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Link to original content: https://pubmed.ncbi.nlm.nih.gov/18322084/
Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence - PubMed Skip to main page content
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Comparative Study
. 2008 Mar 5;28(10):2375-82.
doi: 10.1523/JNEUROSCI.5064-07.2008.

Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence

Heather C Brenhouse  1 , Kai C Sonntag, Susan L Andersen
Affiliations
Comparative Study

Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence

Heather C Brenhouse et al. J Neurosci. .

Abstract

Adolescence is a transitional period during development that is associated with a greater likelihood of addiction to drugs than any other age. In the prefrontal cortex (PFC), D(1) dopamine receptors mediate motivational salience attribution, which plays a role in addiction. Here, we investigated the relationship of age-related D(1) dopamine receptor expression in the PFC with the maturation of cocaine place conditioning. Confocal microscopy revealed that retrogradely traced cortical output neurons to the nucleus accumbens express higher levels of D(1) receptors during adolescence compared with younger and older ages. D(1) expression does not change on GABAergic interneurons across age. Adolescent differences in D(1) expression occur independently of cortical-accumbens connectivity, which proliferates through adulthood. Behaviorally, adolescent rats are more sensitive to cocaine place conditioning than younger and older rats. However, microinjections of the D(1) antagonist SCH23390 into the PFC blocked adolescent place preferences, whereas microinjections of D(1) agonists dose-dependently increased preferences for cocaine-associated environments previously not preferred by juveniles. These results suggest that the heightened expression of D(1) receptors on cortical-accumbens projections may help explain increased sensitivity to environmental events and addictive behaviors during adolescence, whereas the paucity of D(1)-expressing projections may reduce risk in juveniles.

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Figures

Figure 1.
Figure 1.
Effect of age on cocaine place conditioning across three doses of cocaine. a, A significant interaction of age and conditioning was found at 10 mg/kg cocaine (F(2,20) = 3.63; p < 0.05) with adolescents (P41; *p < 0.01), but neither juveniles (P27) nor adults (P100), forming a conditioned preference at this dose. b, A significant interaction of age and conditioning was also found at 20 mg/kg cocaine (F(2,13) = 4.87; p < 0.05), with adolescents (*p < 0.05), but neither juveniles nor adults (@p = 0.07), forming a conditioned preference at this dose. c, All three age groups formed a robust conditioned place preference for a context paired with 40 mg/kg cocaine (*p < 0.05).
Figure 2.
Figure 2.
Histological analysis of intra-NAc fluosphere injection sites. Numerals indicate millimeters from bregma. The largest (solid) and smallest (shaded) bolus sizes of all animals included in analysis are indicated. All injection sites were within ±5% in size.
Figure 3.
Figure 3.
Age-dependent density of projection neurons terminating in the NAc core, as well as GABAergic interneurons and D1-expressing neurons, in the PFC. a, Representative ROI from each of three analyzed ages (juvenile, P27; adolescent, P44; adult, P105) showing age-related changes in retrogradely traced neurons. Left, Atlas plate illustrating the area of PFC within which all ROIs resided (prelimbic region of the PFC). Scale bar, 50 μm. b, Representative ROI showing double-labeling with retrograde tracer (blue) and CAMK-II IR (red), demonstrating that traced cells are glutamatergic projection neurons. Inset, A single double-labeled cell. Scale bar, 50 μm. c, Graphic representation of the density of retrogradely traced projection neurons, and GAD67- and D1-immunoreactive neurons, across three ages. As pictured in a, density of traced neurons increased progressively with age (F(2,13) = 24.8; *p < 0.001).
Figure 4.
Figure 4.
Differential distribution of D1 on PFC projection neurons and GABAergic interneurons across three ages. Sections already labeled with retrograde fluospheres were double-stained for the D1 dopamine receptor and GAD67 (a marker for GABAergic interneurons). a, b, Example of a neuron colocalized with retrograde tracer (blue) and D1 (green; a); and a neuron colocalized with GAD67 (red) and D1 (green; b), with an overlay of both channels shown in right panels. c, Example of a D1-immunoreactive cell not colocalized with either GAD67 or tracer. d, Graphic representation of the density of D1-labeled cells that were colocalized with tracer, GAD67, or neither, across three ages (P27, P44, and P105). D1 expression on retrogradely traced projection neurons was significantly different across ages (F(2,13) = 15.4; *p < 0.01), with a peak colocalization during adolescence. Scale bar, 5 μm.
Figure 5.
Figure 5.
Histological analysis of intra-PFC bilateral cannulas placements. Numerals indicate mm from bregma. All injection sites, as verified by dye spread, fell within the prelimbic region of the PFC, with minimal spread into area 1 of the cingulate cortex and infralimbic regions. Shading indicates percentage of subjects with dye boluses within specified boundaries. Placements located outside of these anatomical regions were excluded from analysis.
Figure 6.
Figure 6.
Provocation of drug-seeking in preadolescents with PFC microinjection of D1 agonists. a, Infusion of the partial D1 agonist SKF38393 directly into the PFC dose-dependently increased cocaine place preference to 10 mg/kg in juvenile rats (F(3,20) = 3.36; p < 0.05). Juveniles infused with vehicle failed to display a preference for the cocaine-paired chamber, whereas those administered the high dose of SKF38393 during conditioning showed a significant postconditioning preference for the cocaine-paired chamber (*p < 0.05). b, Infusion of the full D1 agonist SKF81297 also provoked a significant place preference for 10 mg/kg cocaine (*p < 0.05). c, SKF38393 did not generate a preference for a saline-paired chamber.
Figure 7.
Figure 7.
Effects of cortical D1 activation and inactivation on cocaine conditioned place preference in adolescents. a, Infusion of either vehicle (*p < 0.05) or the D1 agonist SKF81927 (*p < 0.01) resulted in significant place preferences for 10 mg/kg cocaine. Infusion of the D1 antagonist SCH23390 blocked these preferences, resulting in no conditioning effects of the same dose of cocaine. b, Infusion of the D1 antagonist SCH23390 into the PFC had no conditioning effect on its own when saline was substituted for cocaine.
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