Regulation of netrin-1 receptors by amphetamine in the adult brain

Abstract

Netrin-1 is a guidance cue molecule fundamental to the organization of neuronal connectivity during development. Netrin-1 and its receptors, deleted in colorectal cancer (DCC) and UNC-5 homologues (UNC-5), continue to be expressed in the adult brain, although neither their function nor the kinds of events that activate their expression are known. Two lines of evidence suggest a role for netrin-1 in amphetamine-induced dopamine plasticity in the adult. First, DCC is highly expressed by adult dopamine neurons. Second, adult mice with reduced DCC levels do not develop amphetamine-induced behavioral sensitization. To explore the role of netrin-1 in amphetamine-induced plasticity, we examined the effects of sensitizing treatment regimens of amphetamine on DCC and/or UNC-5 protein expression in the adult rat. These treatments produced striking and enduring increases in DCC and UNC-5 expression in the cell body, but not terminal regions, of the mesocorticolimbic dopamine system. Notably, neuroadaptations in the cell body region of mesocorticolimbic dopamine neurons underlie the development of sensitization to the effects of amphetamine. Furthermore, these localized amphetamine-induced changes were prevented by co-treatment with an N-methyl-D-aspartate receptor antagonist, a treatment known to block the development of amphetamine-induced sensitization of behavioral activation, dopamine release and motivated behavior. Using immunohistochemistry, we showed that both DCC and UNC-5 receptors are highly expressed by adult mesocorticolimbic dopamine neurons. These results provide the first evidence that repeated exposure to a stimulant drug such as amphetamine affects netrin-1 receptor expression in the adult brain. Taken together, our findings suggest that changes in netrin-1 receptor expression may play a role in the lasting effects of exposure to amphetamine and other stimulant drugs. Keywords sensitization; DCC; UNC-5; plasticity; dopamine; glutamate Stimulant drugs, such as amphetamine, induce locomotor-activating and rewarding effects by increasing extracellular dopamine (DA) levels in striatal terminal regions. These behavioral and neurochemical effects become sensitized when the drug is administered repeatedly (Stewart and Badiani, 1993;Kalivas and Stewart, 1991;Vezina 2004). Key features of sensitization, including its gradual development and persistence over time, CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptsuggest underlying alterations in the organization of mesocorticolimbic DA circuitry. Indeed, stimulant-induced modifications in dendritic structure have been identified in midbrain DA perikarya and in striatal and cortical DA terminal regions, suggesting alterations in patterns of synaptic connectivity within these regions (Berlanga et al., 2006;Kolb et al., 2003;Mueller et al., 2006; Kolb, 1997, 1999;Sarti et al., 2007). Although the mechanisms underlying amphetamine-induced plasticity of DA circuitry are unclear, it is known that the development of sensitization depends on (1) ...

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

“…There were no differences in the volume of TH-positive fibers between saline-and AMPH-treated littermates in any of the mPFC subregions analyzed (Figure 2c These data indicate that the same AMPH regimen that induces profound changes in adult mPFC DA synaptic connectivity when administered during early adolescence does not alter dopamine connectivity within this region when administered during adulthood (Figure 2d). We have previously shown, that in contrast to early adolescence (Yetnikoff et al, 2011), exposure to the exact same regimen of amphetamine upregulates DCC expression in the VTA when given to adult mice and rats (Yetnikoff et al, 2007(Yetnikoff et al, , 2010. This age-dependent effect is consistent with the idea that DCC signaling within dopamine neurons mediates different events at different developmental times (Flores, 2011).…”

“…DCC expression in dopamine neurons is high during early development and adolescence, in line with the maturational timeline of dopamine pathways. Interestingly, DCC expression is substantially lower during adulthood, suggesting that DCC signaling may play a different, more local, role in the adult brain (Osborne et al, 2005;Grant et al, 2007;Manitt et al, 2010;Reyes et al, 2013;Yetnikoff et al, 2007Yetnikoff et al, , 2010Yetnikoff et al, , 2011Yetnikoff et al, , 2013a. Using rodents, we showed that DCC signaling within the ventral tegmental area (VTA) dopamine neurons determines the extent of their innervation to the mPFC specifically during adolescence and, in turn, organizes the structure and function of mPFC local circuitries (Manitt et al, 2013).…”

The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry

“…The cellular and molecular processes mediating these effects are essentially unknown. Our past work identified a role for the netrin-1 receptor DCC (deleted in colorectal cancer) in the functional organization of mesocorticolimbic DA systems (Flores et al, 2005Grant et al, 2007Grant et al, , 2009Yetnikoff et al, 2007Yetnikoff et al, , 2010, leading us to propose that DCC-mediated netrin-1 signaling is a mechanism whereby risk factors exert their enduring effects on DA function (Flores, 2011). Here, we report that DCC contributes to the organization of mesocorticolimbic DA systems by influencing medial prefrontal cortex (mPFC) DA synaptic connectivity.…”

Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

“…Finally, amphetamine-induced sensitization and upregulation of VTA DCC are prevented by cotreatment of an N-methyl-D-aspartate antagonist during the pretreatment phase. 82,86 These findings suggest that the upregulation of VTA DCC expression by repeated amphetamine exposure may be implicated in the development of sensitization.…”

“…Deleted in colorectal cancer continues to be expressed in tyrosine hydroxylase-positive neurons during peripubertal (postnatal day 33 ± 2 in mice; postnatal day 33 in rats) and adult periods, consistent with previous reports. [81][82][83] Remarkably, there is a dramatic emergence of UNC5H expression by DA neurons in the peripubertal period, which persists until adulthood. 48,82,83 Importantly, from the peripubertal period onward, single VTA DA neurons coexpressed both UNC5H and DCC receptors (Fig.…”