Local administration of a cannabinoid agonist alters norepinephrine efflux in the rat frontal cortex

Abstract

Delta(9)-tetrahydrocannabinol, the main psychoactive ingredient in marijuana, activates specific cannabinoid (CB) receptors to exert complex actions on modulatory neurotransmitters involved in attention and cognition. Previous research has demonstrated that systemic administration of the synthetic cannabinoid agonist, WIN 55,212-2, increases norepinephrine efflux in the frontal cortex. The distribution of CB1 receptors on noradrenergic fibers in the frontal cortex suggests this may be one potential site for the regulation of norepinephrine release. In the present study, we first examined the ability of a CB1 antagonist, applied locally in the frontal cortex of adult male Sprague-Dawley rats, to block the actions of systemic WIN 55,212-2. Pretreatment with SR 141716A (300 microM) significantly attenuated the excitatory effects of WIN 55,212-2 (15 mg/kg, i.p.). Next, the impact of direct perfusion of WIN 55,212-2 into the frontal cortex on extracellular norepinephrine efflux was measured. Direct application of WIN 55,212-2 (100 microM) into the frontal cortex elicited a significant increase in extracellular norepinephrine efflux suggesting that activation of cortical cannabinoid receptors contributes to alterations in norepinephrine levels in this brain region. Finally, local administration of SR 141716A followed by local administration of WIN 55,212-2 revealed a paradoxical inhibition of norepinephrine efflux.

Figure 1

Local perfusion of SR 141716A, a CB1 antagonist, blocks the increase in extracellular norepinephrine in the frontal cortex evoked by a systemic injection of WIN 55,212-2. SR 141716A was administered via reverse perfusion through the probe for 60 minutes (300 μM; black bar). WIN 55,212-2 (15 mg/kg, i.p) was injected 20 minutes after the SR infusion ended (gray diamonds). Control animals (black squares) received aCSF through the probe followed by WIN 55,212-2 injection. Black triangles represent animals that received SR 141716A through the probe followed by a systemic vehicle injection.

Figure 2

Local SR 141716A perfusion has no effect on extracellular NE (gray squares). Local application of WIN 55,212-2 increases extracellular NE (black diamonds). Local perfusion of SR followed by local perfusion of WIN 55,212-2 results in a reduction of extracellullar NE (black triangles).