Role of Neuropeptide S on Behavioural and Neurochemical Changes of an Animal Model of Attention-Deficit/Hyperactivity Disorder.

Neuropeptide S (NPS) is a recently discovered peptide signalling through its receptor NPSR, which is expressed throughout the brain. Since NPSR activation increases dopaminergic transmission, we now tested if NPSR modulates behavioural and neurochemical alterations displayed by an animal model of attention-deficit/hyperactivity disorder (ADHD), Spontaneous Hypertensive Rats (SHR), compared to its control strain, Wistar Kyoto rats (WKY). NPS (0.1 and 1 nmol, intracerebroventricularly (icv)) did not modify the performance in the open field test in both strains; however, NPSR antagonism with [tBu-d-Gly5]NPS (3 nmol, icv) increased, per se, the total distance travelled by WKY. In the elevated plus-maze, NPS (1 nmol, icv) increased the percentage of entries in the open arms (%EO) only in WKY, an effect prevented by pretreatment with [tBu-d-Gly5]NPS (3 nmol, icv), which decreased per se the %EO in WKY and increased their number of entries in the closed arms. Immunoblotting of frontal cortical extracts showed no differences of NPSR density, although SHR had a lower NPS content than WKY. SHR showed higher activity of dopamine uptake than WKY, and NPS (1 nmol, icv) did not change this profile. Overall, the present work shows that the pattern of functioning of the NPS system is distinct in WKY and SHR, suggesting that this system may contribute to the pathophysiology of ADHD.

Single Cocaine Exposure Inhibits GABA Uptake via Dopamine D1-Like Receptors in Adolescent Mice Frontal Cortex.

Cocaine (COC) is a psychostimulant that acts by increasing catecholaminergic neurotransmission mainly due to its effects on the dopamine transporter (DAT). However, other neurotransmitter systems may also be regulated by COC, including the GABAergic system. Since the effect of COC in modulating gamma-aminobutyric acid (GABA) reuptake is not defined, we investigated the molecular mechanisms related to the increase in GABA uptake induced by acute COC exposure and its effects on locomotor activity in adolescent mice. Behavioral experiments showed that COC increased locomotor activity and decreased immobilization time in mice. A single COC exposure reduced both GABA uptake and GAT-1 protein levels. On the other hand, cyclic adenosine monophosphate (cAMP) levels increased after a COC challenge. The major changes induced by acute COC on behavioral and neurochemical assays were avoided by previous treatment with the selective D1 receptor antagonist SCH-23390 (0.5 mg/kg). Our findings suggest that GABA uptake naturally decreases during mice development from preadolescence until adulthood and that dopamine (DA) D1-like receptors are key players in the regulation of GABA uptake levels following a single COC exposure in adolescent mice.