Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours

Abstract

Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction.

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

“…1). In these areas, the peptide and the receptor are largely co-expressed known to interactively control drug-taking and addictive behaviors (Koob, 2013; Sim et al, 2013) suggesting local neurocircuitry modulation. They have been identified in the central nucleus of the amygdala (CeA), the bed nucleus of stria terminalis (BNST), medial prefrontal cortex (mPFC), ventral tegmental area (VTA), lateral hypothalamus (LH), nucleus accumbens (NAcc), and some brain stem areas, including the locus caeruleus and dorsal raphe (Darland, 1998; Neal et al, 1999a,b).…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…Ligands for both D 1 and D 2 have cocaine-like effects when given acutely, and antagonists can block acute cocaine actions (Spealman et al, 1992; Baik, 2013). Activation of D 2 receptors has been shown to blunt cocaine sensitization (Beyer and Steketee, 2002), while D 2 antagonists or receptor knockout generally does not greatly alter acute locomotor activation, sensitization, or CPP (Spyraki et al, 1982; Cabib et al, 1991; Kuribara and Uchihashi, 1993; Mattingly et al, 1994; Cervo and Samanin, 1995; Shippenberg and Heidbreder, 1995; Ushijima et al, 1995; Vanderschuren and Kalivas, 2000; Nazarian et al, 2004; Welter et al, 2007; Sim et al, 2013). Deleting only those D 2 receptors expressed on dopaminergic neurons themselves increases CPP for cocaine (Bello et al, 2011), highlighting the fact that antagonists or global knockout may not have any net effect due to different physiological roles of receptors expressed by different neuronal subtypes.…”

“…It has been shown in several studies that D 2 agonists can induce reinstatement of cocaine seeking behavior (Self et al, 1996; De Vries et al, 1999, 2002; Spealman et al, 1999; Khroyan et al, 2000; Fuchs et al, 2002). Mice lacking D 2 receptors show increased cocaine self-administration (Caine et al, 2002), but reinstatement of seeking induced by stress is attenuated in these mice (Sim et al, 2013). These seemingly conflicting results may be attributable to differences in the neurobiology of drug seeking for different drugs of abuse and different circuitry engaged by various stimuli that produce reinstatement of drug seeking.…”

A NAc for Spinal Adjustments After Cocaine or Stress

“…This suggests that although cocaine and stress both tend to increase spine number or density, they ultimately lead to contrasting functional alterations, which are associated with a redistribution of synaptic strength across a population of D1-MSN spines. These opposing changes in synaptic strength after cocaine versus stress mirror some, but not all, of the psychotropic or stress-induced changes in presynaptic terminal stimulation (7,8) or more indirect synaptic or static measures of the postsynaptic surface (9). Moving forward, it can be hypothesized that this contrasting redistribution of synaptic strength on D1-MSNs after cocaine or stress is a defining characteristic underlying behavioral differences, an idea recently touched on in another paper using the same chronic social defeat stress paradigm (10).…”

“…The authors themselves are careful to point out the caveats in making such conclusions, given that published results vary based on species used, paradigm of stimuli exposure/drug administration, approaches to visualize spine dynamics or estimate synaptic strength, and length of time drug or stress free. The importance of these caveats are exemplified by data that withdrawal from cocaine (3 or 10 days) or morphine (2 weeks) can increase or decrease synaptic strength at D1-MSNs or D2-MSNs, respectively (2,7,8). …”