Phasic dopamine release in two different rat models of attention-deficit/hyperactivity disorder: Spontaneously hypertensive rats (SHR) versus Lphn3 knockout rats

Abstract

We examined DA activity in the medial prefrontal cortex (mPFC) and nucleus accumbens core (NAcc) in two Different Rat Models of Attention-Deficit/Hyperactivity Disorder: Spontaneously Hypertensive Rats (SHR) Versus Lphn3 Knockout Rats. We examined baseline stimulation-evoked phasic DA release, half-life, and DA autoreceptor (DAR) functioning in the mPFC and NAcc, as well as the response to nomifensine (10 mg/kg, IP), a DA transporter (DAT) blocker, on these measures in the NAcc. Both rat models were hypodopaminergic, with notable regional and mechanistic differences. The SHRs displayed decreased DA release in the NAcc compared to their control strain (i.e., WKY rats), with no differences in the mPFC, leading a much lower NAcc-to-PFC DA release ratio in SHRs compared to controls suggesting an imbalance in DA transmission between these regions. The Lphn3 KO rats were considered hypodopaminergic based on the reduced summed DA release in the mPFC and NAcc compared to WT controls, although differences were not observed when examining each site independently. Lphn3 KOs displayed increased DA half-life in the mPFC compared with Lphn3 WT rats, an indication of decreased DAT reuptake, with no differences in the NAcc. DAT blockade by nomifensine had a similar effect on DA release in the NAcc of SHRs and WKYs, but increased DA release in the NAcc of Lphn3 KOs to a greater extent than in WTs. These results suggest that the efficacy of pharmacotherapies used to treat externalizing disorders such as ADHD and/or SUD, likely differ between SHRs and Lphn3 KO rats.

Keywords: Animal models; Dopamine; Genetics; Mesocorticolimbic; Neurochemistry; Neurodevelopment.