Transient D₁Dopamine Receptor Expression on Prefrontal Cortex Projection Neurons: Relationship to Enhanced Motivational Salience of Drug Cues in Adolescence

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.

A Role For The Prefrontal Cortex In Heroin-Seeking After Forced Abstinence By Adult Male Rats But Not Adolescents

“…Given that the compound stimulus of discrete drug-paired cues was not included in the present test of drug-seeking, reexposure to the drug self-administration environment (context) is likely the stimulus driving the lever-pressing we observed. These results are consistent with less robust cue-induced reinstatement of cocaineseeking observed over a shorter experimental time course (Anker and Carroll, 2010); and with reports of faster extinction and less reinstatement of a cocaine-conditioned place preference among adolescents vs adults (Balda et al, 2006, but see Brenhouse et al, 2008), as well as faster Figure 4 (a-c). Neuron number in prelimbic, infralimbic, and M1 cortices.…”

“…Although both glutamatergic and GABAergic cells in prelimbic and infralimbic cortex are implicated in heroinseeking by adult rats (Bossert et al, 2011), double-labeling experiments are necessary to delineate which cell types are differentially activated across age groups, ie, which cells are involved in the enduring motivational salience of drugassociated cues after self-administration during adolescence. Significant changes occur in both glutamatergic and GABAergic cells during adolescence (eg, Andersen et al, 2000;Tseng and O'Donnell, 2007;Brenhouse et al, 2008), potentially contributing to phenomena such as reduced cortical inhibition and coordination in adolescents compared with adults (Sturman and Moghaddam, 2011). Some cells altered by drug intake during adolescence could undergo apoptosis during the transition from adolescence to adulthood, thereby minimizing the enduring effects of early drug exposure.…”

“…Some cells altered by drug intake during adolescence could undergo apoptosis during the transition from adolescence to adulthood, thereby minimizing the enduring effects of early drug exposure. Along these lines, D1 dopamine receptors expressed on glutamatergic projection neurons in the mPFC appear to process the salience of drugassociated contextual cues during reinstatement tests (Brenhouse et al, 2010); thus, a natural decline in D1 receptor expression after adolescence (Andersen et al, 2000;Brenhouse et al, 2008) could also contribute to a loss of salience of drug-associated cues, be they contextual cues or discrete cues paired with drug self-infusions. Resolution between studies like ours demonstrating adolescent resistance to drug effects vs those demonstrating heightened drug sensitivity among adolescents may relate to the duration of drug exposure (eg, whether it ceases during adolescence or continues into adulthood), the intensity of drug exposure (eg, drug doses), and/or the parameters for testing drug effects.…”

Nicotine Alters Limbic Function in Adolescent Rat by a 5-HT1A Receptor Mechanism

“…In particular, the prefrontal cortex (PFC)-basolateral amygdala (BLA)-nucleus accumbens (NAc) triadic circuit, responsible for reward and motivated behavior, is dynamically developing during this period, as are its monoamine afferents (Ernst et al, 2006;Ernst and Fudge, 2009). Mesolimbic DA systems, which are integral to cocaine selfadministration and locomotor sensitization (Thomas et al, 2008), undergo major reorganization during adolescence (Tarazi et al, 1999;Cao et al, 2007b;Benoit-Marand and O'Donnell, 2008;Brenhouse et al, 2008;Andersen et al, 2000) and exhibit unique sensitivity to nicotine (Azam et al, 2007). Less is known about the adolescent maturation of 5-HT systems, which have a significant role in cocaine selfadministration (Rocha et al, 1997;Rodd et al, 2005;Fletcher et al, 2002) and locomotor sensitization (Tassin, 2008).…”

High frequency stimulation-induced plasticity in the prelimbic cortex of rats emerges during adolescent development and is associated with an increase in dopamine receptor function

“…Early studies using juvenile rats showed that dopamine plays a prominent role in regulating inhibitory tone in the mPFC (Seamans et al, 2001, partially through altering the excitability of interneurons (Gorelova et al, 2002;Trantham-Davidson et al, 2004). Later, it was found that there are significant changes in the expression of PFC dopamine receptors throughout adolescent development (Andersen et al, 2000;Brenhouse et al, 2008;Naneix et al, 2012) and accordingly, the dopaminergic regulation of inhibition has been shown to be influenced by age (Paul and Cox, 2013). The delayed maturation of dopamine's function in the mPFC is also consistent with the finding that prefrontal GABAergic cells increase their responsiveness to dopamine receptor stimulation during adolescent development.…”