Anatomical abnormalities in dopaminoceptive regions of the cerebral cortex of dopamine D₁ receptor mutant mice

Abstract

Alteration of dopamine neurotransmission during development can induce specific changes in neuronal structure and function. Here, we report specific morphological and neurochemical changes of projection neurons and interneurons of the medial frontal cortex of the dopamine D(1) receptor null mouse. Using immunostaining of cytoskeletal proteins and a crossbred D(1) receptor null:YFP transgenic reporter line, we demonstrate that the apical dendrites of pyramidal cells are abnormally organized in the prefrontal and anterior cingulate cortices of mice lacking the D(1) receptor. Neuronal processes exhibit a decrease in bundling and an increase in irregular, tortuous patterning as they weave a course towards the pial surface. In addition, there is increased parvalbumin staining of the dendrites of cortical interneurons in D(1) receptor null mice. Both pyramidal and interneuron alterations are evident by the early postnatal period and persist into adulthood. The alterations show regional specificity, in that dendritic profiles of projection neurons and interneurons in somatosensory and visual cortices develop normally. The abnormalities are reminiscent of those induced by prenatal exposure to cocaine in rabbits, an insult which has been shown to produce an attenuation of D(1) receptor-mediated responses through G(salpha). These results suggest that loss of D(1) receptor-mediated signaling during development produces permanent alterations in the cellular organization of specific cortical areas involved in attention, cognition, and emotion. Pharmacological and behavioral studies in the D(1) null mouse should be interpreted in the context of possible altered circuitry, given the presence of these developmental defects in the organization of dopaminoceptive regions of the cerebral cortex.

Quantitative Changes in Gαolf Protein Levels, but not D1 Receptor, Alter Specifically Acute Responses to Psychostimulants

“…Results in D1R knockout mice appear somewhat contradictory since locomotor sensitization induced by cocaine was strongly reduced, as expected, whereas locomotor sensitization to D-amph and cocaineinduced CPP were clearly obtained in these mice (Crawford et al, 1997;Karper et al, 2002;Xu et al, 2000). This apparent discrepancy may be related to the existence of compensatory mechanisms in D1R knockout mice (Karper et al, 2002;Stanwood et al, 2005). Our results show that the partial deficiency of D1R signaling does not prevent the development and the expression of locomotor sensitization to cocaine and D-amph.…”

Genetics of Dopamine and its Contribution to Cocaine Addiction

“…This suggests that D1 receptors play a role in the locomotor activating effects but not the rewarding effects of cocaine. However, as with all knockout models, these data should be interpreted with caution because of developmental abnormalities (Stanwood et al 2005). Similar to the D1 knockout mice, D2 -/-and +/-mice show a blunted locomotor response to a cocaine challenge compared to WT mice.…”

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

“…Alterations in the fetal development of the monoaminergic system can affect short-and long-term attention and cognitive development. Perhaps a point of origin for the disturbances from the effects of cocaine is the reduction of the coupling of the D1 receptor to its G protein-coupled receptor (Jones et al, 2000;Stanwood et al, 2005;Zhen et al, 2001). This uncoupling is sustained into adulthood and is specific for D1 receptors.…”