This project was initiated to fill a void in our knowledge regarding the neurobiological substrates of the the adverse effects of chronic marijuana use on cognition in humans. It is well-known that both acute and chronic marijuana use in humans impairs short-term memory, reaction times, and general higher-order cognitive processing. These studies seek to utilize animal models to explore the effects of both acute and chronic exposure to the main psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC) on the neurophysiology of the hippocampus and now the ventral tegmanetal area (VTA). Our prior published study showed that repeated injections of THC blocked long-term potentiation (LTP), a cellular correlate of learning and memory. Furthermore, a single injection of THC was insufficient to block LTP, the LTP blockade persisted for 3d after the last THC injection, and it was prevented by pretreatment of the animals before each THC injection with the antagonist AM251 (2 mg/kg). Additional experiments now under way will examine the hypothesis that the CB1 cannabinoid receptor is necessary to permit normal cognition and learning and memory over the life span of an organism. For these studies, we are comparing the level of LTP in hippocampal brain slices obtained from CB1+/+ and -/- animals at various ages. In addition, we are defining the actions of acute THC exposure on individual neurons in hippocampal brain slices using whole-cell recordings. The majority of studies to date have utilized synthetic CB agonists to assess the role of CB1 receptors in modulating hippocampal synaptic function. By comparing the effects of THC to those of these synthetic agonists, we hope to identify putative molecular targets of THC that may help explain memory impairments in humans following chronic marijuana use. Our most recent work has found that whereas THC acts as a partial agonist in the inhibition of glutamate release in the hippocampus, it is a full agonist when its effects are measured on the inhibition of GABA release in the hippocampus. We believe that this difference is due to a much higher CB1 receptor density on GABAergic axon terminals versus glutamate terminals in this brain structure, and we have proposed that this provides strong evidence that the primary site of THC's interaction to disrupt hippocampal-dependent memory is on GABAergic systems. In a separate study that is in review, we have reported that the effects of cannabinoids on hippocampal glutamate release can be greatly potentiated when adenosine A1 receptors are blocked. This suggests that endogenous adenosine is involved in regulating the strength of signaling through CB1 receptors in the hippocampus, and that endocannabinoid function is under control of the adenosine system.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2009
Total Cost
$471,589
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
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