Role of dopaminergic projections from ventral tegmental area to paraventricular thalamus in heroin-induced behavioural sensitization of rats.

The ventral tegmental area (VTA) is involved in the behavioral sensitization to heroin, but the possible neural projections and molecular mechanisms remain unclear. Rats first underwent 8 days of heroin sensitization induction, followed by a 10-day drug-free period. Subsequently, a M5 muscarinic acetylcholine receptor antisense oligonucleotide was microinjected into the VTA, and the expression of heroin sensitization was assessed. Secondly, retrograde viral tracing combined with immunofluorescence labeling was used to characterize VTA neuronal populations projecting to the paraventricular thalamic (PVT) and the ventromedial hypothalamus (VMH). Finally, chemogenetic inhibition of VTA-PVT or VTA-VMH dopaminergic projections was performed to evaluate their effects on heroin sensitization. We found that microinjection of a M5 receptor antisense oligonucleotide into the VTA inhibited the expression of heroin sensitization. Furthermore, although the VTA sends dopaminergic projections to both the PVT and the VMH at varying densities, chemogenetic inhibition of VTA-PVT dopaminergic projection specifically attenuates heroin sensitization expression and leads to increased protein kinase B (Akt) phosphorylation and decreased cAMP response element binding protein (CREB) phosphorylation in the PVT. In contrast, inhibition of the VTA-VMH dopaminergic projection had no effect. Our results suggest that M5 receptor in the VTA is critically involved in regulating heroin sensitization. Furthermore, the VTA-PVT dopaminergic projection is essential for heroin sensitization expression and may act by modulating Akt and CREB phosphorylation.