GABA Deficits Enhance the Psychotomimetic Effects of Δ9-THC

Radhakrishnan, Rajiv; Skosnik, Patrick D.; Cortes-Briones, Jose; Sewell, R. Andrew; Carbuto, Michelle; Schnakenberg, Ashley; Cahill, John D.; Bois, Fred; Gunduz‐Bruce, Handan; Pittman, Brian; Ranganathan, Mohini; D’Souza, Deepak Cyril

doi:10.1038/npp.2015.58

Cited by 29 publications

(22 citation statements)

References 52 publications

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“…EEG recording and preprocessing was performed as described previously (Radhakrishnan et al 2015). Briefly, EEG data were collected in an acoustically and electrically shielded booth, and recording was done with the commercially available Active Two acquisition system (Biosemi, the Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans

et al. 2018

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Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively. Human subjects (n = 15) completed four test days during which they received intravenous delta-9-tetrahydrocannabinol (Δ-THC), cannabidiol (CBD), Δ-THC + CBD, or placebo. Subjects engaged in a dual-click paradigm, and outcome measures included P50 gating ratio (S2/S1) and evoked power to S1 and S2. In order to examine CB1R specificity, rats (n = 6) were administered the CB1R agonist CP-55940, CP-55940+AM-251 (a CB1R antagonist), or vehicle using the same paradigm. LFPs were recorded from CA3 and entorhinal cortex. Both Δ-THC (p < 0.007) and Δ-THC + CBD (p < 0.004) disrupted P50 gating ratio compared to placebo, while CBD alone had no effect. Δ-THC (p < 0.048) and Δ-THC + CBD (p < 0.035) decreased S1 evoked theta power, and in the Δ-THC condition, S1 theta negatively correlated with gating ratios (r = -0.629, p < 0.012 (p < 0.048 adjusted)). In rats, CP-55940 disrupted gating in both brain regions (p < 0.0001), and this was reversed by AM-251. Further, CP-55940 decreased evoked theta (p < 0.0077) and gamma (p < 0.011) power to S1, which was partially blocked by AM-251. These convergent human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta-band. Moreover, this suggests that the endocannabinoid system mediates theta oscillations relevant to perception and cognition.

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Section: Methodsmentioning

confidence: 99%

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans

et al. 2018

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“…Accordingly, lower levels of GABAergic functions have been observed in the ACC region of cannabis users compared with control participants (Prescot et al, 2011). Later on, Radhakrishnan et al (2015) have conducted a well-designed double-blind, placebocontrolled, randomized, counter-balanced study in order to assess whether deficits in the GABA system have an impact on the adverse effects of D9-THC in humans. The authors have used Iomazenil which is an antagonist and partial inverse agonist of GABA A receptors in order to model GABA deficits.…”

Section: Effects Of Cannabinoids On Gaba: Evidence From Human Studiesmentioning

confidence: 99%

Modulatory effects of cannabinoids on brain neurotransmission

Cohen

Weizman

Weinstein

2019

Eur J of Neuroscience

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Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti‐nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid‐based drugs effects are not fully known but given the neuro‐modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type‐1 receptors (CB1) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre‐clinical and clinical data on the interactions of CB1 and cannabinoid type‐2 receptors (CB2) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid‐based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health.

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“…+15 and +45, while peak blood ∆ 9 -THC levels occur at the end of the infusion period (i.e. +10) (D'Souza et al, 2012(D'Souza et al, , 2004(D'Souza et al, , 2008Lindgren et al, 1981;Radhakrishnan et al, 2015).…”

Section: Plasma Levelsmentioning

confidence: 99%

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ⁹-THC) in humans

et al. 2018

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Background: Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans. Aims: Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg). Methods: Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention. Results/outcomes: Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions. Conclusions/interpretation: These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.

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GABA Deficits Enhance the Psychotomimetic Effects of Δ9-THC

Cited by 29 publications

References 52 publications

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans

Modulatory effects of cannabinoids on brain neurotransmission

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ⁹-THC) in humans

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GABA Deficits Enhance the Psychotomimetic Effects of Δ9-THC

Cited by 29 publications

References 52 publications

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans

Modulatory effects of cannabinoids on brain neurotransmission

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ9-THC) in humans

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The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ⁹-THC) in humans