Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period

Yetnikoff, Leora; Almey, Anne; Arvanitogiannis, Andreas; Flores, Cecilia

doi:10.1007/s00213-011-2312-6

Cited by 26 publications

(37 citation statements)

References 46 publications

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“…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).…”

Section: Amph In Adolescence But Not In Adulthood Alters Dopamine Isupporting

confidence: 81%

“…A dose of 4 mg/kg of AMPH achieves plasma concentrations 4250 ng/ml in mice (Riffee et al, 1978;Van Swearingen et al, 2013), which is within the range of plasma levels achieved by oral doses of AMPH that have been reported to be abused by adolescents (Kramer et al, 1967;Anggård et al, 1970;Gustavsen et al, 2006). Importantly, we have shown previously that this dose of AMPH, administered in the same regimen as the present experiments, alters the expression of DCC in the VTA (Yetnikoff et al, 2010(Yetnikoff et al, , 2011.…”

Section: Drugs and Dosesupporting

confidence: 77%

“…Variations in DCC expression in dopamine neurons during adolescence lead to dramatic changes in mPFC-dependent behaviors in adulthood, including changes in sensitivity to behavioral effects of drugs of abuse (Manitt et al, 2013). Remarkably, we have also demonstrated that repeated exposure to an abused dose of amphetamine during early adolescence downregulates DCC expression in the rodent VTA (Yetnikoff et al, 2011). Together, these findings raise the intriguing possibility that drugs of abuse during adolescence disrupt the development of dopamine connectivity by regulating DCC signaling within dopamine neurons.…”

Section: Introductionsupporting

confidence: 57%

“…We have shown that the exact amphetamine regimen, administered in early adolescence, decreases DCC receptor expression in the VTA (Yetnikoff et al, 2011). During a pretreatment phase, mice received one injection of AMPH (4 mg/kg) or vehicle (saline), once every other day for a total of 5 days.…”

Section: Experimental Procedures and Timelinementioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Reynolds

Makowski

Yogendran

et al. 2014

Neuropsychopharmacol

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Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.

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Section: Amph In Adolescence But Not In Adulthood Alters Dopamine Isupporting

confidence: 81%

Section: Drugs and Dosesupporting

confidence: 77%

Section: Introductionsupporting

confidence: 57%

Section: Experimental Procedures and Timelinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Reynolds

Makowski

Yogendran

et al. 2014

Neuropsychopharmacol

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Protracted maturation of forebrain afferent connections of the ventral tegmental area in the rat

Yetnikoff

Reichard

Schwartz

et al. 2014

J of Comparative Neurology

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The mesocorticolimbic dopamine system has long attracted the interest of researchers concerned with the unique gamut of behavioral and mental health vulnerabilities associated with adolescence. Accordingly, the development of the mesocorticolimbic system has been studied extensively, but almost exclusively with regard to dopaminergic output, particularly in the nucleus accumbens and medial prefrontal cortex. To the contrary, the ontogeny of inputs to the ventral tegmental area (VTA), the source of mesocorticolimbic dopamine, has been neglected. This is not a trivial oversight, as the activity of VTA neurons, which reflects their capacity to transmit information about salient events, is sensitively modulated by inputs. Here, we assessed the development of VTA afferent connections using the β subunit of cholera toxin (Ctβ) as a retrograde axonal tracer in adolescent (postnatal day 39) and early adult (8–9-week-old) rats. After intra-VTA injections of Ctβ, adolescent and early adult animals exhibited qualitatively similar distributions of retrogradely labeled neurons in the sense that VTA-projecting neurons were present at all of the same rostrocaudal levels in all of the same structures in both age groups. However, quantitation of retrogradely labeled neurons revealed that adolescent brains, compared with early adult brains, had significantly fewer VTA-projecting neurons preferentially within an interconnected network of cortical and striatopallidal forebrain structures. These findings provide a novel perspective on the development of the mesocorticolimbic dopamine system and may have important implications for age-dependent specificity in the function of this system, particularly with regard to adolescent impulsivity and mental health vulnerabilities.

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Adolescence: a time of transition for the phenotype of dcc heterozygous mice

et al. 2013

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Adolescence is a time of transition for dcc heterozygotes as related to sensitization. Our results support the hypothesis that DCC may be a key factor in determining age-dependent individual differences in vulnerability to sensitization. Given that exposure to drugs of abuse during adolescence can have profound consequences for adulthood, the resilience of adult dcc heterozygous mice against adolescent exposure to amphetamine is particularly salient.

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Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period

Cited by 26 publications

References 46 publications

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

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

Protracted maturation of forebrain afferent connections of the ventral tegmental area in the rat

Adolescence: a time of transition for the phenotype of dcc heterozygous mice

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