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Review
. 2017 Jun 21:8:399.
doi: 10.3389/fphar.2017.00399. eCollection 2017.

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

Rafael N Ruggiero  1 , Matheus T Rossignoli  1 , Jana B De Ross  1 , Jaime E C Hallak  1   2 , Joao P Leite  1 , Lezio S Bueno-Junior  1
Affiliations
Review

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

Rafael N Ruggiero et al. Front Pharmacol. .

Abstract

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.

Keywords: animal models; cannabinoids; electrophysiology; functional imaging; schizophrenia; vanilloids.

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Figures

Figure 1
Figure 1
Rodent electrophysiology literature on cannabinoids and vanilloids in schizophrenia-relevant circuits: emphasis on methods. (A) Top: Frequently studied brain sites and axonal pathways. To our knowledge, projections like VTA-mPFC, mPFC-NAc, and mPFC-BLA have not yet been directly examined, and are therefore omitted for simplicity. Dashed lines represent GABAergic pathways. Only the left hemisphere is represented (brain sites adapted from the Brain Explorer, Allen Institute). Bottom: Main electrophysiological findings, mostly from in vivo experiments (see also Figures 2, 3). (B) Top: representative brain sites and manipulations of in vitro studies (coronal sections adapted from Paxinos and Watson, ; see also Figure 3). Bottom: illustrative recording probe, e.g., glass or steel microelectrode, from which LFP (beige area) and single-unit firing (green area) can be recorded upon adequate filtering, amplification, and digitization. The middle voltage trace represents a field potential response to afferent electrical or auditory stimulation, both of which present in the reviewed literature. The gray area roughly indicates the timescale between types of signal. (C) Prevalent behavioral tests in the reviewed literature, most of them performed separately from electrophysiological experiments. Adolesc, adolescent; BLA, basolateral amygdala; condit, conditioning; eCB-LTD, endocannabinoid long-term depression; Ket, ketamine; L5/6, layers 5/6; LFP, local field potentials; MAM, methylazoxymethanol acetate; Meth, methamphetamine; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; NOR, novel object recognition; PCP, phencyclidine; PPI, prepulse inhibition of the acoustic startle; THC, delta-9-tetrahydrocannabinol; TTX, tetrodotoxin; vHipp, ventral hippocampus; VP, ventral pallidum; VTA, ventral tegmental area; WIN, WIN 55,212-2.
Figure 2
Figure 2
Summary of in vivo unit activity studies in rodents. (A) Afferent stimulation experiments on BLA-responsive mPFC cells (Laviolette and Grace, 2006), and the top-down control of dopamine signaling (Draycott et al., ; Melis et al., 2004a). Electrical pulses (lightning icons) and their timestamps (yellow arrowheads) are illustrated along with recording sweeps, and overall effects of cannabinoid manipulations on unit activity responses (vertical arrows). Green and blue neurons are glutamatergic and dopaminergic, respectively. (B) Studies on: (1) CB1 receptor activation in vHipp (Loureiro et al., 2015, 2016); (2) downstream consequences of vHipp hyperactivity (i.e., abnormal NAc-VP-VTA disinhibition) induced by the chronic PCP model of schizophrenia, and ameliorating effects of anandamide upregulation through FAAH inhibition (URB-597) (Aguilar et al., 2014); and (3) URB-597 effects on mPFC firing in PCP-treated rats (Aguilar et al., 2016). Red neurons are GABAergic. (C) Studies on behavioral phenotypes and VTA spontaneous activity, either after pubertal cannabinoid exposure, or in the gestational MAM model (Gomes et al., ; Renard et al., 2016). Activ, activation; Adolesc, adolescent; amph, amphetamine; condit, conditioning; BLA, basolateral amygdala; gestat, gestational; hyperlocom, hyperlocomotion; MAM, methylazoxymethanol acetate; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; normaliz, normalization; PCP, phencyclidine; PPI, prepulse inhibition of the acoustic startle; THC, delta-9-tetrahydrocannabinol; vHipp, ventral hippocampus; VP, ventral pallidum; VTA, ventral tegmental area; WIN, WIN 55,212-2.
Figure 3
Figure 3
Summary of in vivo field potential and in vitro synaptic plasticity studies in rodents. (A) Left: evaluation of mPFC responses (see voltage deflection) to vHipp train stimulation (see lightning icons), and the mPFC capacity to engage in ketamine-potentiated gamma oscillations (see spontaneous field potentials) after adolescent WIN treatment (Raver et al., ; Cass et al., 2014). Right: attenuating effects of rimonabant on methamphetamine-potentiated stereotypy and accumbal gamma oscillations (Morra et al., 2012). Green and red neurons are glutamatergic and GABAergic, respectively. (B) Overall effects of cannabinoid agonists on spontaneous theta oscillations and auditory evoked potentials across entorhinal cortical and hippocampal circuits (Dissanayake et al., ; Hajós et al., 2008), and relationships with schizophrenia-relevant mouse models and manipulations (Smucny et al., 2014). (C) In vitro assessment of mPFC synaptic plasticity and glutamatergic neurotransmission after adolescent WIN or early-life PCP exposure: association with schizophrenia-like symptoms (Lafourcade et al., ; Jew et al., ; Lovelace et al., 2014, 2015). (D) In vitro assessment of CA1 synaptic plasticity and eCB neurotransmission: relationships with schizophrenia risk factors and cannabinoid receptor activation (Du et al., ; Kim and Li, ; Li and Kim, 2016). 2-AG, 2-arachidonoyl-glycerol; adolesc, adolescent; antag, antagonism; dent, dentate; eCB-LTD, endocannabinoid long-term depression; ent, entorhinal; γ, gamma oscillations; hyperlocom, hyperlocomotion; KO, knockout; L, layer; LTP, long-term potentiation; meth, methamphetamine; mGluR, metabotropic glutamate receptors; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; PCP, phencyclidine; relev, relevant; SCZ, schizophrenia; θ, theta oscillations; vHipp, ventral hippocampus; WIN, WIN 55,212-2.
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