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.

Dysregulation of dopamine (DA) receptor signalling induces specific changes in behaviour, neuronal circuitry and gene expression in the mammalian forebrain. In order to better understand signalling adaptations at the molecular level, we used high-density oligonucleotide microarrays (Codelink Mouse 20K) to define alterations in the expression of transcripts encoding regulator of G-protein coupled receptor signalling in dopamine D1 receptor knockout mice (Drd1a-KO). Regulator of G-protein signalling (Rgs) 2, Rgs4, and Rgs9 were significantly decreased in the striatum (STR) of Drd1a-KO mice. These changes were confirmed by in situ hybridization, and were also observed in the nucleus accumbens (NAc). In contrast, analysis of the medial frontal cortex (MFC) revealed a significant decrease in Rgs17 expression exclusively, and a modest up-regulation of Rgs5 transcript. The expression of these gene products were not significantly altered in the dopamine-poor visual cortex (VC). The Drd1a-KO mouse, and a rabbit model of in utero cocaine exposure, in which D1R signalling is permanently reduced, possess analogous morphological and functional alterations in dopamine-modulated brain circuits; thus we also examined long-lasting changes in RGS transcript expression following prenatal exposure to cocaine. In sharp contrast to the Drd1a-KO, Rgs2 and Rgs4 were unchanged, and Rgs9 and Rgs17 transcripts were increased in prenatal cocaine-exposed progeny. These data suggest that an absolute absence of D1R signalling (Drd1a-KO) and hypomorphic D1R signalling (prenatal cocaine) produce common alterations in neuronal morphology, but distinct outcomes in molecular neuroadaptations.

Ontogenetic treatment of rats with the dopamine D(2)-like receptor agonist quinpirole produces a significant increase in dopamine D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon known as D(2) priming. The present study was designed to investigate the effects of priming of the D(2) receptor on the expression of three different members of the regulator of G-protein signaling (RGS) family: Rgs4, Rgs9 and Rgs17. Male offspring were ontogenetically treated with quinpirole or saline from postnatal days (P)1-21 and raised to adulthood. On approximately P65, animals were given an acute quinipirole injection (0.1 mg/kg) and the number of yawns was recorded for 1 h after the injection. Yawning has been shown to be a behavioural event mediated by the dopamine D(2)/D(3) receptor. Animals ontogenetically treated with quinpirole demonstrated a significant 2.5-fold increase in yawning as compared to controls. Rgs transcripts were analysed through in situ hybridization several weeks later. Rats ontogenetically treated with quinpirole demonstrated a significant decrease in Rgs9 expression in the frontal cortex, but a more robust decrease in the striatum and nucleus accumbens as compared to controls. Regarding Rgs17, ontogenetic quinpirole produced a modest but significant increase in expression in the same brain areas. There were no significant differences in Rgs4 expression produced by drug treatment in any of the brain regions analysed. This study demonstrates that ontogenetic quinpirole treatment, which results in priming of the D(2) receptor, results in significant decreases in Rgs9, which has been shown to regulate G-protein coupling to D(2) receptors.

Prenatal cocaine exposure in a rabbit intravenous model has revealed selective disruption of brain development and pharmacological responsiveness. We therefore examined the pharmacokinetic properties of cocaine in this model. Dutch-belted rabbits were surgically implanted with a catheter in the carotid artery, allowed to recover, and then injected intravenously with a cocaine bolus. Cocaine and benzoylecgonine concentrations were measured in arterial blood plasma and analyzed by nonlinear regression and noncompartmental analyses. Peak cocaine concentration occurred by 30s, was transient, and distribution was rapid. The profile of cocaine in the rabbit is similar to that observed in humans using cocaine at recreational doses.