Repeated exposure to Δ9-tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity

The present study examined the effect of chronic exposure to Δ9-tetrahydrocannabinol (THC) on heroin-induced locomotor sensitisation and Fos-immunoreactivity (Fos-IR). Adult male albino Wistar rats (n = 60) were injected intraperitoneally (i.p.) 21 times with vehicle, 0.05, 0.5, or 5.0 mg/kg THC (once every 48 h for 41 days). Locomotor activity was assessed for 180 min on pre-exposure days 1, 21, and 41. Following a 2-week washout period, rats were divided into five equal groups (n = 12) and injected subcutaneously (s.c.) with vehicle or heroin (0.5 mg/kg). Locomotor activity was recorded for 240 min. In drug-naïve rats, heroin significantly increased locomotor activity. THC pre-exposure further increased heroin-induced locomotion. After an interval of 2 weeks, rats pre-exposed to vehicle and 5.0 mg/kg THC in the first part of the experiment were randomly assigned to one of four treatment groups (n = 6) and injected s.c. with vehicle or 0.5 mg/kg heroin and perfused 2 h later. Fos-IR was examined in several brain regions. Acute heroin increased Fos-IR in drug-naïve rats in the caudate-putamen (CPu; central, medial and dorsomedial regions), nucleus accumbens (NAC; core and shell regions), bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala (CEA), periaqueductal grey (PAG; dorsolateral, dorsomedial, and lateral), and the Edinger-Westphal nucleus. Pre-exposure to THC significantly increased heroin-induced Fos-IR in the dorsomedial CPu and the NAC (core). Conversely, THC pre-exposure reduced heroin-induced Fos-IR in the BNST, CEA, and the PAG (dorsolateral and lateral). The present study demonstrates that THC pre-exposure increases the locomotor stimulating effects of heroin and provides new evidence for the neural correlates that may underlie cannabinoid and opioid cross-sensitisation.