CANNABIS AND SCHIZOPHRENIA A Longitudinal Study of Swedish Conscripts

http://www.student.oulu.fi/~taneliha/15min_Vertailevan_Endokrinologian_opiskelijaesitelma_Endokannabinoidit/Suurin%20osa%20k%E4ytetyist%E4%20artikkeleista/Cannabinoid%20physiology%20and%20pharmacology%2030%20years%20of%20progress.pdf

Cannabinoid physiology and pharmacology: 30 years of progress

Cannabis is one of the most frequently used substances. Cannabis and its constituent cannabinoids are known to impair several aspects of cognitive function, with the most robust effects on short-term episodic and working memory in humans. A large body of the work in this area occurred in the 1970s before the discovery of cannabinoid receptors. Recent advances in the knowledge of cannabinoid receptors’ function have rekindled interest in examining effects of exogenous cannabinoids on memory and in understanding the mechanism of these effects. The literature about the acute effects of cannabinoids on memory tasks in humans is reviewed. The limitations of the human literature including issues of dose, route of administration, small sample sizes, sample selection, effects of other drug use, tolerance and dependence to cannabinoids, and the timing and sensitivity of psychological tests are discussed. Finally, the human literature is discussed against the backdrop of preclinical findings. Acute administration of Δ-9-THC transiently impairs immediate and delayed free recall of information presented after, but not before, drug administration in a dose- and delay-dependent manner. In particular, cannabinoids increase intrusion errors. These effects are more robust with the inhaled and intravenous route and correspond to peak drug levels. This profile of effects suggests that cannabinoids impair all stages of memory including encoding, consolidation, and retrieval. Several mechanisms, including effects on long-term potentiation and long-term depression and the inhibition of neurotransmitter (GABA, glutamate, acetyl choline, dopamine) release, have been implicated in the amnestic effects of cannabinoids. Future research in humans is necessary to characterize the neuroanatomical and neurochemical basis of the memory impairing effects of cannabinoids, to dissect out their effects on the various stages of memory and to bridge the expanding gap between the humans and preclinical literature.

The acute effects of cannabinoids on memory in humans: a review

The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neurons in rat brain slices. Stimulus-evoked GABA A receptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212–2 (EC 50 of 138 nm). This effect was blocked by the CB1 receptor antagonist SR141716A (1 μm) but not by the opioid antagonist naloxone. In contrast, evoked GABA B -mediated IPSCs were insensitive to the CB agonist. WIN 55,212–2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), measured while sodium channels were blocked by tetrodotoxin (TTX). Blockade of voltage-dependent calcium channels (VDCCs) by cadmium also eliminated the effect of WIN 55,212–2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large increase in the frequency of mIPSCs that was inhibited by both cadmium and WIN 55,212–2. The presynaptic effect of WIN 55,212–2 was also investigated using the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212–2 on evoked IPSCs. Together, these data suggest that presynaptic CB1 receptors reduce GABA A - but not GABA B -mediated synaptic inhibition of CA1 pyramidal neurons by inhibiting VDCCs located on inhibitory nerve terminals.

https://www.jneurosci.org/content/jneuro/20/7/2470.full.pdf

Mechanisms of Cannabinoid Inhibition of GABAASynaptic Transmission in the Hippocampus

Cannabinoid receptor binding and messenger RNA expression in human brain: An in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains

The hypothesis is advanced that marihuana and espedaily Δ9-tetrahydrocannabinol, impair certain aspects of hippocampal neural functioning which are necessary for normal cognitive operations

Cannabis: Neural Mechanisms and Behavior – a Theoretical Review

Paid male volunteers were allowed to smoke marihuana cigarettes calibrated to deliver a dose of 25 µg per kilogram of delta-9-tetrahydrocannabinol (Δ-9-THC). All subjects were given propranolol or placebo (administered in a double-blind fashion), in 4 divided doses beginning 24 hours before and ending 2 hours prior to smoking. Marihuana smoking resulted in significant disruption in the recall of narrative material and moderate impairment in performance on a modified version of the Reitan Trail Making test. Stroop-Color Word performance was not affected by marihuana. Propranolol, a beta adrenergic blocking agent, failed to interact with marihuana to reduce its disruptive effects on any of the tests.

Effects of propranolol on marihuana-induced cognitive dysfunctioning

Cannabis: review of behavioral effects in animals.

Δ9-tetrahydrocannabinol alters flow of blood to subcortical areas of the conscious rat brain

In an attempt to ascertain the effect of retrieval cues on recall deficits which occur following intoxication with marijuana. 40 male volunteers were presented with word lists following the smoking of a single one gram marijuana (0.94% Δ9-THC) or placebo cigarette and then were required to recall these words immediately after presentation. Recall occurred under a condition in which cues representative of to-be-remembered words were present or in an uncued condition. Results indicated that recall was depressed following marijuana administration under both cued and uncued conditions with cues being only mildly effective in reversing the recall deficit. There was no increase in the number of internal intrusions under marijuana, but the number of external intrusions was significantly elevated under the cued condition.

William G. Drew

Papers

Cannabis: Neural Mechanisms and Behavior – a Theoretical Review

Effects of propranolol on marihuana-induced cognitive dysfunctioning

Cannabis: review of behavioral effects in animals.

Δ9-tetrahydrocannabinol alters flow of blood to subcortical areas of the conscious rat brain

Marijuana and memory impairment: the effect of retrieval cues on free recall.