Different effects of chronic THC on the neuroadaptive response of dopamine D2/3 receptor‐mediated signaling in roman high‐ and roman low‐avoidance rats

Abstract

The Roman high (RHA)- and low (RLA)-avoidance rat sublines have been identified as an addiction-prone and addiction-resistant phenotype based on their high vs. low locomotor responsiveness to novelty and high vs. low ability to develop neurochemical and behavioral sensitization to psychostimulants, respectively. Most studies though have focused on psychostimulants and little is known about the neuroadaptive response of these two lines to cannabinoids. This study investigated the effects of chronic exposure to Δ -tetrahydrocannabinol (THC) on dopamine D receptor (D R) availabilities and functional sensitivity in the mesostriatal system of RHA and RLA rats. At baseline, RLA rats exhibited higher densities of mesostriatal D2/3R but lower levels of striatal CB R mRNA and displayed a lower locomotor response to acute THC as compared to RHAs. Following chronic THC treatment, striking changes in D R signaling were observed in RLA but not in RHA rats, namely an increased availability and functional supersensitivity of striatal D R, as evidenced by a supersensitive psychomotor response to the D R agonist quinpirole. Moreover, in RLA rats, the lower was the locomotor response to acute THC, the higher was the psychomotor response to quinpirole following chronic THC. These results showing a greater neuroadaptive response of RLA vs. RHA rats to chronic THC thus contrast with previous studies showing a resistance to neuroadaptive response of RLAs to psychostimulants, This suggests that, contrasting with their low proneness to psychostimulant drug-seeking, RLAs may exhibit a heightened proneness to cannabinoid drug-seeking as compared to RHA rats.

Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer’s disease

“…As a decrease in dopamine synthesis in AD human brain has been described 42 , 43 the increase in D 2/3 R density could be due to a compensatory phenomenon in response to this decrease in dopamine availability. Interestingly, such a compensation phenomenon has been observed in Parkinson's disease in unmedicated patients 44 , and in an experimental model of reduction in dopamine system activity 45 , 46 .…”

Neurobehavioral and neurodevelopmental profiles of a heuristic genetic model of differential schizophrenia- and addiction-relevant features: The RHA vs. RLA rats

“…receptor in RHA rats, these findings may suggest that differences between both rat lines in the balance of CB1-D2/D3 transmission could be related to the divergent responses to abused drugs of RHA and RLA rats (Tournier et al, 2018). Of note, the endocannabinoid systems, acting through several signaling pathways, seem to be involved in the regulation of neural cell survival, neurogenesis and neuronal maturation across development (e.g.…”