Modulation of Excitatory Synaptic Transmission by Δ⁹-Tetrahydrocannabinol Switches from Agonist to Antagonist Depending on Firing Rate

Abstract

⌬9 -Tetrahydrocannabinol (THC), the principal psychoactive ingredient in marijuana, acts as a partial agonist on presynaptic cannabinoid type 1 (CB1) receptors to inhibit neurotransmitter release. Here, we report that THC inhibits excitatory neurotransmission between cultured rat hippocampal neurons in a manner highly sensitive to stimulus rate. THC (1 M) inhibited excitatory postsynaptic currents (EPSCs) and whole-cell I Ca evoked at 0.1 Hz but at 0.5 Hz THC had little effect. The cannabinoid receptor full agonistsand 2-arachidonylglycerol (1 M) inhibited EPSCs independent of stimulation at 0.1 or 0.5 Hz. THC occupied CB1 receptors at 0.5Hz, but the receptors failed to couple to presynaptic Ca 2ϩ channels. Consequently, 1 M THC blocked the inhibition of EPSC amplitude by Win55212-2 when EPSCs were evoked at 0.5 Hz. A depolarizing prepulse to 0 mV reversed THC inhibition of I Ca , but reversal of the inhibition produced by Win55212-2 required a pulse to ϩ80 mV, suggesting that the voltage-dependent reversal of G␤␥ inhibition of voltage-gated Ca 2ϩ channels accounts for the frequency-dependence of cannabinoid action. THC blocked depolarization-induced suppression of EPSCs evoked at 0.5 Hz, indicating that it inhibited retrograde endocannabinoid signaling in a frequency-dependent manner. Thus, THC displayed a statedependent switching from agonist to antagonist that may account for its complex actions in vivo.

Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways

“…In contrast, CBD was without effect on the resting membrane potential (Vm) at all concentrations tested (0.1 mM, 0.2 Ϯ 2.1 mV from a control Vm of -60.7 Ϯ 2.1 mV; 1 mM, 1.5 Ϯ 1.6 mV from a control Vm of -57.6 Ϯ 1.6 mV; 10 mM, 0.3 Ϯ 0.7 from a control Vm of -62.0 Ϯ 3.7 mV; all n = 5 and P > 0.05). Similar reductions in spontaneous AP frequency were observed following the application of the CB1 agonist, WIN 55,212-2 (0.1 mM Figure 1B) and the CB1 partial agonist, THC (10 mM, Figure 1B), as has been shown previously (Shen and Thayer, 1999;Bajo et al, 2009;Roloff and Thayer, 2009). To determine if the effects of CBD were mediated by a Gai/o G-protein coupled receptor (GPCR), experiments were performed on cultures treated with Pertussis toxin (PTX, 200 ng·mL -1 , 18 h).…”

Dual Neuroprotective and Neurotoxic Effects of Cannabinoid Drugs in Vitro

“…2). Our findings are supported by recent reports showing that cannabinoids can mediate distinct signaling mechanisms in a single neuron, depending on the state of the neuron (Kellogg et al 2009;Roloff and Thayer 2009). Furthermore, THC was shown to activate proapoptotic mechanisms in cerebral cortical slices obtained from the neonatal rat brain, but not from adult brain (Downer et al 2007), indicating different sensitivity to the pro-apoptotic effect of THC of immature cortical cells, compared to mature, differentiated cortical cells.…”

“…Indeed, agonist-selective effects of cannabinoid ligands have been reported (Georgieva et al 2008;Glass and Northup 1999;Hudson et al 2010;Mukhopadhyay and Howlett 2005). The physiological state of the neuron at the time of the application of the cannabinoid (Roloff and Thayer 2009) or its maturity (Downer et al 2007) can also affect the outcome of the cannabinoid treatment. Furthermore, diverse types of cells can react differently to the same cannabinoid (Sanchez et al 1998).…”

Adolescent Exposure to Chronic Delta-9-Tetrahydrocannabinol Blocks Opiate Dependence in Maternally Deprived Rats

“…The coupling efficiency of CB1 receptors, the firing rate of the synapse, and/or the endocannabinoid release have been recently proved to be involved in this pharmacological property. For example, THC may antagonize responses to endogenously released endocannabinoids by targeting CB1 receptors in a far less selective manner than endocannabinoids (for review, see Pertwee, 2008;Roloff and Thayer, 2009). Additional studies are now in progress in the laboratory to elucidate this hypothesis with special attention to the basal endocannabinoid levels in AFR and D rats.…”