Pharmacologic Neuroimaging of the Ontogeny of Dopamine Receptor Function

Abstract

Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.

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

“…We now also show a similar age-related decline in quinpirole-induced erectile response. Such findings are consistent with major developmental alterations of D2-like receptor function during adolescence (Chen et al, 2010). Nicotine pretreatment during the early adolescent period produced an extended enhancement of these functional responses to quinpirole, suggesting an alteration of D2-like receptor signaling.…”

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

“…This has been associated with pruning following early adolescent synaptogenesis, and myelination processes continuing well into adulthood (Brenhouse and Andersen, 2011). The increased D-amphetamine response and intranetwork functional connectivity within the adult striatal network, as observed in our study, may partially reflect a continued development of dopaminergic pathways, with regard to midbrain dopaminergic neuron firing, and expression of striatal dopamine transporters and post-synaptic D1-and D2-like receptors (Chen et al, 2010;McCutcheon and Marinelli, 2009;Teicher et al, 1995).…”

Adolescent alcohol exposure: Are there separable vulnerable periods within adolescence?

“…In general DA receptors tend to peak in striatum during early/mid-adolescence and to decrease thereafter to reach adult levels by ~P60, although developmental patterns often differ for specific DA receptor subtypes (e.g., Andersen et al, 2000; Tarazi & Baldessarini, 2000). Indeed, using MRI, evidence of DA D1 receptor hypofunction was evident in striatal areas of juvenile and early adolescent rats, with a functional predominance of D2 over D1 DA receptors observed from approximately P20-P35 (Chen et al, 2010). In contrast to the generally early/mid-adolescent peak in DA receptors in striatal regions, DA receptors in PFC typically rise until adolescence/emerging adulthood, peaking at ~ P60 and declining thereafter to reach adult levels by ~ P80 (Andersen et al, 2000).…”