behavioral switch from tolerance to sensitization during the prolonged withdrawal, which could offer a window for therapeutic intervention via manipulations of D1 receptors.
    Brain Structure and Function 06/2013; 219(5). DOI:10.1007/s00429-013-0599-2 · 5.62 Impact Factor
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    • "The timing of the withdrawal-potentiated startle effect following morphine also coincides with the decrease in drug levels in the brain (Barjavel et al, 1995; Hipps et al, 1976). 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. "
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    ABSTRACT: A number of lines of evidence suggest that negative emotional symptoms of withdrawal involve reduced activity in the mesolimbic dopamine system. This study examined the contribution of dopaminergic signaling in structures downstream of the ventral tegmental area to withdrawal from acute morphine exposure, measured as potentiation of the acoustic startle reflex. Systemic administration of the general dopamine receptor agonist apomorphine or a cocktail of the D1-like receptor agonist SKF82958 and the D2-like receptor agonist quinpirole attenuated potentiated startle during morphine withdrawal. This effect was replicated by apomorphine infusion into the nucleus accumbens shell. Finally, apomorphine injection was shown to relieve startle potentiation during nicotine withdrawal and conditioned place aversion to morphine withdrawal. These results suggest that transient activation of the ventral tegmental area mesolimbic dopamine system triggers the expression of anxiety and aversion during withdrawal from multiple classes of abused drugs.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2012; 37(11):2405-15. DOI:10.1038/npp.2012.97 · 7.05 Impact Factor
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    • "Finally, DA system plays a critical role in drug craving and relapse, conditions that occur with dependence and withdrawal. Administration of D1 and D2 receptors agonists attenuated somatic withdrawal signs [23–25]. Therefore B. arborea extract might attenuate morphine dependence by acting directly on the mesocorticolimbic dopaminergic pathway, since it has been demonstrated the affinity of the extract for D1 and D2 receptors [5]. "
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    ABSTRACT: The aim of the present study was to investigate, in vivo, the effect of a Brugmansia arborea extract (BRU), chromatographic fractions (FA and FNA), and isolated alkaloids on the expression and the acquisition of morphine tolerance and dependence. Substances were acutely (for expression) or repeatedly (for acquisition) administered in mice treated with morphine twice daily for 5 or 6 days, in order to make them tolerant or dependent. Morphine tolerance was assessed using the tail-flick test at 1st and 5th days. Morphine dependence was evaluated through the manifestation of withdrawal symptoms induced by naloxone injection at 6th day. Results showed that BRU significantly reduced the expression of morphine tolerance, while it was ineffective to modulate its acquisition. Chromatographic fractions and pure alkaloids failed to reduce morphine tolerance. Conversely BRU, FA, and pure alkaloids administrations significantly attenuated both development and expression of morphine dependence. These data suggest that Brugmansia arborea Lagerh might have human therapeutic potential for treatment of opioid addiction.
    Evidence-based Complementary and Alternative Medicine 02/2012; 2012(1):741925. DOI:10.1155/2012/741925 · 1.88 Impact Factor
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