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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2020 Jan 24;177(7):1514–1524. doi: 10.1111/bph.14914

Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and Δ9‐tetrahydrocannabinol

Ilya D Ionov 1,✉, Irina I Pushinskaya 2, David D Frenkel 2, Niсholas P Gorev 2, Larissa A Shpilevaya 2
PMCID: PMC7060361  PMID: 31696510

Abstract

Background and Purpose

Memantine and marijuana smoking have been found to inhibit tremor in parkinsonian patients, although the observed effects were relatively weak. The tremorolytic effects of combinations of memantine and cannabinoids have not been studied. Here, we have evaluated the anti‐tremor activity of memantine, Δ9‐tetrahydrocannabinol (THC) given alone and of their combination. The involvement of some neuroanatomical structures in the effects of the combination was evaluated.

Experimental Approach

Haloperidol‐induced tremulous jaw movements (TJMs) in rats were used as a model of parkinsonian‐like tremor. To evaluate the role of central receptor systems in the drug effects, receptor ligands were administered locally into certain brain areas.

Key Results

Memantine and THC alone were without effect, although co‐administration of these drugs decreased the number of haloperidol‐induced jaw movements. The anti‐tremor activity of the combination was antagonized (a) by injections of l‐glutamate into the dorsal striatum, entopeduncular nucleus, substantia nigra pars reticulata, globus pallidus, and supratrigeminal and trigeminal motor nuclei but not into the subthalamic and cuneiform nuclei; (b) by injections of CGS 21680 into the ventrolateral striatum; and (c) by injections of bicuculline into the rostral part of the parvicellular reticular nucleus.

Conclusions and Implications

Memantine and THC supra‐additively inhibit haloperidol‐induced TJMs, suggesting that co‐administration of these drugs might be a new approach to the treatment of tremor. Our results identified brain areas influencing parkinsonian‐like tremor in rats and can help advance the development of novel treatments for repetitive involuntary movements.

Abbreviations

CfN

cuneiform nucleus

dStr

dorsal striatum

EPN

entopeduncular nucleus

GP

globus pallidus

MEM

memantine

PcRr

parvicellular reticular nucleus, rostral part

PD

Parkinson's disease

SNr

substantia nigra pars reticulata

STN

subthalamic nucleus

SupTr

supratrigeminal nucleus

THC

Δ9‐tetrahydrocannabinol

TJM

tremulous jaw movement

TrMN

trigeminal motor nucleus

vlStr

ventrolateral striatum

What is already known

  • Memantine and marijuana smoking alone exert some tremorolytic effects in parkinsonian patients.

Wha this study adds

  • Memantine and Δ9‐tetrahydrocannabinol in combination, but not separately, inhibited haloperidol‐induced mandibular tremor in rats.

  • The brain sites and receptors involved in these effects of the combination were identified.

What is the clinical significance

  • Combinations of memantine and Δ9‐tetrahydrocannabinol might be a new approach to anti‐tremor therapy.

1. INTRODUCTION

Parkinson's disease (PD) is characterized by progressive damage to dopaminergic neurons in the substantia nigra and bradykinesia, postural rigidity, and tremor are the major features of the disease (Hornykiewicz, 1998; Kalia & Lang, 2015; Tretiakoff, 1919). The reduction in dopaminergic activity detected in parkinsonian brain has encouraged attempts to pharmacologically replace the missing neurotransmitter. Treatment with 3,4‐dihydroxy‐l‐phenylalanine (https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3639), a precursor of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940, has provided marked relief of some motor symptoms (Cotzias, Papavasiliou, & Gellene, 1969) and levodopa currently is the main anti‐parkinsonian drug. In the past decades, although a number of other methods of treating PD have been proposed, there is still a clear need for novel therapeutic strategies.

The development of new approaches for the treatment of parkinsonian tremor may be a special task. Tremor mechanistically differs from other parkinsonian signs. The severity of tremor, unlike that of bradykinesia and rigidity, showed poor or no correlation with the intensity of brain dopaminergic transmission (Benamer et al., 2003; Pirker, 2003) and did not clearly worsen with progression of PD (Louis et al., 1999). The difference in mechanisms underlying tremor and other PD‐associated motor dysfunctions is supported by different sensitivity of these signs to pharmacological treatment (Schrag, Schelosky, Scholz, & Poewe, 1999) and by existence of a tremor‐predominant form of parkinsonism (Josephs, Matsumoto, & Ahlskog, 2006).

A novel approach for the treatment of parkinsonian tremor may be through the use of compounds such as https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4253, a https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=75 antagonist and https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2424 a partial agonist at https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=13 receptors. Memantine produced a tremorolytic effect in parkinsonian patients (Fischer, Jacobi, Schneider, & Schönberger, 1977; Merello, Nouzeilles, Cammarota, & Leiguarda, 1999; Rabey, Nissipeanu, & Korczyn, 1992; Schneider et al., 1984) and a similar favourable effect was observed in patients after marijuana smoking (Lotan, Treves, Roditi, & Djaldetti, 2014; Venderová, Růžička, Vorřisšek, & Višňovský, 2004). These findings suggest that THC, believed to be the primary psychoactive constituent of marijuana (Mechoulam, 1970), might also exert tremorolytic activity.

It is possible that memantine and THC would influence parkinsonian tremor via non‐overlapping mechanisms and, if this is the case, co‐administration of the drugs may be more effective than using either of them alone. We intended here to test this possibility.

In our experiments, a tremulous jaw movement (TJM) model was used, as this model shares many of the pharmacological, temporal, and anatomical characteristics of human parkinsonian tremor (Collins‐Praino et al., 2011). These jaw movements can be induced by many conditions that simulate PD‐associated central dopaminergic deficit, in particular, by blockade of central dopaminergic receptors (see Collins‐Praino, Podurgiel, Kovner, Randall, & Salamone, 2012). Here, we induced TJM in rats with https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=86, a dopamine receptor antagonist, as this model is considered to be possibly related to parkinsonian motor dysfunction (see Correa et al., 2004; Salamone et al., 1998).

This study also aimed to identify the brain regions involved in the effects of the memantine + THC combination. Some neuroanatomical structures might be involved in the regulation of haloperidol‐induced TJMs. It is believed that an overactivity of glutamatergic processes in the striatum can be an important cause of PD motor symptoms (Strafella, Ko, Grant, Fraraccio, & Monchi, 2005) and this possibility is supported by the findings that transection of glutamatergic corticostriatal projections suppresses haloperidol‐induced parkinsonian‐like disorders in rats (Scatton, Worms, Lloyd, & Bartholini, 1982; Warenycia, McKenzie, Murphy, & Szerb, 1984). The entopeduncular nucleus (EPN), globus pallidus (GP), subthalamic nucleus (STN), and substantia nigra pars reticulata (SNr), apparently, also may be involved in the regulation of TJM activity and these areas are thought to form a glutamatergic circuit that participates in the development of parkinsonism (Wichmann & DeLong, 1996; Williams & Dexter, 2014). Inhibition of experimental TJM in rats can also be produced by antagonism of https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=19 in the ventrolateral striatum (vlStr; Salamone et al., 2008). Possibly, the jaw muscle activity is regulated by the rostral part of the parvicellular reticular formation (PcRr), a https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1067‐enriched area (Ginestal & Matute, 1993) that sends projections to the premotor neurons of the supratrigeminal nucleus (SupTr; Ter Horst, Copray, Liem, & van Willigen, 1991). The SupTr probably controls the trigeminal motor nucleus (TrMN; Fujio et al., 2016), which, in turn, innervates the masticatory musculature. The SupTr possibly stimulates jaw muscle activity via ionotropic glutamate receptors (Nakamura et al., 2008). The chewing muscle activity may be regulated by glutamatergic processes in the cuneiform nucleus (CfN; Hashimoto, Katayama, Ishiwata, & Nakamura, 1989). All these brain areas might be targeted by the memantine + THC combination and, here, we have tested these possibilities.

2. METHODS

2.1. Animals

All animal care and experimental animal procedures were conducted according to the European Communities Council Directive 2010/63/EU and approved by the Local Ethics Committee for Animal Experimentation. Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny, Browne, Cuthill, Emerson, & Altman, 2010) and with the recommendations made by the British Journal of Pharmacology.

Male Sprague Dawley rats (“Timpharm” Animal Farm, Moscow region, Russia; RRID:MGI:5651135), weighing 280–300 g at the time of testing, were included in the experiments. The animals were housed four per cage in a well‐ventilated colony room having a 12‐hr light/dark cycle (lights on at 7:00 a.m.) and temperature of 22°C. The rats received standard laboratory rat chow and tap water ad libitum. The animals were adapted to these conditions for a minimum of 2 weeks before the experiments. For the experiments, the animals were divided randomly into groups.

2.2. Pharmacological interventions

https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=86 was dissolved in 1% lactic acid (vehicleHAL; Costall, Hui, & Naylor, 1978), and MEM and THC were dissolved in sterile physiological saline (0.9% NaCl in apyrogenic water) containing 5% ethanol and 2% Tween 80 (vehicleMEM/THC; Bosier et al., 2012). Haloperidol (0.01, 0.05, and 0.5 mg·kg−1; 1.0 ml·kg−1) was injected i.p.; memantine (0.5, 2.5, and 25.0 mg·kg−1; 1.0 ml·kg−1) and THC (0.1, 0.5, and 5.0 mg·kg−1; 1.0 ml·kg−1) were injected i.m.. All three drugs were given once a day for 10 consecutive days. Haloperidol was injected between 8:30 a.m. and 10:30 a.m.; memantine and THC were administered 30 min before haloperidol.

https://www.guidetopharmacology.org/GRAC/DatabaseSearchForward?searchString=L-glutamic+acid+&searchCategories=all&species=none&type=all&comments=includeComments&order=rank&submit=Search+Database monosodium salt monohydrate (glutamate; 5.0 and 50.0 fg), https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=375 (2‐p‐(2‐carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamidoadenosine hydrochloride hydrate; 0.5 and 12.5 pg), and (−)‐bicuculline methiodide (https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2312; 2.0 and 40.0 ng) were injected intracerebrally immediately after haloperidol. These agents were dissolved in sterile saline (vehicle).

The choice of the doses was based on the results of previous studies (Arnt & Scheel‐Krüger, 1979; Bosier et al., 2012; Ciotu, Lupuliasa, Chiriţă, Zbarcea, & Negreş, 2016; Colombari, Bonagamba, & Machado, 1994; Iseri et al., 2011; Popoli & Caporali, 1993; Steinpreis & Salamone, 1993; Uchida et al., 2005; Verrico, Jentsch, Roth, & Taylor, 2004). The doses were calculated as anhydrous bases and all the drugs were dissolved just before administration.

2.3. Assessment of TJMs

Observations of rats took place in a 30 × 30 × 30‐cm clear Plexiglas chamber with a wire mesh floor that was elevated 40 cm from the table top. This allowed for the viewing of the animal from several angles, including underneath. TJMs were defined as rapid vertical deflections of the lower jaw that resembled chewing but were not directed at any particular stimulus (Salamone et al., 1998). Yawning, gaping, and tongue protrusions were not counted as jaw movements; if an animal groomed, no jaw movements were counted during that time. Each individual deflection of the jaw was recorded by trained observers who were blinded to the experimental condition of the rat being observed. Studies of inter‐rater reliability indicate that greater than 96% agreement between observers is obtained by using this method.

Prior to the start of each experiment, all rats received 2 days of habituation in the observation chamber for 30 min. Fifty minutes after the last haloperidol injection, the animal was placed in the Plexiglas observation chamber and allowed 10 min to habituate, after which TJMs were counted for 5 min.

Tactile stimulation of the animals (handling) was minimized for at least 24 hr before the start of the experiment.

2.4. Intracerebral administration

The tested agents were injected intracerebrally using stainless steel 26‐gauge guide cannulae and 33‐gauge injection cannulae.

2.4.1. Installation of guide cannulas

The cannulas were installed under aseptic conditions. The animal was anaesthetized with (±)‐ketamine hydrochloride (ketamine) and xylazine hydrochloride (xylazine; 75 and 7.5 mg·kg−1, i.p., respectively), injected with gentamicin sulfate (5 mg·kg−1, i.m.), and fixed in a stereotaxic frame (David Kopf, USA) in flat‐skull position using non‐traumatic ear bars. The guide cannula was implanted into the brain tissue by using stereotaxic coordinates (Paxinos & Watson, 1998). The microinjection coordinates are shown in Table 1.

Table 1.

Microinjection parameters

Structure Coordinatesa of guide cannula (mm) Location of injection cannula tipb
AP (from bregma) ML DV (from dura)
Dorsal striatum (dStr) +0.70 +2.5 3.4 0.6
Ventrolateral striatum (vlStr) +0.50 +4.0 5.9 1.0
Globus pallidus (GP)c −1.60 +3.4 5.0 1.5
Entopeduncular nucleus (EPN)d −2.50 +2.6 5.8 2.0
Subthalamic nucleus (STN) −3.80 +2.5 6.0 2.0
Substantia nigra pars reticulata (SNr) −5.60 +2.0 7.2 1.0
Supratrigeminal nucleus (SupTr) −9.00 +1.8 5.7 2.0
Cuneiform nucleus (CfN) −8.30 +1.8 5.2 1.0
Trigeminal motor nucleus (TrMN) −9.00 +2.0 6.2 2.0
Parvicellular reticular nucleus, rostral part (PcRr) −10.80 +2.3 6.7 2.0
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a

Coordinates according to the Paxinos and Watson (1998) atlas: AP, anterior–posterior; DV, dorsoventral; ML, mediolateral.

b

Extension (in mm) of the injection cannula beyond the tip of the guide cannula.

c

In the Paxinos and Watson (1998) atlas, “lateral globus pallidus.”

d

In the Paxinos and Watson (1998) atlas, “medial globus pallidus.”

After insertion, the guide cannula was affixed to the skull with dental acrylic cement and stainless steel screws. A stylette inside the guide cannula prevented obstruction. The incision area was treated topically with Polysporin Triple antibiotic ointment. At the end of the surgical procedures, the animal received an injection of flunixin meglumine (2.5 mg·kg−1, i.m.). The animal was allowed 7 days of recovery after the surgery, with ad libitum access to food and water.

2.4.2. Microinjection procedure

The injection cannula was connected to a Hamilton microsyringe by polyethylene tubing, and a volume of 1.0 μl of vehicle or drug solution was delivered into the brain tissue at a constant rate of 0.5 μl·min−1. After the injection was complete, the injection cannula was left in place for an additional 2 min and then withdrawn and replaced by an obturator (Corrigall, Coen, Zhang, & Adamson, 2001).

2.5. Histological identification of microinjection sites

Upon completion of the experiments, rats were deeply anaesthetized with a ketamine/xylazine mixture (100/7.5 mg·kg−1, i.p.) and perfused intracardially with physiological saline solution followed by paraformaldehyde solution (4%). After decapitation, a volume of 0.5 μl of saline containing 0.5% neutral red was injected in the sites of injections for better visualizing and also to control the spread of the volume injected. The brains were removed and stored in 10% formalin with 30% sucrose until they sank. Afterwards, the brains were frozen, and coronal serial 20‐ to 50‐μm sections were cut using a microtome. Sections were stained with cresyl violet in order to localize the sites of microinjections according to the Paxinos and Watson (1998) atlas.

2.6. Outline of the experiments

Initially, the dose–effect relationship for the tremorogenic action of haloperidol was determined, and the lowest effective dose of the drug was identified. This dose was used in all subsequent experiments. In the next studies, anti‐tremor activity of memantine and THC, given alone, was evaluated and ineffective doses of memantine and THC were selected. Further, the anti‐tremor effects of memantine and THC alone and in combination were compared. In these experiments, each group consisted of eight animals. In separate experiments, the sensitivity of the memantine + THC effect to a range of receptor ligands, namely, l‐glutamate, CGS 21680 (an adenosine A2A receptor agonist), and bicuculline (a https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=72 antagonist), was examined. All the animals were cannulated and received one of the following treatments: (a) haloperidol (i.p.), vehicleMEM/THC (i.m.), and vehicle (i.c.); (b) haloperidol (i.p.), vehicleMEM/THC (i.m.), and agonist/antagonist (i.c.); (c) haloperidol (i.p.), memantine–THC combination (i.m.), and vehicle (i.c.); and (d) haloperidol (i.p.), memantine–THC combination (i.m.), and agonist/antagonist (i.c.). Each treatment group consisted of 12 rats.

2.7. Selection of results for statistical analysis

All the cannulated animals were tested for TJM activity. Further, the brains of the cannulated rats were histologically examined and, in each group, the first eight animals with correct cannula placements were included in the data analyses. Data from animals with misplaced cannulas were discarded. Figure 1 shows the sites of microinjections in animals included in the statistical analyses.

Figure 1.

Figure 1

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Sites of microinjections. Plates are taken from the Paxinos and Watson (1998) atlas, and the coordinates of the sections from bregma (in mm) are displayed in parentheses. Abbreviations are explained in Table 1. The number of injection sites in the figures is less than the total number of sites detected in this section because several circles overlap

2.8. Data and statistical analysis

The data and statistical analysis comply with the recommendations of the British Journal of Pharmacology on experimental design and analysis in pharmacology. The Shapiro–Wilk W test was used to assess the normality of the data distribution. As the normality assumptions could not be accepted, comparisons were made with non‐parametric Mann–Whitney U test. Pairwise analysis of TJM activity was performed between intact, solvent‐treated, and drug‐treated animals. Differences with a P value of less than .05 were considered statistically significant.

Data are expressed as mean ± SEM. The statistical analyses were undertaken using GraphPad® Prism 7 (GraphPad Software Inc., CA, USA; GraphPad Prism, RRID:SCR_002798).

2.9. Materials

Haloperidol, memantine, THC solution, glutamate, CGS 21680, bicuculline, ketamine, xylazine, and flunixin meglumine were obtained from Millipore Sigma (St. Louis, MO, USA). Gentamicin sulfate was supplied by Krka (Slovenia) and Polysporin Triple antibiotic ointment by Johnson & Johnson Inc.

2.10. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Christopoulos et al., 2019; Alexander, Mathie et al., 2019).

3. RESULTS

3.1. Tremorogenic action of haloperidol

Haloperidol (0.01 and 0.05 mg·kg−1) failed to increase the number of TJMs (5.5 ± 0.73 and 6.12 ± 0.74, respectively, compared with 4.5 ± 0.42 TJMs in the corresponding vehicleHAL‐treated control group). However, at 0.5 mg·kg−1, haloperidol was tremorogenic, inducing 21.38 ± 1.90 TJMs, significantly greater than those in the control group. This dose of haloperidol was used in the subsequent experiments.

3.2. Influence of memantine and THC on haloperidol‐induced TJMs

Animals receiving memantine at doses of 0.5, 2.5, and 25.0 mg·kg−1 demonstrated 16.12 ± 0.72, 15.50 ± 1.02, and 14.75 ± 1.29 jaw movements, respectively, compared with 18.00 ± 0.71 TJMs in rats injected with haloperidol + vehicleMEM/THC showing no significant differences between memantine‐treated and vehicleMEM/THC‐treated groups. The number of TJMs in the rats treated with 2.5 and 25.0 mg·kg−1 were not significantly different.

THC, given alone, did not affect the tremorogenic effect of haloperidol, as 0.1, 0.5, and 5.0 mg·kg−1 THC induced 16.38 ± 0.85, 14.62 ± 1.10, and 14.88 ± 0.91 TJMs respectively, compared with 17.12 ± 0.72 TJMs in the haloperidol+ vehicleMEM/THC group. The number of TJMs in the rats treated with 5.0 mg·kg−1 did not significantly differ from that in animals treated with 0.5 mg·kg−1. As a result of these initial experiments, memantine at 2.5 mg·kg−1 and THC at 0.5 mg·kg−1 were used in the following experiments.

3.3. Effects of memantine–THC combination on haloperidol‐induced TJMs

The rats injected with vehicleHAL + vehicleMEM/THC demonstrated 4.88 ± 0.52 TJMs, whereas in the haloperidol + vehicleMEM/THC group, there were significantly more (17.38 ± 0.82) TJMs. Memantine (2.5 mg·kg−1) or THC (0.5 mg·kg−1) given alone did not influence the haloperidol‐induced effect and the mean number of jaw movements in the drug‐treated animals was 16.38 ± 1.05 and 17.12 ± 1.18, respectively. However, the combination of memantine and THC almost totally reversed the tremorogenic effect of haloperidol, with the combination‐treated rats showing 6.62 ± 0.50 TJMs. This level of TJMs was not different from that in the animals treated with vehicleHAL + vehicleMEM/THC.

3.4. The brain areas involved in the effects of the memantine + THC combination

Several receptor‐mediated processes in the brain have been described concerning the regulation of jaw movements (see Section 1). With these reports in mind, we performed the experiments described below.

3.4.1. Dependence of the memantine + THC effect on glutamatergic processes in the dorsal striatum

The effect of the combination was antagonized by intra‐dorsal striatum (dStr) administration of glutamate. Although the dose of 5.0 fg was ineffective (no difference was revealed between agonist‐treated animals and the corresponding control group), injection of 50.0 fg of glutamate increased TJM activity in the combination‐treated animals (Figure 2a). Note that this dose of glutamate (50 fg), in the absence of the combination, did not alter the tremorogenic effect of haloperidol (Figure 2a).

Figure 2.

Figure 2

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Inhibition of the combination effect by injections into different brain areas: (a) dorsal striatum, (b) entopeduncular nucleus, (c) substantia nigra pars reticulata, (d) globus pallidus, (e) ventrolateral striatum, (f) rostral part of the parvicellular reticular nucleus, (g) supratrigeminal nucleus, and (h) trigeminal motor nucleus. HAL, haloperidol (0.5 mg·kg−1); MEM, memantine (2.5 mg·kg−1); THC, Δ9‐tetrahydrocannabinol (0.5 mg·kg−1). Data are presented as individual numbers of jaw movements, with means ± SEM; n = 8. # P < .05, significantly different from haloperidol + vehicle group. *P<.05, significantly different from memantine + THC group

3.4.2. Dependence of the memantine + THC effect on glutamatergic processes in the EPN

Glutamate (5.0 fg) injected into the EPN, failed to influence the effect of the combination but, at the higher dose (50 fg) did suppress the combination effect (Figure 2b). Again, glutamate (50 fg) did not affect the number of TJMs induced by haloperidol.

3.4.3. Dependence of the memantine + THC effect on glutamatergic processes in the SNr

Glutamate injected into the SNr significantly reversed the memantine + THC‐induced decrease in TJM activity only at the dose of 50 fg. Intra‐SNr injections of glutamate alone at this dose did not alter the tremorogenic effect of haloperidol (Figure 2c).

3.4.4. Dependence of the memantine + THC effect on glutamatergic processes in the GP

Intra‐GP injections of only the higher dose of glutamate (50fg) significantly reduced the effect of the memantine + THC combination. Glutamate alone failed to influence tremorogenic activity of haloperidol (Figure 2d).

3.4.5. Dependence of the memantine + THC effect on glutamatergic processes in the STN

In this set of experiments, the animals injected with haloperidol, vehicleMEM/THC., and vehicle demonstrated 18.62 ± 1.10 TJMs, and treatment with the memantine + THC combination significantly reduced this value to 7.62 ± 0.86 TJMs. However, intra‐STN injections of glutamate at either 5.0 or 50.0 fg failed to suppress the effect of the combination, showing 7.50 ± 0.78 or 9.75 ± 0.98 TJMs, respectively.

3.4.6. Dependence of the memantine + THC effect on A2A receptor mediated processes in the vlStr

Injections of the A2A receptor agonist CGS 21680 into the vlStr reversed the effects of the memantine + THC combination on haloperidol‐induced TJMs. (Figure 2e). CGS 21680 at the lower dose (0.5 pg ) was without effect but the higher dose (12.5 pg) significantly increased the number of TJMs in the memantine + THC group. Given by itself, CGS 21680 (12.5 pg) did not affect the number of TJMs induced by haloperidol alone.

3.4.7. Dependence of the memantine + THC effect on GABAA‐ergic processes in the PcRr

The contribution of GABAA receptor‐mediated processes to the effects of the combination were assessed with bicuculline. Intra‐PcRr injections of bicuculline, an antagonist of GABAA receptors, at the dose of 2.0 ng did not influence the effect of the memenatine +THC combination (Figure 2f). However, a higher dose of this antagonist (40 ng) did significantly increase the number of TJMs in the group treated with the memantine + THC combination. Injection of bicuculline (40 ng) in animals treated with haloperidol only did not affect the number of TJMs (Figure 2f).

3.4.8. Dependence of the memantine + THC effect on glutamatergic processes in the CfN

In these experiments, haloperidol per se produced 21.12 ± 0.83 TJMs and the memantine + THC combination reduced this number to 8.38 ± 0.78 TJMs. Intra‐CfN injections of glutamate (5.0 or 50.0 fg) failed to change the memantine + THC effect, as the mean number of TJMs was 9.12 ± 0.69 and 10.38 ± 0.68, respectively. These values did not differ from those in the rats treated with the memantine + THC combination + vehicle.

3.4.9. Dependence of the memantine + THC effect on glutamatergic processes in the SupTr

Intra‐SupTr injections of glutamate at either dose (5.0 or 50.0 fg) significantly inhibited the effect of the memantine + THC combination. The 50.0‐fg dose was significantly more effective than the lower dose. Glutamate (50 fg) failed to affect the tremorogenic effect of haloperidol (Figure 2g).

3.4.10. Dependence of the memantine + THC effect on glutamatergic processes in the TrMN

Glutamate at the doses of 5.0 and 50.0 fg, when injected into the TrMN, significantly reversed the memantine + THC effect. The higher dose of glutamate (50.0 fg) was significantly more effective than the lower dose (5.0 fg). Glutamate at the dose of 50 fg failed to influence tremorogenic effect of haloperidol (Figure 2h).

4. DISCUSSION

NMDA receptor antagonists and marijuana have been reported to exhibit an anti‐parkinsonian and tremorolytic activity but the therapeutic effect of these interventions in PD patients was only weak (Fischer et al., 1977; Lotan et al., 2014; Merello et al., 1999; Rabey et al., 1992; Schneider et al., 1984; Venderová et al., 2004). In the present study, the ability of memantine and of THC to influence repetitive tremor‐like jaw movements (TJMs) in rats, a model relevant to PD, was evaluated. In this model, the TJMs were induced by haloperidol.

In our model, memantine and THC, when given alone, were inactive over a relatively wide dose ranges and the dose–response relationship for both drugs could be characterized as a plateau effect. Given this, it does not seem likely that further increase in the doses of memantine or THC would lead to significant inhibition of TJM activity. However, a substantial increase in tremorolytic effect was achieved through combining the drugs. Combination of low and ineffective doses of memantine and THC largely reversed the tremorogenic effect of haloperidol (Section 3.3). In these experiments, memantine and THC appeared to interact supra‐additively.

This supra‐additive effect of the combination might be underpinned by the activity of THC. In addition to its intrinsic tremorolytic action, THC may heighten the memantine effect. Stimulation of CB1 receptors reportedly can inhibit NMDA receptor‐dependent signalling pathways (Hampson, Miller, Palchik, & Deadwyler, 2011; Liu, Bhat, Bowen, & Cheng, 2009), thereby enhancing MEM‐induced effect. This cannabinoid action possibly underlies the synergy between another agonist of CB1/2 receptors, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=733, and memantine in producing hypothermia in rats (Rawls, Cowan, Tallarida, Geller, & Adler, 2002).

Some comments can be made about the processes involved in the effects of the combination of memantine + THC. It is quite possible that systemically administered memantine and THC act by affecting the striatum, an area that is thought to be essential for the development of parkinsonian‐like motor dysfunctions, and experimental parkinsonism can be causally related to a deficiency in striatal dopaminergic neurotransmission (see Wadenberg, Soliman, VanderSpek, & Kapur, 2001). Both memantine and THC reportedly stimulate dopamine release in the striatal tissue (Malone & Taylor, 1999; Spanagel, Eilbacher, & Wilke, 1994). This may lead to an inhibition of haloperidol‐induced central dopaminergic deficiency and, as a result, suppress parkinsonian‐like TJM activity. An inhibition of corticostriatal glutamatergic transmission might be another target for memantine + THC action. An overactivation of corticostriatal glutamatergic pathways may play an important role in the development of extrapyramidal disorders (Strafella et al., 2005). This view is supported, particularly, by the fact that an inhibition of corticostriatal drive in rats suppresses haloperidol‐induced catalepsy, an animal model of parkinsonian bradykinesia and rigidity (Scatton et al., 1982; Warenycia et al., 1984). Both memantine and THC were found to inhibit corticostriatal synaptic transmission (see Brown, Brotchie, & Fitzjohn, 2003; Lu, Lin, & Wang, 2010) that can underpin the combination effect we observed.

Our data allowed us to identify the brain areas involved in the regulation of the memantine + THC effect. Several of the examined structures—dStr, EPN, GP, SNr, and STN—participate in the so‐called direct and indirect basal ganglia pathways, which are thought to be important for the striatal regulation of motor activity. In this network, a special role is possibly played by the glutamatergic connections (Albin, Young, & Penney, 1989; Smith, Bevan, Shink, & Bolam, 1998; Williams & Dexter, 2014). In our experiments, we found that the “direct” dStr–EPN/SNr pathway contributed to the glutamatergic regulation of the anti‐tremor effects of the memantine + THC combination (Figure 2a–c). At the same time, the “indirect” dStr–GP–STN–EPN/SNr pathway was only partly involved in this regulation, as intra‐GP injections of glutamate appeared effective (Figure 2d) but administration of glutamate into the STN failed to influence tremorolytic action of the MEM–THC combination. In all likelihood, the STN is unnecessary for GP–EPN/SNr connectivity. Indeed, pallidal neurons are known to be directly connected to the EPN, bypassing the STN (see Bolam & Smith, 1992). It is possible that the EPN neurons can process information stemming from both the “direct” and “indirect” pathways (Lavian et al., 2017).

The memantine + THC combination effect was also reversed by glutamate injections into the SupTr and TrMN (Figure 2g,h), suggesting that the combination directly affects the premotor and motor neurons participating in the control of the jaw muscle. The combination effect was found to be antagonized by intra‐vlStr administration of an adenosine A2A receptor agonist, CGS 21680 (Figure 2e). These data are consistent with the ability of an A2A receptor antagonist, MSX‐3, to inhibit https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=90‐induced TJMs in rats (Salamone et al., 2008). The effect of CGS 21680 in our experiments could be caused by a stimulation of the striatal glutamatergic activity which, as noted above, may be essential for the development of parkinsonian‐like motor disorders. Stimulation of A2A receptors prevented the CB1 receptor‐mediated inhibition of glutamate release in superfused rat striatal nerve terminals (Martire et al., 2011). The memantine + THC effect was also abolished by intra‐PcRr injections of bicuculline, an antagonist of GABAA receptors (Figure 2f) and it seems possible that GABAA‐ergic processes within the PcRr inhibit TJM activity. Collectively, these data shed light on the neural circuitry governing the parkinsonian‐like TJM activity in rats and can help advance the development of novel treatments for repetitive involuntary movements.

In these results, there is another point of interest. The effect of the memantine + THC combination was antagonized by intra‐TrMN glutamate injections (Figure 2h). This finding suggests the ability of the combination to inhibit glutamatergic drive onto TrMN motoneurons. The overactivation of glutamate receptors is thought to be a probable cause of motoneuronal death in such a rapidly progressive, fatal disease as amyotrophic lateral sclerosis (ALS; see Ionov, 2007; Ionov & Roslavtseva, 2012). Accordingly, the search for effective protection of the motor neurons from glutamatergic drive is a high priority. In light of this, the combined use of memantine and THC might be a novel therapeutic approach to the treatment of ALS.

In summary, we showed here, for the first time, that low‐dose combination of memantine and THC efficiently inhibited the development of repetitive involuntary tremor‐like movements in rats. Given the possible translational value of this effect, further study of the memantine + THC combination seems warranted.

AUTHOR CONTRIBUTIONS

I.D.I. conceived and designed the study, performed the experiments, analysed the data, and wrote the manuscript. I.I.P., D.D.F., N.P.G., and L.A.S. performed the experiments and analysed the data. All authors read and approved the final version of the manuscript.

CONFLICT OF INTEREST

The authors declare no conflicts of interest. I.I.P., D.D.F., N.P.G., and L.A.S. are employees of a commercial company Timpharm LTD.

DECLARATION OF TRANSPARENCY AND SCIENTIFIC RIGOUR

This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigour of preclinical research as stated in the BJP guidelines for https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14207 and https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14206 and as recommended by funding agencies, publishers, and other organizations engaged with supporting research.

ACKNOWLEDGEMENTS

I.D.I. is indebted to his long‐standing mentors, Prof. Igor Efimovich Kovalev and Prof. Lev Aramovich Piruzyan. Technical support of this research by “Timpharm Ltd.” (Moscow, Russia) is highly appreciated. The authors are grateful to Dr Nicholas N. Severtsev for his collaboration. The study was supported by the Ministry of Science and Higher Education of the Russian Federation (Project АААА‐А18‐118012390247‐0).

Ionov ID, Pushinskaya II, Frenkel DD, Gorev NP, Shpilevaya LA. Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and Δ9‐tetrahydrocannabinol. Br J Pharmacol. 2020;177:1514–1524. 10.1111/bph.14914

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