Chronic Δ9-tetrahydrocannabinol treatment has dose-dependent effects on open field exploratory behavior and [3H] SR141716A receptor binding in the rat brain

Abstract

Aims: Acute and chronic Δ⁹-THC exposure paradigms affect the body differently. More must be known about the impact of chronic Δ⁹-THC on cannabinoid-1 (CB1R) and mu-opioid (MOR) receptor levels in the brain. The present study examined chronic Δ⁹-THC's effects on CB1R and MOR levels and locomotor activity.

Main methods: Adolescent Sprague-Dawley rats were given daily intraperitoneal injections of Δ⁹-THC [0.75mg/kg (low dose or LD) or 2.0 mg/kg (high dose or HD)] or vehicle for 24 days, and locomotion in the open field was tested after the first and fourth weeks of chronic Δ⁹-THC exposure. Brains were harvested at the end of treatment. [³H] SR141716A and [³H] DAMGO autoradiography assessed CB1R and MOR levels, respectively.

Key findings: Relative to each other, chronic HD rats showed reduced vertical plane (VP) entries and time, while LD rats had increased VP entries and time for locomotion, as assessed by open-field testing; no effects were found relative to the control. Autoradiography analyses showed that HD Δ⁹-THC significantly decreased CB1R binding relative to LD Δ⁹-THC in the cingulate (33%), primary motor (42%), secondary motor (33%) somatosensory (38%), rhinal (38%), and auditory (50%) cortices; LD Δ⁹-THC rats displayed elevated binding in the primary motor (33% increase) and hypothalamic (33% increase) regions compared with controls. No significant differences were observed in MOR binding for the LD or HD compared to the control.

Significance: These results demonstrate that chronic Δ⁹-THC dose-dependently altered CB1R levels throughout the brain and locomotor activity in the open field.

Keywords: Addiction; Autoradiography; CB1; Cannabis; Mu-opioid; Δ9-Tetrahydrocannabinol.

Fig. 1.

Timeline figure of the study's design.

Fig. 2.

Effects of chronic 0.75 and 2.0 mg/kg Δ⁹-THC in the open-field test (LD and HD rats, respectively). Parameters include floor plane (FP) moves (A), FP distance (B), vertical plane (VP) entries (C), VP time (D), center distance (E), and center time (F). *p < .05 indicates an overall treatment effect between LD and HD rats in VP time and entries after the first and fourth weeks of chronic drug exposure.

Fig. 3.

A: Mean [³H] SR141716A autoradiography binding (μCi/g) + the SEM of CB1Rs across central ROIs in the vehicle, 0.75, and 2.0 mg/kg Δ⁹-THC rats. *p < .05 indicates significant binding differences between treatment groups with a black bar, noted in the (A) cingulate (Cg), primary and secondary motor (M1, M2) cortices, the somatosensory (S) cortex, the rhinal (Rh) and auditory (Aud) cortices, and (B) the hypothalamus (Hyp). B: Representative autoradiography images of [³H] SR141716A specific binding in ROIs of rats chronically treated with vehicle, LD Δ⁹-THC (0.75 mg/kg), or HD Δ⁹-THC (2.0 mg/kg).

Fig. 4.

A: Mean [³H] DAMGO autoradiography (μCi/g) + the SEM of mu-opioid receptor levels across central ROIs in the vehicle, 0.75, and 2.0 mg/kg Δ⁹-THC rats. B: Representative autoradiographic images of [³H] DAMGO binding of ROIs in coronal sections of Sprague-Dawley rat brains. Measurements were obtained for the outlined ROIs, 1: caudate putamen (CPu), 2: entorhinal (En), 3: nucleus accumbens (NAc) core, 4: nucleus accumbens shell, 5: hippocampus (HP), 6: mediodorsal thalamic nucleus (MD), 7: ventral posterolateral thalamic nucleus (VPL), 8: ventromedial thalamic nucleus (VM), 9: medial amygdaloid nucleus (MeAD), 10: central amygdaloid nucleus (CeM), 11: anterior basolateral amygdaloid nucleus (BLA), 12: Pt, 13: medial habenular nucleus (MHb), 14: posteromedial cortical amygdaloid nucleus (PMCo).