Different logical approaches based on existing literature produce two contradicting hypotheses.

My initial hypothesis was that downregulation of CB1 receptors by cannabis use would increase cell excitability. This is facilitated by a decreased function of endocannabinoids. Under normal circumstance CB1 activity decreases presynaptic cAMP as CB1 receptors directly inhibit adenylate cyclase (Elphick & Egertová, 2001). PKA, a cAMP dependent protein, can negatively modulate A-type potassium channels through phosphorylation. Therefor the CB1 receptor indirectly enhances A-type potassium channels. CB1 can also directly inhibit n-type calcium channels. The net result is decreased neurotransmitter release.

When downregulation of CB1 receptors occurs in chronic cannabis users they should see improved firing rate when sober. This lead me to believe increased firing could improve through glutamate-dependent LTP. However according to literature, a majority of neurons containing CB1 receptors in the hippocampus are GABAergic (Tsou et al 1999. Pertwee, 2008. Monory et al, 2006). An increase in GABAergic firing will lead to decreased glutamate-dependent LTP, one of the potential reasons for cognitive impairment in chronic cannabis users (Shrivastava et al, 2011 for a review). Yet research indicates a mechanism which would support my initial hypothesis (see quote from Elphick & Egertová, 2000 below).

My new question and hypothesis are: Why does cannabis use not promote post-synaptic CB1-independent LTP by its inhibition of GABAergic interneurons through CB1 receptor activity? When cannabis is stimulating the CB1 receptor, less GABA is released and subsequently more glutamatergic neurotransmission occurs. This should induce enhanced LTP formation in the hippocampal post-synapses where CB1 influence is not yet presently known. However cannabis use and its immediate memory impairment do not support this hypothesis.

The introduced hypotheses clearly contradict each other and pose a paradoxical problem.

One hypothesis states that chronic cannabis use can cause downregulation of CB1 receptors. While sober, this downregulation will lead to reduced endocannabinoid signalling, increasing glutamatergic neurotransmission in hippocampal tissues and enhancing LTP. The increased glutamatergic activity is supported byElphick & Egertová, 2000.

But is contradicted by several studies indicating that a high percentage of neurons affected by cannabinoids are GABAergic. Leading to an increase of GABA release and inhibited glutamatergic neurotransmission. The cognitive impairment from chronic cannabis use seems to support these studies.

Based on these studies, my second hypothesis states that during increased CB1 activity, more glutamate is released which should enhance LTP. Immediate effects of cannabis such as memory impairment contradict this hypothesis.

The problem is that we do not see enhanced memory formation in chronic cannabis user nor do we se enhanced memory formation during a cannabis high. But I do not see where I make a mistake in my logic or assumptions.

-Jelle