Differential response to specific 5-Ht(7) versus whole-serotonergic drugs in rat forebrains: a phMRI study

We recently suggested that serotonin 7 (5-Ht7) receptors may play a role in ADHD-like symptoms, at least in animal models. A mixed 5-Ht(1a/7) agonist, 8-OH-DPAT, counteracted the augmented levels of basal impulsivity, observed after treatment with a selective 5-Ht7 antagonist, SB269970 (Leo et al., 2009). In the present study, these serotonergic compounds were investigated by pharmacological magnetic resonance imaging (phMRI) at 4.7 T in adult isoflurane-anaesthetized rats. Axial echo-planar images were collected from the prefrontal cortex (PFC), ventral (nucleus accumbens, NAcc) and dorsal (dStr) striata, the hippocampus and the thalamus. After consecutive image collection for 30 min (50 baseline images), adult rats received either SB269970 (3mg/kg), 8-OH-DPAT (0.06 mg/kg) or saline intra-peritoneally (i.p.) via a remote cannula; the images were then collected for further 30 min (50 post-treatment images). Data were analysed 1) through an activation map generated on brain templates, obtained by using animals from each experimental group; 2) by a two-way ANOVA for the evaluation of temporal profiles, extracted within selected ROIs of each animal. Both compounds increased the BOLD signal in the areas of interest: SB269970, the selective 5-Ht7 antagonist, induced a significant effect in the PFC, particularly the orbital (oPFC) region, and in the NAcc. This effect started 6 to 12 min after drug administration, reached a maximum (+2.8%/+2.3%) at 12 to 18 min, and then moved to the dorsal thalamic nuclei. In contrast, the effects of 8-OH-DPAT were first observed in midline thalamic nuclei, and later appeared in forebrain regions: its effects were modest and transient within the NAcc and oPFC (+1.7% at 18 to 24 min after injection), whereas they were higher and long-lasting in the dStr and PFC, specifically the medial (mPFC) region (+3.1%/+4.0% from 15 min after drug administration onwards). The brain BOLD changes, reported as a consequence of selective 5-Ht7 antagonist administration, seemed restricted to the oPFC, NAcc and dorso-thalamic circuits, whereas the non-selective blockade of serotonergic receptors affected the mPFC, dStr and mid(line)-thalamic circuitry. The present findings revealed two differential serotonergic sub-pathways, as evidenced by the detection of physiological vascular feedback and/or neuronal activation.