Distinct roles of dopamine D3 receptors in modulating methamphetamine‐induced behavioral sensitization and ultrastructural plasticity in the shell of the nucleus accumbens

Abstract

Persistent changes in behavior and psychological function that occur as a consequence of exposure to drugs of abuse are thought to be mediated by the structural plasticity of specific neural circuits such as the brain’s dopamine (DA) system. Changes in dendritic morphology in the nucleus accumbens (NAc) accompany druginduced enduring behavioral and molecular changes, yet ultrastructural changes in synapses following repeated exposure to drugs have not been well studied. The current study examines the role of DA D3 receptors in modulating locomotor activity induced by both acute and repeated methamphetamine (METH) administration and accompanying ultrastructural plasticity in the shell of NAc in mice. We found that D3 receptor mutant (D3−/−) mice exhibited attenuated acute locomotor responses as well as the development of behavioral sensitization to METH compared with wild-type mice. In the absence of obvious neurotoxic effects, METH induced similar increases in synaptic density in the shell of NAc in both wild-type and D3−/− mice. These results suggest that D3 receptors modulate locomotor responses to both acute and repeated METH treatment. In contrast, the D3 receptor is not obviously involved in modulating baseline or METH-induced ultrastructural changes in the NAc shell.

A selective D3 receptor antagonist YQA14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice

“…However, acute injection of YQA14 prior to METH administration significantly inhibited METHinduced hyperactivity, suggesting a reduction in METH reward and psychomotor-stimulation. This is consistent with the significantly attenuated acute locomotor responses observed following administration of METH in D 3 R −/− mice compared with the effects observed in wild-type mice [30] . These results are also consistent with the ability of YQA14 and other D 3 R antagonists, such as SB-277011A, NGB2904, and PG-01037, to significantly inhibit METH or cocaine selfadministration [12,13,18,21,22,[31][32][33][34] and METH-or cocaine-enhanced electrical brain stimulation rewards, two of the other most common animal models used to evaluate drug reward systems [14-16, 22, 33, 35] .…”

“…The experimental results observed in the present study are also consistent with findings in studies of other D 3 R antagonists (ie, nafadotride, U99194A and GR103691) that have shown that blockade of D 3 Rs attenuates the behavioral sensitization produced by repeated amphetamine administration [42,43] . The D 3 receptor mutant (D 3 R −/− ) mice also exhibited attenuated acute locomotor responses as well as the development of behavioral sensitization to METH compared with the results in wild-type mice [30] . Taken together, these results suggest an important role for D 3 Rs in METH-induced locomotor sensitization and possibly in relapse toward METH-seeking behavior.…”

mRNA changes in nucleus accumbens related to methamphetamine addiction in mice

“…The METH injection paradigm used in this study has been demonstrated in previous studies to produce robust locomotor sensitization4748. Mice were given once-daily injections of saline for two consecutive days (day 1-2), after which they were randomly grouped into two.…”

The dopamine D3 receptor regulates the effects of methamphetamine on LPS-induced cytokine production in murine mast cells

“…D3R −/− mice have been previously described (Zhu et al, 2012). D3R −/− mice and control WT mice were bred under specific pathogen-free conditions in the same room of our animal facility.…”

“…For example, a recent study showed that inhibition of the dopamine D3R attenuated the rewarding and incentive motivational effects of METH in rats (Chen et al, 2014). Our previous study showed that the D3R plays distinct roles in modulating METH-induced behavioural sensitization (Zhu et al, 2012). Therefore, D3Rs may be potential targets for the treatment of METH dependence (Higley et al, 2011;Tziortzi et al, 2011).…”