The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement.
"Dopamine D1 receptors, when activated, can modulate cellular activity through the dopamine‐and cAMP‐regulated phosphoprotein (DARPP‐32) via phosphorylation of Threonine‐34 (pDARPP‐32) (Hemmings et al., '84; Ouimet et al., '84; Fienberg et al., '98). Immunochemistry studies involving pDARPP‐32 in the mesolimbic nuclei focus on dopamine activity under drug and alcohol manipulation (Maldve et al., 2002; Nairn et al., 2004; Zachariou et al., 2005). In both male and female rodents dopaminoceptive hypothalamic nuclei show pDARPP‐32 differences during steroid hormone treatment and sexual behavior (Mani et al., 2000; Auger et al., 2001 McHenry et al., 2012) of particular interest is that D1 dopamine antagonist treatment reduces copulatory behavior in male rats (McHenry et al., 2012). "
"As a consequence, the activation of D1 receptors increases the phosphorylation of NMDA receptors through DARPP-32 pathway. It was demonstrated that the phosphorylation of the NR1 subunit of NMDA receptors strongly decreases the acute ethanol inhibition of NMDA receptors . However, after a long-term withdrawal from chronic ethanol treatment, diverse neuroadaptations in NMDA receptors can be observed. "
[Show abstract][Hide abstract] ABSTRACT: In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day) or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as "sensitized" and the 33% with the lowest levels as "non-sensitized". The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of locomotor sensitization to ethanol.
PLoS ONE 06/2014; 9(6):e98296. DOI:10.1371/journal.pone.0098296 · 3.23 Impact Factor
"In the nAcb, expression of NMDA receptor-dependent long-term potentiation has been demonstrated (,,) and plasticity within nAcb is thought to mediate instrumental learning processes and many aspects of drug addiction in which coincident activation of NMDA and dopamine D1 receptors is required (,,,). The nAcb may thus constitute a locus where NMDA receptors promote drug reinforcement . In addition, the nAcb appears to be involved in a number of functions such as motivation, attention and reward (,) which are modulated by the mesolimbic dopaminergic system . "
[Show abstract][Hide abstract] ABSTRACT: Nucleus accumbens (nAcb), a major site of action of drugs of abuse and dopamine (DA) signalling in MSNs (medium spiny neurons), is critically involved in mediating behavioural responses of drug addiction. Most studies have evaluated the effects of DA on MSN firing properties but thus far, the effects of DA on a cellular circuit involving glutamatergic afferents to the nAcb have remained rather elusive. In this study we attempted to characterize the effects of dopamine (DA) on evoked glutamatergic excitatory postsynaptic currents (EPSCs) in nAcb medium spiny (MS) neurons in 1 to 21 day-old rat pups. The EPSCs evoked by local nAcb stimuli displayed both AMPA/KA and NMDA receptor-mediated components. The addition of DA to the superfusing medium produced a marked decrease of both components of the EPSCs that did not change during the postnatal period studied. Pharmacologically isolated AMPA/KA receptor-mediated response was inhibited on average by 40% whereas the isolated NMDA receptor-mediated EPSC was decreased by 90%. The effect of DA on evoked EPSCs were mimicked by the D1-like receptor agonist SKF 38393 and antagonized by the D1-like receptor antagonist SCH 23390 whereas D2-like receptor agonist or antagonist respectively failed to mimic or to block the action of DA. DA did not change the membrane input conductance of MS neurons or the characteristics of EPSCs produced by the local administration of glutamate in the presence of tetrodotoxin. In contrast, DA altered the paired-pulse ratio of evoked EPSCs. The present results show that the activation D1-like dopaminergic receptors modulate glutamatergic neurotransmission by preferentially inhibiting NMDA receptor-mediated EPSC through presynaptic mechanisms.
PLoS ONE 05/2014; 9(5):e86970. DOI:10.1371/journal.pone.0086970 · 3.23 Impact Factor
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