In our ongoing studies to identify the mechanisms through which cannabinoids alter brain function, we have begun collaborating with the Designer Drug Research Unit (DDRU) at the NIDA Intramural Research Program, to compare the pharmacological effects of """"""""designer"""""""" cannabinoids with those of conventional """"""""natural"""""""" cannabinoids such at delta-9-tetrahydrocannabinol (delta-9-THC), found in the marijuana plant. Designer cannabinoids are psychoactive molecules that are often marketed as """"""""incense"""""""" or other plant-related formulations. The psychoactive components of these drugs are typically synthesized in clandestine laboratories by amateur chemists, and in most cases structurally resemble cannabinoid molecules. The synthetic cannabinoids are made in bulk and sprayed onto plant material. The fact that these molecules are made in illicit laboratories without regulatory control often leads to exposure to adulterants and contaminants that can result in unintended toxicity. In addition, the structure of these synthetic cannabinoids is such that they have stronger effects, and longer durations of action at the same cannabinoid receptors that are activated by delta-9-THC. Although many of these drugs are widely consumed, their safety is generally untested, and their complete pharmacological sites of action remain unknown. The illicit nature of these compounds and their incompletely understood pharmacological actions has resulted in a large increase in world-wide emergency room visits by individuals using these drugs. Our initial studies have examined 3 compounds that were isolated from material seized by the U.S. Drug Enforcement Agency (DEA), and subsequently synthesized by professional chemists. These preliminary studies show that the compounds AM-2201, and XLR-11 are full agonists at CB1 receptors that inhibit glutamate release in the hippocampus. This is in contrast to delta-9-THC, which acted as a partial agonist, demonstrating approximately one-half of the ability to inhibit glutamate responses as the synthetic molecules. In addition, these synthetic cannabinoids were much more potent than delta-9-THC on this measure. Another compound that we tested, known as JWH-018, was also more efficacious than delta-9-THC, but less potent than the other 2 synthetic compounds. Our general conclusion thus far is that the synthetic cannabinoids can bind to the cannabinoid CB1 receptor with much greater potency and efficacy than delta-9-THC. We predict that this will lead to a much greater inhibition of neurotransmitter release, and a greater disruption of hippocampus-dependent cognition, and perhaps result in much higher levels of anxiety in humans. Additionally, these pharmacological properties of the synthetic cannabinoids would result in much longer durations of action, compared to delta-9-THC, because of the higher potency.

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Lupica, Carl R; Hoffman, Alexander F (2018) Cannabinoid disruption of learning mechanisms involved in reward processing. Learn Mem 25:435-445
Hoffman, Alexander F; Lycas, Matthew D; Kaczmarzyk, Jakub R et al. (2017) Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with ?9 -tetrahydrocannabinol. Addict Biol 22:390-399
Lupica, Carl R; Hu, Yuhan; Devinsky, Orrin et al. (2017) Cannabinoids as hippocampal network administrators. Neuropharmacology 124:25-37
Wang, Huikun; Lupica, Carl R (2014) Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes. Prog Neuropsychopharmacol Biol Psychiatry 52:24-7
Hoffman, Alexander F; Lupica, Carl R (2013) Synaptic targets of ?9-tetrahydrocannabinol in the central nervous system. Cold Spring Harb Perspect Med 3:
Fitzgerald, Megan L; Chan, June; Mackie, Kenneth et al. (2012) Altered dendritic distribution of dopamine D2 receptors and reduction in mitochondrial number in parvalbumin-containing interneurons in the medial prefrontal cortex of cannabinoid-1 (CB1) receptor knockout mice. J Comp Neurol 520:4013-31
Laaris, Nora; Good, Cameron H; Lupica, Carl R (2010) Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology 59:121-7
Good, Cameron H; Lupica, Carl R (2010) Afferent-specific AMPA receptor subunit composition and regulation of synaptic plasticity in midbrain dopamine neurons by abused drugs. J Neurosci 30:7900-9
Hoffman, Alexander F; Laaris, Nora; Kawamura, Masahito et al. (2010) Control of cannabinoid CB1 receptor function on glutamate axon terminals by endogenous adenosine acting at A1 receptors. J Neurosci 30:545-55