MODULATION OF MESOLIMBIC DOPAMINE DYSFUNCTION IN A MOUSE MODEL OF ALZHEIMER’S DISEASE BY A ∆<SUP>9</SUP>-TETRAHYDROCANNABINOL AND CANNABIDIOL COMBINATION

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and a range of non-cognitive symptoms, including impairments in sociability, anxiety, and psychotic symptoms at advanced stages. The endocannabinoid system has recently emerged as a promising multifaceted target for mitigating these symptoms in AD. Given the link between dopaminergic dysfunction and certain non-cognitive symptoms, this study aimed to investigate the effects of a 1:1 combination of ∆⁹-tetrahydrocannabinol (THC; 0.5 mg/kg, i.p.) and cannabidiol (CBD; 0.5 mg/kg, i.p.), previously shown to reduce cognitive impairment in an AD model, on dopamine (DA) signaling in the mesolimbic system of APP/PS1 mice. DA release in the nucleus accumbens (NAcc) was measured using fluorescent DA biosensors combined with fiber photometry following electrical stimulation of the ventral tegmental area (VTA) in 6-month-old male and female APP/PS1 and wild-type (WT) mice. Our results show that APP/PS1 mice exhibit reduced DA release in the NAcc in response to VTA stimulation. Notably, acute administration of THC and CBD at a non-psychoactive dose partially reversed this DA deficit in APP/PS1 mice. This effect was blocked by pretreatment with the CB₁ receptor antagonist rimonabant (1 mg/kg, i.p.), indicating a key role for this receptor in the effects of THC and CBD. Altogether, these findings demonstrate that the combination of these two natural cannabinoids can modulate midbrain DA circuitry in APP/PS1 mice, potentially alleviating non-cognitive symptoms associated with mesolimbic brain regions in this AD model.