TOLERANCE TO THE CARDIOVASCULAR EFFECTS OF Δ⁹‐TETRAHYDROCANNABINOL IN THE RAT

Abstract

1Daily intraperitoneal injections of A9-tetrahydrocannabinol (A9-THC, 10 mg/kg) resulted in tolerance to the effects of the cannabinoid on body weight and body temperature within 1-2 weeks of treatment.2 Tolerance failed to develop to the suppression of spontaneous motor activity produced by A9-THC during 28 days of treatment with the cannabinoid (10 mg/kg, i.p. per day). 3 Following treatment with vehicle for 28 days, intravenous administration of A9-THC in anaesthetized rats produced a transient pressor response followed by a sustained hypotension and bradycardia. 4 Tolerance to the hypotensive and negative chronotropic responses to intravenous A9-THC was readily apparent in animals which had received daily intraperitoneal injections of A9-THC (10 mg/kg) for 28 days. Tolerance failed to develop to the pressor actions of intravenous A9-THC after 28 days of pretreatment.

Blood pressure regulation by endocannabinoids and their receptors

“…However, initial enthusiasm was tempered by the inability to separate the neurobehavioral and cardiovascular effects of cannabinergic ligands and also by a report of the development of rapid tolerance to the hypotensive and bradycardic effects of THC (Adams et al, 1976). Even though a subsequent study in spontaneously hypertensive rats (SHR) found no evidence for tolerance to the same effects during a 10-day treatment period (Kosersky, 1978), interest in this issue waned over the next 20 years.…”

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…Unfortunately, the initial high anticipation was tempered by a report of the development of rapid tolerance to the hypotensive and bradycardic effects of THC (Adams et al, 1976) and by the failure to separate the cardiovascular and neurobehavioral effects of cannabinoids. Albeit a later study in spontaneously hypertensive rats (SHR) demonstrated no tolerance to the same effects during a 10-day treatment period (Kosersky, 1978), interest in this issue had vanished for the next two decades.…”

Cardiovascular Pharmacology of Cannabinoids

“…Although an early study in normotensive rats indicated rapidly developing tolerance to the hypotensive and bradycardic effects of THC (Adams et al 1976), a subsequent study in spontaneously hypertensive rats (SHR) found no evidence for tolerance for the same effects during a similar, 10-day treatment period (Kosersky 1978).…”