Addictive drugs and plasticity of glutamatergic synapses on dopaminergic neurons: what have we learned from genetic mouse models? - PubMed (original) (raw)
Addictive drugs and plasticity of glutamatergic synapses on dopaminergic neurons: what have we learned from genetic mouse models?
Jan Rodriguez Parkitna et al. Front Mol Neurosci. 2012.
Abstract
Drug-induced changes in the functional properties of neurons in the mesolimbic dopaminergic system are attractive candidates for the molecular underpinnings of addiction. A central question in this context has been how drugs of abuse affect synaptic plasticity on dopaminergic cells in the ventral tegmental area. We now know that the intake of addictive drugs is accompanied by a complex sequence of alterations in the properties of excitatory synapses on dopaminergic neurons, mainly driven by signaling and redistribution of NMDA- and AMPA-receptors. It has, however, been unclear how these molecular changes are related to the behavioral effects of addictive drugs. Recently, new genetic tools have permitted researchers to perform genetic intervention with plasticity-related molecules selectively in dopaminergic cells and to subsequently study the behaviors of genetically modified mice. These studies have started to reveal how plasticity and drug-induced behavior are connected as well as what role plasticity in dopaminergic cells may have in general reward learning. The findings thus far show that there is not a one-to-one relation between plastic events and specific behaviors and that the early responses to drugs of abuse are to a large extent independent of the types of synaptic plasticity so far targeted. In contrast, plasticity in dopaminergic cells indeed is an important regulator of the persistence of behaviors driven by drug associations, making synaptic plasticity in dopaminergic cells an important field of study for understanding the mechanisms behind relapse.
Keywords: addiction; dopamine; genetically modified mice; glutamate; neural plasticity.
Figures
Figure 1
Deletion of loxP flanked sequences by the Cre recombinase. A fragment of the NR1 (Grin1) gene is shown as a line with solid black rectangles representing exons. The numbers above the rectangles correspond to exons. The two triangles represent the loxP sequences introduced in introns, placed in the same orientation and flanking exons 11–18 (Niewoehner et al., 2007). The Cre recombinase has a nuclear localization signal and is normally shuttled to the nucleus after translation, where it catalyzes a deletion of the gene fragment flanked by the loxP sites. Thus, gene inactivation will occur soon after the gene promoter driving Cre expression becomes active, typically around the 13th day of embryonic development (Parlato et al., 2006). The CreERT2 is a fusion protein of the Cre and a modified ligand binding domain of the estrogen receptor (ERT2). The modification prevents binding of endogenous estrogens but allows binding of tamoxifen, a synthetic steroid (represented by a circle with a “T”). Additionally, the presence of the ERT2 domain enables interaction with the mechanisms normally responsible for keeping the estrogen receptor in the cytosol, in particular interaction with Hsp90. Binding of tamoxifen to the ERT2 releases its interaction with the cytosolic proteins and permits shuttling to the nucleus, where it catalyzes the deletion of the gene fragment flanked by loxP sequences.
Figure 2
Deletion of NMDA receptors selectively in dopaminergic cells.
Figure 3
Drug-induced synaptic strengthening of excitatory synapses on dopaminergic neurons.
Figure 4
Afferents to the ventral tegmental area (VTA). On the diagram, origins of the main excitatory inputs are shown as blue circles, origins of the main inhibitory inputs as yellow circles, and the VTA and substantia nigra (SN) as red circles. Excitatory inputs originate from the prefrontal cortex (PFC), periaqueductal grey (PAG), the pedunculopontine nucleus (PPN), the laterodorsal tegmentum (LTG), lateral hypothalamus (LHA), lateral preoptic area (LPOA) and the reticular formation (Rt). The subthalamic nucleus (STH) was reported to send projections to the SN but not the VTA. It should be noted that the excitatory projections are forming synapses not only on dopaminergic cells, but on other types of neurons present in the VTA as well. GABAergic signaling regulates the activity of the VTA, both through local inhibitory neurons as well as afferents coming from the nucleus accumbens septi (NAc), ventral pallidum (VP), globus pallidus (GP), amygdaloid nuclei (Amy) and the mesopontine rostromedial tegmental nucleus. Additionally, a fraction of the afferents from the PPN was found to be GABAergic. The diagram does not show all inputs to the VTA, notably omitting serotonergic and cholinergic afferents and also inputs to non-dopaminergic neurons. For an excellent review of the architecture of the mesolimbic system please see Sesack and Grace (2010).
Figure 5
Changes in cocaine-related behaviors in mice with deletions of NMDARs or GluR1. Studies: 1, Engblom et al. (2008); 2, Zweifel et al. (2008); 3, Luo et al. (2010); 4, Mameli et al. (2009); 5, Dong et al. (2004); and 6, Mead et al. (2005). SA, Self administration.
References
LinkOut - more resources
Full Text Sources