Cannabinoid Modulation of Object Recognition and Location Memory—A Preclinical Assessment

C H A P T E R

31 Cannabinoid Modulation of Object Recognition and Location MemorydA Preclinical Assessment Rose Chesworth*,1, Georgia Watt*, Tim Karl*,x *School of Medicine, Western Sydney University, Campbelltown, NSW, Australia; xNeuroscience Research Australia, Randwick, NSW, Australia 1 Corresponding author

List of Abbreviations 2-AG 2-arachidonoylglycerol A2A Adenosine 2A Ab1-42 Amyloid-b 1-42 ACEA Arachidonyl-20 -chloroethylamide AD Alzheimer’s disease APPxPS1 Amyloid precursor protein/presenilin 1 BDNF Brain-derived neurotrophic factor CAMKIV Calcium-/calmodulin-dependent protein kinase type IV CBD Cannabidiol CB1R Cannabinoid receptor 1 CB2R Cannabinoid receptor 2 CP CP55,940 CREB cAMP response element-binding protein COX-2 Cyclooxygenase DBH Dopamine b-hydroxylase DISC1 Disrupted in Schizophrenia 1 eCB Endocannabinoid FAAH Fatty acid amide hydrolase Fmr1 Fragile X Mental Retardation 1 GABA g-Aminobutyric acid HP Hemopressin i.c.v. Intracerebroventricular

IL Interleukin iNOS Inducible nitric oxide synthase i.p. Intraperitoneal KO Knockout LTD Long-term depression LTP Long-term potentiation mPFC Medial prefrontal cortex NMDAR n-methyl-D-aspartate receptor NOL Novel object location NOR Novel object recognition OEA Oleoylethanolamide PEA Palmitoylethanolamide PFC Prefrontal cortex PND Postnatal day RVD (m)RVD-hemopressin(a) s.c. Subcutaneous THC D9-tetrahydrocannabinol THCV Tetrahydrocannabivarin TNF-a Tumour necrosis factor a VD (m)VD-hemopressin(a) WIN WIN-55,212-2 WT Wild type-like

1. INTRODUCTION The endogenous cannabinoid (endocannabinoid: eCB) system is a highly complex receptor system that is widely distributed through the central and peripheral nervous systems. It is involved in a range of cellular and molecular processes that regulate functions such as analgesia (Burston and Woodhams, 2014), anxiety (Lutz et al., 2015),

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31. CANNABINOID MODULATION OF OBJECT RECOGNITION

inflammation (De Laurentiis et al., 2014) and learning and memory (Kruk-Slomka et al., 2016). The eCB system is constituted by two main receptors (e.g., cannabinoid receptors 1 and 2, CB1R and CB2R, respectively) and endogenous ligands that regulate neurotransmission and govern neurodevelopment (i.e., 2-arachidonoylglycerol [2-AG] and N-arachidonoylethanolamine [anandamide]) (Battista et al., 2012). The effects of endocannabinoids are primarily mediated by CB1R and CB2R, but endocannabinoids can also affect other receptors (e.g., peroxisome proliferatoreactivated receptors and transient receptor potential channels) (Lu and Mackie, 2016). Extensive research has been carried out into the behavioural and neural processes modulated by the eCB system, using pharmacological agents that target cannabinoid receptors (e.g., phytocannabinoids, cannabinoid receptor agonists/antagonists, synthetic cannabinoids) or endocannabinoid enzymes (e.g., fatty acid amide hydrolase [FAAH], monoacylglycerol lipase), as well as genetic tools that permit modulation of cannabinoid receptors on specific cell types. Recently there has been considerable interest in targeting the eCB system to treat a range of disorders (e.g., epilepsy, anxiety) (Korem et al., 2016; Rosenberg et al., 2017), particularly those which involve cognitive impairment (e.g., neurodegenerative disorders such as Alzheimer’s disease [AD], schizophrenia) (Karl et al., 2012; Bedse et al., 2015; Capasso et al., 2016). However, there is extensive debate on how endocannabinoid signalling impacts on cognition (e.g., it has been shown to both facilitate and impair cognition, for reviews, see (Broyd et al., 2016; Curran et al., 2016)). Issues such as the type of cannabinoid tested (synthetic cannabinoid or phytocannabinoid), dose range, treatment regime (acute vs. long-term) and the animal model used to explore how cannabinoids modulate cognition (e.g., rodent models of schizophrenia vs. AD) all have considerable impact on study outcomes. Thus it is critical to understand in more detail how cannabinoids impact on behavioural and neural processes governing learning and memory. This chapter will review recent preclinical evidence (<5 years) illustrating how pharmacological and genetic manipulations of endocannabinoid signalling impact on learning and memory processes, and in particular, recognition memory (i.e., object recognition and its variant, object location). These cognitive domains are evaluated using the well-established preclinical novel object recognition (NOR) test and the novel object location (NOL) test (Antunes and Biala, 2012). We will examine the effects of acute and chronic cannabinoid treatment in control rodents, as well as in models of memory impairment (e.g., genetic and pharmacological models of AD, models of hypoxia-ischaemia or cerebral malaria), and discuss potential mechanisms underlying the effects of cannabinoid treatment on object recognition/location memory. The majority of published data cited in this chapter report effects in adult animals; however, we will highlight age differences where appropriate (e.g., adolescent or aged animals). We will also differentiate between different types of memory (e.g., acquisition, consolidation or recall of memory) affected by cannabinoid manipulation (for a detailed review, see (Morena and Campolongo, 2014)).

2. PRECLINICAL ASSESSMENT OF OBJECT RECOGNITION MEMORY: NOVEL OBJECT RECOGNITION AND NOVEL OBJECT LOCATION TESTS 2.1 The Test Paradigms The NOR test is designed to assess short- or long-term recognition memory in mice and rats and relies on the innate preference of rodents for novelty. NOR protocols consist of two stages: training and test, separated by a delay of variable length. Training and test sessions are often between 5 and 15 min long, although some protocols vary the session length dependent on the duration of object exploration an animal exhibits (e.g., Rabbani et al., 2012; Vaseghi et al., 2013). Sessions ideally occur within a dimly lit arena to reduce anxiety and encourage object exploration; some protocols also involve habituation to the arena (e.g., placing animals into the arena without any objects) and/or habituation to objects in the arena prior to training (Antunes and Biala, 2012). In the training session the arena contains two identical objects placed in opposite corners of the arena, with enough space for animals to move past the objects without interacting with them. Animals can explore the objects and the arena freely during training. The objects used should be of similar size and texture, so that one object does not elicit more spontaneous investigation than the other (Antunes and Biala, 2012). Following training, there is a delay between 3 min and 4 h (to assess short-term memory) or between 24 and 72 h (to assess long-term memory) (Antunes and Biala, 2012). In the test session, animals

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are presented with one object identical to that presented during training (the familiar object) and one object not presented during training (the novel object). Animals can again explore the objects and test arena freely. Time spent sniffing each object (e.g., nose <2 cm away from object) and rearing on each object is recorded by an experimenter blind to the treatment condition of the test animals. Several measures can be used to determine novel object preference, including the percentage of time spent with the novel object (i.e., [time spent exploring novel object/time spent exploring both objects]  100) (Antunes and Biala, 2012); a difference score (time spent with novel object e time spent with familiar object) (Bevins and Besheer, 2006) and a discrimination ratio ([novel object exploration e familiar object exploration]/total object exploration) (Barker and Warburton, 2008). NOR procedures are illustrated in Fig. 31.1A. NOL is a spatial variation of NOR, instead of varying the objects used between training and test; the same two identical objects are used for both training and test, but the location of one of the objects is changed during the test session. The novelty of the new location increases exploration of the object which has been relocated. NOL procedures are illustrated in Fig. 31.1B.

2.2 Manipulation of Different Types of Memory in NOR and NOL Acute pharmacological manipulation can assess different types of NOR or NOL memory (Morena and Campolongo, 2014). Administration of a pharmacological agent prior to training evaluates the effects of that agent on memory acquisition, whereas pharmacological manipulation following training evaluates the effects of the agent on memory consolidation. When agents are administered prior to the test session, it impacts the recall or the location of objects (i.e., this is an assessment of how well animals remember training). When pharmacological agents are administered in a chronic fashion (e.g., daily treatment for >7 days), NOR or NOL discrimination is impaired, and it is unclear exactly which memory component is affected by this manipulation. Most acute studies cited in this chapter assess NOR or NOL consolidation (i.e., drug administration after training).

FIGURE 31.1 Procedures for novel object recognition (NOR) and novel object location (NOL). (A) In NOR, object identity is changed between training and test; object location is unchanged. (B) In NOL the location of one object changes between training and test; identical objects are used during training and test.

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3. ACUTE EFFECTS OF CANNABINOIDS ON NOR AND NOL MEMORY Methodological details for references in this section are presented in Table 31.1.

3.1 Pharmacological Excitation of CB1R by Phytocannabinoids, Synthetic Cannabinoids and CB1R Agonists Acute phytocannabinoid and synthetic cannabinoid treatment dose-dependently impairs NOR and NOL memory for up to 24 h. The phytocannabinoid D9-tetrahydrocannabinol (THC), a CB1R and CB2R agonist, impairs consolidation of object learning in mice at higher doses (Barbieri et al., 2016), whereas lower doses do not affect consolidation of object learning in adolescent or adult rats (Swartzwelder et al., 2012). Similarly, administration of the synthetic cannabinoids JWH-081, JWH-018, JWH-018-Cl and JWH-018-Br, which are also CB1R and CB2R agonists, impairs NOR consolidation for up to 24 h in adult mice (Barbieri et al., 2016; Basavarajappa and Subbanna, 2014). The perirhinal cortex appears critical for cannabinoid-induced NOR impairment; infusion of the synthetic cannabinoid and CB1R/CB2R agonist HU210 into the perirhinal cortex of rats dose-dependently impairs NOR consolidation (Sticht et al., 2015). Interestingly, acute administration of the THC analogue tetrahydrocannabivarin (THCV) has no effect on NOR or NOL consolidation; this may be due to it having a different mechanism of action to THC (THCV is a CB1R antagonist and CB2R partial agonist) (Cascio et al., 2015). Similarly, the phytocannabinoid cannabidiol (CBD), which is a low affinity indirect agonist of CB1R and CB2R (Pertwee, 2008), does not acutely affect consolidation of NOR memory in rats (Fagherazzi et al., 2012). It seems CB1R plays a role in acute cannabinoid-induced NOR impairment, as studies using specific CB1R agonists indicate that elevated CB1R signalling impairs object recognition memory. Administration of the CB1R peptide agonists (m)RVD-hemopressin(a) (RVD) and (m)VD-hemopressin(a) (VD) impair consolidation of object recognition memory for up to 24 h in mice (Zhang et al., 2016). Similarly, the CB1R agonist WIN-55,212-2 (WIN) dose dependently impairs both consolidation and recall of object memory for up to 24 h in rats and mice (Galanopoulos et al., 2014; Mouro et al., 2017; Hasanein and Teimuri Far, 2015). In this context it is important to mention that WIN can have opposing effects on NOR based on the delay between training and test, and habituation of animals to the test apparatusdwith a 1 h delay; WIN impairs NOR when administered after training in rats not habituated to the apparatus but enhances NOR when rats are habituated to the apparatus (Campolongo et al., 2013). However, with a 24 h delay, WIN enhances NOR when administered after training in rats not habituated to the apparatus but impairs NOR when rats are habituated to the apparatus (Campolongo et al., 2013). Supporting a role for CB1R in acute cannabinoid-induced NOR impairment are findings showing that pretreatment with the CB1R antagonist AM251 reverses NOR impairment induced by JWH-018 compounds or WIN (Barbieri et al., 2016; Mouro et al., 2017) and pretreatment with the potent, selective CB1R antagonist/inverse agonist rimonabant reverses WIN- or footshock-induced impairment of object consolidation (Basavarajappa and Subbanna, 2014; Galanopoulos et al., 2014; Busquets-Garcia et al., 2016). It is possible that CB1R interacts with other receptor systems to mediate NOR memory, as CB1R and adenosine 2A receptors (A2AR) can form heteromers (Ferre et al., 2010), and acute administration of the A2AR antagonist SCH58261 prevents WIN-induced NOR consolidation impairment (Mouro et al., 2017).

3.2 Pharmacological Inhibition of CB1R by CB1R Antagonists/Inverse Agonists Acute administration of the potent, selective CB1R antagonist/inverse agonists AM251 and AM281 has no effect on consolidation of NOR or NOL memory (AM251 (Cascio et al., 2015; Zamberletti et al., 2012a); AM281 (Rabbani et al., 2012)), but AM281 can reverse NOR impairment induced by acute scopolamine (Rabbani et al., 2012). Also, rimonabant and the CB1R neutral antagonist NESS0327 have no effect on consolidation or recall of NOR or NOL memory in mice or rats (Galanopoulos et al., 2014; Busquets-Garcia et al., 2016; Gomis-Gonzalez et al., 2016). These studies were conducted under conditions where control animals demonstrated object recognition, suggesting that under baseline conditions, CB1R antagonist/inverse agonists have no effect on NOR consolidation or recall. However, under conditions of greater cognitive load, where control mice do not exhibit object recognition, infusion of the CB1R peptide antagonist hemopressin improves NOR consolidation (Zhang et al., 2016), suggesting that a balance of CB1R activity may be necessary for NOR consolidation.

TABLE 31.1 Effects of Acute Cannabinoid Treatment on NOL and NOR in Control Animals

References

Species D Strain

Sex

Age

Test

Rabbani et al. (2012)

NMRI mice (background not specified)

Male

8e12 weeks

NOR

Barbieri et al. (2016)

CD-1 mice (background not specified)

Male

Adult (25e30 g; age not specified)

Swartzwelder et al. (2012)

SpragueeDawley rats

Male

Basavarajappa and Subbanna (2014)

Male CB1R KO and WT mice (C57BL/ 6J background)

Cannabinoid Drug/s

Delay Between Training and Test

Dose, Route

Dosing Regime

AM281 (CB1R cannabinoid antagonist/ inverse agonist)

2.5 and 5 mg/kg; i.p.

40 min prior to test 15 min

Acute administration of AM281 (2.5 or 5 mg/kg) has no effect on NOR memory consolidation.

NOR

JWH-018 (synthetic cannabinoid), JWH-018-Cl (synthetic cannabinoid), JWH-018-Br (synthetic cannabinoid), THC (CB1R/CB2R partial agonist), AM251 (CB1R inverse agonist)

JWH-018-R compounds: 0.01e1 mg/kg; THC: 0.1e3 mg/ kg, AM251: 1 mg/ kg; i.p.

2 or 24 h JWH-018-R compounds administered 15 min posttraining; AM251 (1 mg/kg) was administered 20 min before JWH-018-R compounds or THC

Acute administration of the synthetic CB1R agonists (JWH-018. JWH018-Cl, JWH-018-Br) impairs object recognition over a range of doses and with different delays between training and test.

PND 30 (adolescent) or PND 70 (adult)

NOR

THC (CB1R/CB2R 1 mg/kg; i.p. partial agonist)

Immediately after training

24 h

Treatment with 1 mg/kg THC immediately after training does not impair NOR consolidation in adolescent or adult rats tested 24 h later.

12e16 weeks

NOR

JWH-081 (CB1R agonist)

30 min prior to training

1, 4 or 24 h

Acute administration of the synthetic cannabinoid JWH-081, a CB1R and CB2R agonist impairs

1.25 mg/kg; i.p.

Results Summary

Continued

TABLE 31.1 Effects of Acute Cannabinoid Treatment on NOL and NOR in Control Animalsdcont’d

References

Species D Strain

Sex

Age

Test

Cannabinoid Drug/s

Dose, Route

Dosing Regime

Delay Between Training and Test

Results Summary consolidation of object recognition for up to 4 h, but not 24 h posttreatment in adult mice Acute intraperirhinal cortex infusions of the CB1R agonist HU210 impair NOR discrimination at two different doses and using different delays between training and test.

LongeEvans rats

Male

Adult (300e350 g; NOR age not specified)

HU210 (CB1R/ CB2R agonist)

0.01 or 1 mg/mL, at 3 min prior to a rate of 0.5 mL/ training min for 2 min, into the perirhinal cortex

15, 60 min or 24 h

Cascio et al. (2015) SpragueeDawley rats

Male

Adult (no age specified)

NOR and NOL

AM251 (CB1R inverse agonist), THCV (homologue of THC)

AM251: 0.5 mg/ kg i.p.; THCV: 2 mg/kg; i.p.

3 min

Acute administration of the THC analogue THCV or the CB1R antagonist AM251 has no effect on NOR or NOL consolidation.

Fagherazzi et al. (2012)

Wistar rats

Male

8 weeks

NOR

CBD (low affinity 2.5, 5 or 10 mg/kg; Immediately after indirect agonist of i.p. training CB1R and CB2R)

24 h

Acute CBD (2.5e10 mg/ kg) has no effect on consolidation of NOR memory.

Galanopoulos et al. (2014)

SpragueeDawley rats

Male

12 weeks

NOR

WIN (CB1R agonist), rimonabant (CB1R antagonist)

WIN: 0.03, 0.1, 0.3 mg/kg, rimonabant: 0.03 mg/kg; i.p.

Rimonabant administered immediately after training; WIN administered 10 min after rimonabant

1 or 24 h

Acute WIN treatment (0.3 mg/kg) impairs NOR consolidation at a 1 and 24 h delay as well as recall of NOR after a 24 h delay. No effect of rimonabant on NOR consolidation.

Male

8e12 weeks

NOR

WIN(CB1R agonist), AM251 (CB1R inverse agonist), SCH58261 (A2AR antagonist)

WIN: 1 mg/kg; AM251: 3 mg/kg; i.p.; SCH58261: 1 mg/kg i.p.

All drugs or drug combinations: immediately after training

24 h

Acute treatment with the CB1R agonist WIN dose dependently impairs both consolidation and recall of object memory for up to 24 h in rats and mice. Pretreatment with the CB1R antagonist AM251 reverses NOR impairment induced by WIN. Acute administration of the A2AR antagonist SCH58261 prevents WIN-induced NOR consolidation impairment.

Sticht et al. (2015)

Mouro et al. (2017) C57BL/6 mice

45 min prior to training (AM251) or 30 min prior to training (THCV)

Hasanein and Wistar rats Teimuri Far (2015)

Male

Adult (250e280 g; NOR age not specified)

URB597 (FAAH inhibitor); WIN (CB1R agonist)

URB597: 0.1, 0.3 and 1 mg/kg; WIN: 1 mg/kg; i.p.

WIN administered 40 min 10 min prior to training. URB597 administered 20 min prior to training

URB597 (0.1, 0.3 and 1 mg/kg) administration alone does not impair NOR acquisition WIN impairs NOR acquisition.

Campolongo et al. SpragueeDawley (2013) rats

Male

Adult (no age specified)

NOR

WIN (CB1R agonist)

0.1, 0.3, 1 mg/kg; i.p.

Immediately after training

1 or 24 h

Opposing effects of WIN on NOR recognition depending on retention interval and habituation to test apparatus: 1 h retention: 0.3 mg/kg WIN impairs NOR when administered after training in rats not habituated to apparatus, but enhances NOR when rats are habituated to apparatus (no effects of 0.1 or 1 mg/ kg doses). 24 h retention: 0.3 mg/kg WIN enhances NOR when administered after training in rats not habituated to apparatus, but impairs NOR when rats are habituated to apparatus.

Busquets-Garcia et al. (2016)

Swiss albino CD-1, Male CB1R KO and WT controls (CD-1 background); CB1R conditional KO and WT (floxed/floxed) controls (mixed background, predominantly C57BL/6N)

8e10 weeks

NOR

Rimonabant (CB1R antagonist/ inverse agonist), AM6545 (CB1R antagonist), AM630 (CB2R antagonist)

Rimonabant: Immediately after 1 mg/kg, training AM6545: 1 mg/ kg, AM630: 1 mg/ kg; i.p.

24 h

Acute treatment with the CB1R antagonist rimonabant does not affect consolidation of NOR memory.

Zamberletti et al. (2012a)

Lister Hooded rats Male

6 weeks

NOR

AM251 (CB1R inverse agonist)

0.5 mg/kg; i.p.

1h

No effect of acute AM251 on consolidation of NOR memory.

80 min prior to training

Continued

TABLE 31.1

Effects of Acute Cannabinoid Treatment on NOL and NOR in Control Animalsdcont’d Cannabinoid Drug/s

References

Species D Strain

Sex

Age

Test

Gomis-Gonzalez et al. (2016)

Fmr1 KO and WT mice (FVB.129P2Pde6bþ Tyrc-ch Fmr1tm1Cgr/J)

Male

12e16 weeks

NOR

Rimonabant (CB1R Rimonabant 0.03, Immediately after antagonist/ 0.1, 0.3, and 1 mg/ training inverse agonist), kg; i.p. NESS0327 (CB1R neutral antagonist)

24 h

Acute treatment with the CB1R antagonist rimonabant or the CB1R neutral antagonist NESS0327 does not affect consolidation of NOR memory.

Thanos et al. (2016)

C57BL/6 mice

Male

9e10 weeks

NOR

5, 20, 40 mg/kg; SBFI26, a i.p. pharmacological inhibitor of epidermal- and brain-specific fatty acid binding proteins 5 and 7; this compound increases anandamide signalling

50 min prior to training

30 min

Acute inhibition of fatty acid binding proteins and subsequently elevation of anandamide signalling does not affect consolidation of NOR memory.

Male

Adult (no age specified)

NOR and NOL

AM404 (endocannabinoid transport inhibitor)

15 min prior to training

3 min

Acute administration of the endocannabinoid transport inhibitor AM404 dose-dependently impairs NOR consolidation under conditions of high arousal (e.g., brighter lighting, no handling, no bedding in test apparatus) but not under conditions of low arousal, and does not alter NOL memory consolidation.

Campolongo et al. Wistar rats (2012)

Dose, Route

0.5, 1, 5 mg/kg; i.p.

Dosing Regime

Delay Between Training and Test

Results Summary

A2AR, adenosine 2A receptor; CBD, cannabidiol; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; Frm1, fragile x mental retardation 1; i.p., intraperitoneal; KO, knockout; NOL, novel object location; NOR, novel object recognition; PND, postnatal day; THC, D9-tetrahydrocannabinol; THCV, tetrahydrocannabivarin; WIN, WIN-55,212-2; WT, wild type-like.

4. EFFECTS OF CHRONIC CANNABINOID TREATMENT ON NOR AND NOL MEMORY

469

3.3 Pharmacological Agents That Target Endocannabinoid Tone Cannabinoid compounds, which indirectly elevate anandamide tone but do not directly target CB1R, have no acute effects on NOL and recognition memory on their own but can reverse cannabinoid- or stress-induced NOR impairment. Acute treatment with URB597 (a FAAH inhibitor that leads to anandamide accumulation and activation of CB1R) does not impair consolidation of object recognition memory (Hasanein and Teimuri Far, 2015); however, acute elevation of the levels of endogenous cannabinoids via URB597 administration dose-dependently reverses NOR impairment induced by acute WIN (Hasanein and Teimuri Far, 2015). Also, SBFI26, a pharmacological inhibitor of epidermal- and brain-specific fatty acid binding proteins 5 and 7, which effectively increases anandamide signalling, does not impair consolidation of object memory (Thanos et al., 2016). Finally, the endocannabinoid transport inhibitor AM404 dose-dependently impairs NOR consolidation but only under conditions of high arousal (e.g., brighter lighting and no pretest handling) and does not affect NOL memory consolidation (Campolongo et al., 2012).

4. EFFECTS OF CHRONIC CANNABINOID TREATMENT ON NOR AND NOL MEMORY Chronic treatment (i.e., >7 days) with cannabinoids which elevate CB1R signalling often impairs object recognition or location memory, while chronic administration of CB1R inverse agonists or CB2R agonists generally has no effect on object recognition or location memory. These cognition-impairing effects occur when animals are tested during treatment or after a washout period. Methodological details for references in this section are presented in Table 31.2.

4.1 CB1R Agonists Chronic adolescent and adult treatment with THC or the synthetic cannabinoids, AB-PINACA and AB- FUBINACA, impairs NOR memory when animals are tested during the treatment period (THC: Rodriguez et al., 2017; Puighermanal et al., 2013) or after treatment cessation (AB-PINACA and AB- FUBINACA: Kevin et al., 2017). Persistent impairment of NOR memory is present in mice when there is a longer delay between training and test (e.g., 24 h (Aso et al., 2015)) but not when the training-test delay is shorter (e.g., 30 mine1 h (Segal-Gavish et al., 2017a; BilkeiGorzo et al., 2017)). In rats, THC-induced NOR memory deficits are sex-dependent, such that in males, persistent impairment of NOR is present only under conditions of greater cognitive demand but not under conditions of lower cognitive demand (Kevin et al., 2017); whereas THC-induced NOR impairment is present in females under both conditions (Zamberletti et al., 2012b, 2014, 2015). There has been one report of recovery from THC-induced NOR impairment 6 days after treatment cessation; however, the treatment paradigm used in this study was short (i.e., 6 days (Puighermanal et al., 2013)). Chronic adolescent WIN treatment appears to impair NOR and NOL memory when rats are tested drug free in adulthood ((Kirschmann et al., 2017; Abboussi et al., 2016; Abush and Akirav, 2012; Lovelace et al., 2015) but see (Alteba et al., 2016)). This effect is dose-dependent and is not present following chronic treatment with low-dose WIN when animals are tested either during drug treatment (Martin-Moreno et al., 2012) or drug-free (Kirschmann et al., 2017). WIN-induced NOR impairment can be reversed following acute administration of the dopamine D3R antagonist U-99194A (Abboussi et al., 2016) suggesting D3R interacts with CB1R via heteromers to mediate NOR memory. Chronic treatment with the CB1R agonist CP-55,940 (CP) has age- and strain-dependent effects on object recognition and location memory. Chronic CP treatment can impair object recognition and location memory in rats when administered in early adolescence (e.g., postnatal day [PND] 29þ (Renard et al., 2013)) but not when administered in late adolescence (e.g., PND 56þ (Klug and van den Buuse, 2012)) or adulthood (PND 70þ (Renard et al., 2013)). It appears that there is a window of susceptibility in early adolescence to CP-induced NOR impairment in the rat. In mice, chronic mid-adolescent CP treatment (PND 42þ) does not impact on NOR memory (Klug and van den Buuse, 2013). In all these studies, animals were tested drug free, ensuring the absence of any residual drug effects on learning and memory. Chronic treatment with the CB1R agonist arachidonyl-20 -chloroethylamide (ACEA) has no effect on NOR memory when animals are tested drug free (Arain et al., 2015). It should be noted that this is the only study investigating the behavioural effects of chronic ACEA, and parameters such as dose, treatment regime, training-test delay and sex may impact on whether chronic ACEA impairs object location and recognition memory.

TABLE 31.2

Effects of Chronic Cannabinoid Treatment on NOL and NOR in Control Animals Cannabinoid Drug/s

Dose, Route

Treatment starts: NOR 8 weeks; treatment duration: 14 days; test: 24 h after final injection

CBD (CB1R/CB2R indirect agonist)

2.5, 5 or 10 mg/kg, Daily for 14 days i.p.

24 h

Chronic CBD does not affect NOR performance in drugfree control rats.

Male

NOR Treatment starts: PND 70; treatment ends: PND 91; test: 24, 72 h and 10 d after the last AM251 administration

AM251 (CB1R inverse agonist)

0.5 mg/kg, i.p.

Daily for 3 weeks

1h

No effect of chronic AM251 on NOR performance in control rats, for up to 10 days after AM251 administration ended.

Rodriguez et al. C57BL/6 mice (2017)

Male

NOR Treatment starts: PND 53; treatment ends: PND 98; test: PND 80-98

THC (CB1R/CB2R partial agonist)

5 mg/kg i.p.

Daily for 45 days

1h

Chronic adolescent THC impairs NOR discrimination in control mice, when animals are tested during drug treatment.

Puighermanal et al. (2013)

Swiss albino mice (C57BL/6N background)

Male

NOR Treatment starts: adult (no PND provided); treatment duration: 6 days; test: during treatment and for 6 days after treatment cessation

THC (CB1R/CB2R partial agonist)

10 mg/kg i.p.

Daily for 6 days

24 h

Subchronic THC in adulthood impairs NOR during treatment and for up to 4 days after treatment.

Kevin et al. (2017)

Albino Wistar rats

Male

NOR Treatment starts: PND 31; treatment ends: PND 55; test: PND 69-72

THC (CB1R/CB2R partial agonist); synthetic cannabinoids: AB-PINACA and AB-FUBINACA

THC: 1 and 5 mg/ kg; synthetic cannabinoids: 0.2 and 1 mg/kg; i.p.

2 or 60 min Daily for 12 days: THC: 1 mg/kg for 6 days then 5 mg/ kg for 6 days; synthetic cannabinoids: 0.2 mg/kg for 6 days, then 1 mg/ kg for 6 days

Chronic adolescent THC or synthetic cannabinoids impair NOR in adulthood.

Aso et al. (2015) APPxPS1 mice and Male WT littermates (mixed background)

Treatment starts: NOR 6 months; treatment duration: 5 weeks; test: 10 days after treatment cessation

THC (CB1R/CB2R partial agonist), CBD (CB1R/CB2R indirect agonist), THC þ CBD combination

THC, 0.75 mg/kg; CBD, 0.75 mg/kg; THC þ CBD, 0.75 mg/kg each

Daily for 5 weeks; 10 day washout

Chronic THC impairs NOR performance in drug-free WT control mice. Chronic CBD, as well as THC þ CBD has no effect on NOR performance in drugfree mice.

References

Species D Strain

Sex

Fagherazzi et al. (2012)

Wistar rats

Male

Zamberletti et al. (2012a)

Lister Hooded rats

Age at Treatment and Test

Test

Dosing Regime

Delay Between Training and Test

24 h

Results Summary

Bilkei-Gorzo et al. (2017)

C57BL/6J mice

Male

Treatment starts: 2 NOL (young), 12 (mature), 18 (old) months/treatment duration: 28 days; test: >5 days after treatment cessation

THC (CB1R/CB2R partial agonist)

3 mg/kg, via minipumps

Continuous dosing 30 min via minipumps for 28 days, tested 14 days after cessation of THC treatment

Chronic low-dose THC has no effect on NOL performance in 2-month-old control mice.

Zamberletti et al. (2014)

SpragueeDawley rats

Female

NOR Treatment starts: PND 35; treatment and ends: PND 45; test: NOL PND 75þ

THC (CB1R/CB2R partial agonist)

Escalating dose regime: 0.5, 1, 2 mg/kg, i.p.

Twice daily, for 10 days (0.5 mg/ kg, PND 35e36; 1 mg/kg, PND 37 e41; 2 mg/kg, PND 42e45)

3 min

Chronic THC administration in adolescence impairs NOR drug-free female rats.

Zamberletti et al. (2015)

SpragueeDawley rats

Female

NOR Treatment starts: PND 35; treatment and ends: PND 45; test: NOL PND 75þ

THC (CB1R/CB2R partial agonist)

Escalating dose regime: 0.5, 1, 2 mg/kg, i.p.

Twice daily, for 10 days (0.5 mg/ kg, PND 35e36; 1 mg/kg, PND 37 e41; 2 mg/kg, PND 42e45)

3 min

Chronic THC administration in adolescence impairs NOR and NOL in female rats when tested drug free in adulthood.

Zamberletti et al. (2012b)

SpragueeDawley rats

Male þ female Treatment starts: PND 35; treatment end: PND 45; test: PND 65

THC (CB1R/CB2R partial agonist)

Escalating dose Twice daily for regime: 2.5 mg/kg, 10 days PND 35e37; 5 mg/ kg, PND 38e41; 10 mg/kg, PND 42 e45; i.p.

3 min

Chronic adolescent THC treatment impairs NOR in drug-free female but not male rats.

Kirschmann et al. (2017)

SpragueeDawley rats

Male

Treatment starts: NOR PND 34; treatment ends: PND 54; test: PND 54 or 106

WIN (CB1R agonist)

1.2 mg/kg, i.p. or Daily injections for 35 min self-administration 20 days, OR WIN via jugular catheter self-administration for 11 days

Chronic adolescent WIN treatment acutely (PND 54) impairs NOR, but this effect is not present when rats are tested in adulthood (PND 106).

Abboussi et al. (2016)

Wistar rats

Male

Treatment starts: PND 27e30; treatment ends: PND 47e50; test: PND 67e70þ

WIN (CB1R agonist)

1 mg/kg, i.p.

Chronic adolescent WIN treatment impairs NOR in control animals when animals tested drug free in adulthood; this is reversed following acute administration of the dopamine D3 receptor antagonist U-99194A.

NOR

NOR

20 injections over 30 days

24 h

Continued

TABLE 31.2 Effects of Chronic Cannabinoid Treatment on NOL and NOR in Control Animalsdcont’d Age at Treatment and Test

Test

Dose, Route

Dosing Regime

Delay Between Training and Test

Male

Treatment starts: PND 45e60; test: PND 61, 70, 90

NOR and NOL

WIN (CB1R agonist)

1.2 mg/kg, i.p.

Daily for 14 days

30 min

Chronic WIN in adolescent control animals impairs NOL for up to 75 days posttreatment, and NOR for up to 10 days posttreatment.

C57BL/6 mice

Female

Treatment starts: NOR PND 35; treatment ends: PND 45; test: PND 70þ

WIN (CB1R agonist)

Escalating dose regime: 0.5, 1, 2 mg/kg, i.p.

Twice daily, for 10 days (0.5 mg/ kg, PND 35e36; 1 mg/kg, PND 37 e41; 2 mg/kg, PND 42e45)

5 min

Chronic WIN treatment in adolescence impairs NOR in adulthood in mice.

Rats (strain not specified)

Male þ female Treatment starts: NOR PND 45; treatment ends: PND 60; test: PND 90þ

WIN (CB1R agonist)

1.2 mg/kg i.p.

Daily for 16 days

30 min

Chronic adolescent WIN has no effect on NOR and NOL performance in control rats, when animals are tested drug free.

References

Species D Strain

Sex

Abush and Akirav (2012)

SpragueeDawley rats

Lovelace et al. (2015)

Alteba et al. (2016)

Martin-Moreno Transgenic APP et al. (2012) mice and WT littermates (C57BL/6 background)

Cannabinoid Drug/s

Results Summary

Male

NOR Treatment starts: 7 months; treatment duration: 4 months; test: 11 months

WIN (CB1R agonist) and JWH133 (selective CB2R antagonist)

0.2 mg/kg, in Continuous dosing 24 h drinking water (for - administered both WIN and through drinking JWH-133) water for 4 months

Chronic WIN and chronic JWH-133 have no effect on NOR memory in control mice, when animals are tested during drug treatment.

Renard et al. (2013)

Lister Hooded and Male Wistar rats

NOR Treatment starts: PND 29 or PND 70; and NOL treatment ends: PND 50 or PND 91; test: 28 days after treatment cessation

CP(CB1R agonist)

Increasing dose Daily for 3 weeks regime: 0.15, 0.20 and 0.30 mg/kg for 7 days at each dose, i.p.

30 or 120 min

Chronic CP produces greater impairment of drug-free NOL and NOR in adolescence rats compared with adult rats; this effect is more prominent in Wistar rats compared with Lister Hooded rats.

Klug and van den Buuse (2012)

Outbred Wistar rats

CP (CB1R agonist)

0.2 mg/kg i.p.

120 min

No effect of chronic CP in late adolescence on NOR performance in drug-free control rats.

Male þ female Treatment starts: 8 weeks; treatment ends: 10 weeks; test: 12 weeks

NOR

5 per week for 2 weeks

Klug and van den Buuse (2013)

WT and BDNF HET Male þ female Treatment starts: mice (background PND 42; treatment not specified) end: PND 63; test: PND 77þ

Arain et al. (2015)

SpragueeDawley rats

Male

Osborne et al. (2017)

SpragueeDawley rats

CP (CB1R agonist)

0.4 mg/kg,

5 per week, for 3 weeks

120 min

No effect of chronic CP in late adolescence on NOR performance in drug-free male or female control mice.

NOR Treatment starts: PND 70; treatment ends: PND 76; test: PND 88

ACEA; CB1R agonist

1 mg/kg, i.p.

1 mg/kg daily for 6 days

15 min or 24 h

Subchronic administration of the CB1R agonist ACEA has no effect on drugfree NOR performance in control animals after a 15 min or 24 h delay between training and test.

Male

Treatment starts: PND 56e80; test: PND 72

NOR

CBD (CB1R/CB2R indirect agonist)

10 mg/kg i.p.

Twice daily for 21 days

1h

Chronic late adolescent CBD treatment has no effect on NOR memory in adult rats when animals are tested during CBD treatment.

Cheng et al. (2014)

APPxPS1 mice and Male WT littermates (C57BL/6J x C3H/ HeJ mixed background)

Treatment starts: 24 weeks; treatment ends: 30 weeks; test: 30 weeks

NOR

CBD (CB1R/CB2R indirect agonist)

20 mg/kg

Daily for 8 weeks

1h

Chronic CBD has not effect on NOR performance in drugfree WT controls.

Campos et al. (2015)

C57BL/6 mice

Female

Treatment starts: NOR 6e8 weeks old; treatment duration: 6 days; test: 5 days after treatment cessation

CBD (CB1R/CB2R indirect agonist)

30 mg/kg, i.p.

Daily for 3 or 7 days

24 h

Subchronic CBD has no effect on NOR performance in drugfree control mice.

Male

NOR Treatment starts: 3 months or 12 months; treatment duration: daily for 5 weeks; test: 10 days after treatment cessation

THC (CB1R/CB2R partial agonist) þ CBD (CB1R/CB2R indirect agonist) combination

THC 0.75 mg/ kg þ CBD 0.75 mg/kg, i.p.

Daily for 5 weeks; 10 day washout

24 h

Chronic treatment with THC þ CBD combination has no effect on drug-free NOR performance in 3-month-old C57BL/6 mice or 12-month-old WT control mice.

DISC1 KO mice Male and WT littermates (mixed C57BL/6 x CBA background)

Treatment starts: NOR PND 42; treatment ends: PND 51; test: PND 54þ

THC (CB1R/CB2R partial agonist)

10 mg/kg i.p.

Daily for 10 days

1h

Adolescent THC has no effect on NOR performance in WT mice, when animals are tested drug free.

Aso et al. (2016) APPxPS1 and WT littermates (mixed background), or C57BL/6J mice

Segal-Gavish et al. (2017b)

NOR

ACEA, arachidonyl-20 -chloroethylamide; APPxPS1, amyloid precursor protein/presenilin 1; BDNF, brain-derived neurotrophic factor; CBD, cannabidiol; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; CP, CP55,940; i.p., intraperitoneal; KO, knockout; NOL, novel object location; NOR, novel object recognition; PND, postnatal day; THC, D9-tetrahydrocannabinol; WIN, WIN-55,212-2; WT, wild type-like.

474

31. CANNABINOID MODULATION OF OBJECT RECOGNITION

4.2 CB1R Antagonists/Inverse Agonists and CB2R Agonists Chronic treatment with CB1R antagonists/inverse agonists or CB2R agonists does not appear to modulate NOR or NOL memory. Repeated treatment of adolescent rats with the CB1R antagonist/inverse agonist AM251 has no effect on NOR memory for up to 10 days following training (Zamberletti et al., 2012a), and the potent, selective CB2R antagonist JWH-133 administered for 4 months has no effect on NOR memory in mice when tested during treatment (Martin-Moreno et al., 2012). Chronic CBD treatment has no effect on NOR memory in adolescent and adult mice and rats when animals are tested during treatment (Osborne et al., 2017) or drug free after treatment cessation (Fagherazzi et al., 2012; Cheng et al., 2014; Campos et al., 2015). This effect occurs across a range of CBD doses (e.g., 5e30 mg/kg). Interestingly, administration of THC and CBD at 1:1 ratios does not impair NOR memory in adult mice (3, 6 or 12 months old) (Aso et al., 2015, 2016), whereas THC alone caused persistent NOR impairment in this study, suggesting CBD may counteract the cognition-impairing effects of THC (Aso et al., 2015).

5. EFFECTS OF CANNABINOID RECEPTOR 1 GENE MODIFICATION ON NOR AND NOL MEMORY CB1R gene deletion, either throughout the entire brain or specifically in isolated regions or cell types, can impact on NOR discrimination. The nature of gene deletion studies does not permit discrimination of gene deficiency effects across different types of memory processes (e.g., consolidation, recall). Methodological details for references in this section are presented in Table 31.3. Germline deletion of CB1R enhances NOR memory for up to 24 h after training, compared with wild type-like (WT) control mice (Subbanna et al., 2013). In line with the pharmacological studies discussed above, CB1R knockout (KO) mice are protected from NOR impairments induced by the synthetic cannabinoid JWH-081 in control mice, supporting a role for CB1R in NOR memory (Basavarajappa and Subbanna, 2014). It appears CB1R on cells expressing g-aminobutyric acid (GABA) are involved in mediating NOR memory, as deletion of CB1R on GABAergic cells across the entire brain impairs NOR (Albayram et al., 2016). Interestingly, NOR impairment triggered by acute stress (e.g., footshock, tail suspension) appears mediated by dopamine b-hydroxylase (DBH) cells, as mice lacking CB1R on DBH cells do not exhibit stress-induced NOR impairment. This effect is reversed by intrahippocampal administration of rimonabant, as well as central administration of the peripherally restricted CB1R antagonist AM6545 (Busquets-Garcia et al., 2016).

6. MOLECULAR MECHANISMS UNDERLYING CANNABINOID-INDUCED CHANGES TO NOR AND NOL MEMORY IN CONTROL ANIMALS Methodological details for references in this section are presented in Table 31.4.

6.1 Changes in Long-Term Potentiation and Long-Term Depression Impairment in synaptic plasticity appears to contribute to cannabinoid-induced NOR deficits in control animals. NOR impairment induced by the CB1R agonist JWH-018 reduces electrically evoked long-term potentiation (LTP) in the CA1 region of the hippocampus (Barbieri et al., 2016; Basavarajappa and Subbanna, 2014). Chronic WIN-induced object recognition impairment reduces LTP in the ventral subiculum-nucleus accumbens pathway (Abush and Akirav, 2012) and also reduces endocannabinoid-dependent long-term depression (LTD) and metabotropic glutamate receptor 2/3 (mGluR2/3)edependent LTD in the medial prefrontal cortex (PFC) (Lovelace et al., 2015). In addition, CB1R agonist-induced NOR impairment is associated with impaired calcium-/calmodulin-dependent protein kinase type IV (CAMKIV) and cAMP response element-binding protein (CREB) phosphorylation. Reductions in these markers, in addition, to reduced LTP and LTD, suggest impaired synaptic mechanisms of learning and memory following CB1R agonist treatment. JWH-induced impairment in hippocampal LTP is reversed by application of the CB1R antagonist AM251 (Barbieri et al., 2016)dan effect not present in CB1R KO mice (Basavarajappa and Subbanna, 2014)dsuggesting a CB1R-dependent mechanism underlying cannabinoid-induced changes in plasticity.

TABLE 31.3

Effects of Cannabinoid Receptor Gene Manipulation on Novel Object Location (NOL) and Novel Object Recognition (NOR)

References

Species D Strain

Sex

Age

Basavarajappa and Subbanna (2014)

CB1R KO and WT mice (C57BL/6J background)

Male 12e16 weeks

Busquets-Garcia et al. (2016)

Test

Cannabinoid Drug/ s Dose, Route

NOR

JWH-081 (CB1R/ CB2R agonist)

Swiss albino CD-1; Male 8e10 weeks CB1R KO and WT controls (CD-1 background); CB1R conditional KO and WT (floxed/floxed) (mixed background, predominantly C57BL/6N)

NOR

Subbanna et al. (2013)

Male 12e16 weeks C57BL/6J mice or CB1R WT and KO mice on a C57BL/6J background

Albayram et al. (2016)

Conditional Male 8e16 weeks GABA-specific CB1R KO mice and control littermates (background not specified)

Dosing Regime

Delay Between Training and Test

Results Summary

Acute: JWH-081 1, 4, or 24 h administered 30 min prior to training

CB1R KO mice are protected from NOR impairment induced by the synthetic cannabinoid JWH-081.

Rimonabant (CB1R Rimonabant antagonist), AM6545 (1 mg/kg), AM6545 (CB1R antagonist). (1 mg/kg), i.p.

Acute: rimonabant administered immediately after training

24 h

NOR impairment triggered by acute stress (e.g., footshock, tail suspension) appears mediated by dopamine b-hydroxylase cells, as mice lacking CB1R on dopamine b-hydroxylase cells do not exhibit stressinduced NOR impairment, and this effect is reversed by intrahippocampal administration of the CB1R antagonist rimonabant, as well as central administration of the peripherally restricted CB1R antagonist AM6545.

NOR

n/a

n/a

n/a

1, 4 or 24 h

Germline deletion of CB1R enhances NOR memory for up to 24 h after training, compared with WT control mice.

NOR

n/a

n/a

n/a

30 min

Deletion of CB1R on GABAergic cells across the entire brain impairs NOR.

1.25 mg kg i.p.

CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; GABA, g-aminobutyric acid; i.p., intraperitoneal; KO, knockout; WT, wild type-like.

TABLE 31.4

Molecular Mechanisms Contributing to Cannabinoid-Induced Changes in NOL and NOR

References

Species D Strain

Sex

Age

Test

Barbieri et al. (2016)

CD-1 mice (background not specified)

Male

Tissue collection: adult (25e30 g)

NOR

Basavarajappa and Subbanna (2014)

CB1R KO and WT Male mice (C57BL/6J background)

Tissue collection: 12e16 weeks

NOR

Rodriguez et al. (2017)

C57BL/6 mice

Male

Treatment: PND NOR 53; treatment cessation: PND 98; test: PND 80e98; tissue collection: PND 99

Puighermanal et al. (2013)

Swiss albino mice (C57BL/6N background)

Male

NOR Treatment: adult (no age specified); test: during treatment and for 6 days after treatment cessation; tissue collection:

Cannabinoid Drug/s

Delay Between Training and Test Results Summary

Dose, Route

Dosing Regime

JWH-018 (synthetic cannabinoid), JWH-018-Cl (synthetic cannabinoid), JWH-018-Br (synthetic cannabinoid), THC (CB1R/CB2R partial agonist), AM251 (CB1R inverse agonist)

JWH-018-R compounds (0.01e1 mg/kg), THC (0.1e3 mg/ kg), AM251 (1 mg/kg) i.p.

Acute: JWH-018-R 2 or 24 h compounds administered 15 min posttraining; AM251 (1 mg/kg) was administered 20 min before JWH-018-R compounds or THC

JWH-018 compounds reduce electrically evoked LTP in the CA1 region of the hippocampus, and reduce Kþ-evoked glutamate and GABA release in the CA1 region of the hippocampus. These changes are reversed following application of the CB1R antagonist AM251, suggesting a CB1R mechanism.

JWH-081 (CB1R agonist)

1.25 mg kg i.p.

Acute: JWH-018 administered 30 min prior to training

1, 4 or 24 h

JWH-081-induced NOR impairment is associated impaired CAMKIV and CREB phosphorylation, and reduced hippocampal LTP. These effects occur only in WT, but not in CB1R KO mice, suggesting NOR memory mechanisms are CB1R dependent.

THC (CB1R/CB2R 5 mg/kg i.p. partial agonist)

Chronic: daily for 45 days

1h

Chronic adolescent THC impairs NOR discrimination. Cortical CB1R and NMDA subunit NR1 protein levels are reduced by chronic adolescent THC exposure.

THC (CB1R/CB2R 10 mg/kg i.p. partial agonist)

Chronic: daily for 6 days

24 h

Subchronic THC in adulthood impairs NOR during treatment, and for up to 4 days after treatment. Subchronic THC downregulates CB1R on GABAergic cells in the hippocampus, and mice lacking CB1R on hippocampal GABAergic cells do not exhibit THC-induced memory impairment.

THC: 1 and 5 mg/ kg; synthetic cannabinoids: 0.2 and 1 mg/kg; i.p.

Chronic: daily for 2 or 60 min 12 days (THC: 1 mg/kg for 6 days then 5 mg/ kg for 6 days; synthetic cannabinoids: 0.2 mg/kg for 6 days, then 1 mg/ kg for 6 days)

Chronic adolescent THC or synthetic cannabinoids impair NOR in adulthood. THC and AB-PINACA reduce cerebellar endocannabinoids: anandamide, OEA, 2-AG, PEA. Six weeks post-dosing, plasma levels of cytokines IL-1a and IL-12 were reduced by AB-FUBINACA pretreatment.

Kevin et al. (2017) Albino Wistar rats Male

Treatment: PND NOR 31; treatment cessation: PND 55; test: 69e72; tissue collection: PND 103

THC (CB1R/CB2R partial agonist); synthetic cannabinoids: AB-PINACA and AB-FUBINACA

Zamberletti et al. (2014)

SpragueeDawley rats

Female

Treatment: PND NOR 35; treatment and cessation: PND 45; NOL tissue collection: PND 75

THC (CB1R/CB2R Escalating dose partial agonist) regime: 0.5, 1, 2 mg/kg, i.p.

Chronic: twice daily, for 10 days (0.5 mg/kg, PND 35e36; 1 mg/kg, PND 37e41; 2 mg/kg, PND 42e45)

3 min

Chronic THC administration in adolescence impairs NOR and NOL memory and reduces glutamate decarboxylase 67 and basal GABA levels within the adult PFC. Glutamate decarboxylase expression is reduced both in parvalbumin- and cholecystokinin-containing interneurons in the PFC.

Zamberletti et al. (2015)

SpragueeDawley rats

Female

Treatment: PND NOR 35; treatment and cessation: PND 45; NOL tissue collection: PND 75

THC (CB1R/CB2R Escalating dose partial agonist) regime: 0.5, 1, 2 mg/kg, i.p.

Chronic: twice daily, for 10 days (0.5 mg/kg, PND 35e36; 1 mg/kg, PND 37e41; 2 mg/kg, PND 42 e45)

3 min

Chronic THC administration in adolescence impairs NOR and NOL and increases PFC expression of the proinflammatory markers, TNF-a, iNOS and COX-2, and reduces PFC expression of the anti-inflammatory cytokine, IL-10. This neuroinflammatory phenotype is associated with up-regulation of CB2R on microglia cells. Blocking microglia activation with ibudilast during THC treatment prevents the increases in TNF- a, iNOS, COX-2 levels as well as the up-regulation of CB2R on microglia cells. Continued

TABLE 31.4

Molecular Mechanisms Contributing to Cannabinoid-Induced Changes in NOL and NORdcont’d Test

Dose, Route

Dosing Regime

Delay Between Training and Test Results Summary

Species D Strain

Sex

Zamberletti et al. (2012b)

SpragueeDawley rats

Male þ female Treatment: PND NOR 35; treatment cessation: PND 45; test: PND 65; tissue collection: PND 82

THC (CB1R/CB2R Escalating dose partial agonist) regime: 2.5 mg/ kg, PND 35e37; 5 mg/kg, PND 38e41; 10 mg/kg, PND 42e45; i.p.

Chronic: twice daily for 10 days

3 min

Chronic adolescent THC treatment impairs NOR in female, but not male rats. Chronic THC treatment reduces NMDAR binding in the hippocampus.

Abush and Akirav SpragueeDawley (2012) rats

Male

Treatment: PND NOR and 45; treatment cessation: PND 60; NOL test: PND 61, 70, 90; tissue collection: PND 90

WIN (CB1R agonist)

1.2 mg/kg, i.p.

Chronic: WIN administered daily for 14 days

30 min

Chronic WIN in adolescence causes persistent NOR and NOL impairment, and reduced LTP in the ventral subiculum-nucleus accumbens pathway for 24 h - 10 days after treatment cessation

Lovelace et al. (2015)

Female

Treatment: PND NOR 35; treatment cessation: PND 45; test: PND 70þ; tissue collection: PND 70þ

WIN (CB1R agonist)

Escalating dose regime: 0.5, 1, 2 mg/kg, i.p.

Chronic: twice daily, for 10 days (0.5 mg/kg, PND 35e36; 1 mg/kg, PND 37e41; 2 mg/kg, PND 42 e45)

5 min

Chronic WIN treatment in adolescence impairs NOR in adulthood. Chronic WIN reduces mPFC endocannabinoiddependent LTD, metabotropic glutamate 2/3 dependent LTD, and reduces CB1R co-localized with vesicular glutamate transporter 1 in the PFC in adulthood. No effect of adolescent WIN treatment on monoglyceride lipase expression in the PFC in adulthood.

C57BL6 mice

Age

Cannabinoid Drug/s

References

2-AG, 2-arachidonoylglycerol; CAMKIV, calcium-/calmodulin-dependent protein kinase type IV; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; CP, CP55,940; COX-2, cyclooxygenase; CREB, cAMP response element-binding protein; GABA, g-aminobutyric acid; IL, interleukin; iNOS, inducible nitric oxide synthase; i.p., intraperitoneal; KO, knockout; LTP, long-term potentiation; LTD, long-term depression; NMDAR, n-methyl-Daspartate receptor; NOL, novel object location; NOR, novel object recognition; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; PFC, prefrontal cortex; PND, postnatal day; s.c., subcutaneous; THC, D9-tetrahydrocannabinol; THCV, tetrahydrocannabivarin; TNF-a, tumour necrosis factor a; WIN, WIN-55,212-2; WT, wild type-like.

7. THE ECB SYSTEM AS A TREATMENT TARGET TO REVERSE COGNITIVE IMPAIRMENT

479

6.2 Inflammation and Neuroprotective Factors Cannabinoid-induced NOR impairment is associated with a neuroinflammatory phenotype. Chronic THC-induced impairment in object recognition is accompanied by elevated expression of PFC inflammatory markers tumour necrosis factor a (TNF-a), inducible nitric oxide synthase and cyclooxygenase 2 (COX-2) and reduced PFC expression of the anti-inflammatory cytokine, interleukin (IL-10) (Zamberletti et al., 2015). This neuroinflammatory phenotype is associated with upregulation of CB2R on microglia (Zamberletti et al., 2015). Elevated cytokine levels are not present in plasma following chronic THC administration, but treatment with the synthetic cannabinoid AB-FUBINACA reduces plasma levels of cytokines IL-1a and IL-12 (Kevin et al., 2017).

6.3 Changes in Neurotransmitter System Receptor Expression Chronic treatment with THC or synthetic cannabinoids, in a manner which impairs NOR and NOL, also downregulates cannabinoid, glutamate and GABA receptor expression, often in brain regions critical for learning and memory (e.g., PFC, hippocampus). CB1R: chronic adolescent THC or subchronic (3e7 days) adult THC in mice impairs NOR during treatment and for up to 4 days after treatment cessation and also reduces cortical CB1R protein levels in adolescents (Rodriguez et al., 2017) and downregulates CB1R on GABAergic cells in the hippocampus in adulthood (Puighermanal et al., 2013). In line with this, mice lacking CB1R on hippocampal GABAergic cells do not exhibit THC-induced NOR memory impairment, supporting the involvement of hippocampal CB1R in THC-induced NOR deficits (Puighermanal et al., 2013). Finally, chronic adolescent treatment with THC or the synthetic cannabinoid AB-PINACA reduces levels of the cerebellar ethanolamides anandamide, palmitoylethanolamide (PEA), 2-AG and oleoylethanolamide (Kevin et al., 2017). GABA: chronic cannabinoid treatment that impairs NOR reduces PFC GABA levels and GABA precursor molecules; chronic THC administration in adolescence impairs NOR and NOL memory and reduces PFC basal GABA levels, as well as GAD67 in parvalbumin- and cholecystokinin-containing PFC interneurons (Zamberletti et al., 2014). Glutamate: cannabinoid-induced NOR impairment appears dependent on forebrain glutamatergic signalling. Chronic adolescent THC treatment impairs NOR memory and reduces glutamate n-methyl-D-aspartate receptor (NMDAR) binding in the hippocampus of female rats; these effects are not present in male rats (Zamberletti et al., 2012b). These sex differences appear specific to rats, as chronic adolescent THC in male mice impairs NOR discrimination and reduces their cortical NMDAR subunit NR1 protein levels (Rodriguez et al., 2017).

7. THE ECB SYSTEM AS A TREATMENT TARGET TO REVERSE COGNITIVE IMPAIRMENT Recently there has been considerable interest in modulating the eCB system as a potential treatment target for a range of disorders, including neurodegeneration (Karl et al., 2012; Fagan and Campbell, 2014) and schizophrenia (Arnold et al., 2012; Saito et al., 2013); in particular, to reverse cognitive decline in these disorders. In contrast to the negative or neutral effects of cannabinoids on object recognition and location memory in control animals (outlined above), it appears that cannabinoid treatment can reverse pharmacologically or genetically induced impairments in object recognition and object location memory. It seems cannabinoids only improve NOR and NOL memory when memory impairment is present (i.e., in an animal model of memory impairment) but not in control animals, in which cannabinoids often impair or have no effect on recognition memory. Cannabinoid-induced improvement in NOR and NOL memory appears associated with amelioration of deficits in synaptic plasticity, inflammation and cannabinoid, glutamate and GABA receptor signalling. Methodological details for references in this section are presented in Table 31.5.

7.1 Rodent Models of Neurodegeneration and Neuronal Loss Treatment with CB1R agonists can ameliorate cognitive impairment in models of ageing, neurodegenerative disorders and traumatic brain injury. Chronic low-dose THC reverses age-related decline in NOR performance in C57BL/6J mice (Bilkei-Gorzo et al., 2017). In genetic (amyloid precursor protein/presenilin 1 (APPxPS1) transgenic mice) and pharmacological (administration of amyloid-b 1e42 (Ab1-42)) mouse models of AD, acute treatment with

TABLE 31.5 Effects of Acute and Chronic Cannabinoid Treatment on NOL and NOR in Animal Models of Memory Impairment References

Species D Strain

Sex

Age

Test

Cascio et al. (2015)

SpragueeDawley rats

Male

Adult (no age specified)

NOR and NOL

Fagherazzi et al. (2012)

Wistar rats

Male

Zhang et al. (2016)

GomisGonzalez et al. (2016)

Cannabinoid Drug/s

Delay Between Training and Test Results Summary

Dose, Route

Dosing Regime

AM251 (CB1R antagonist), THCV (THC homologue)

AM251: 0.5 mg/ kg i.p.; THCV: 2 mg/kg i.p.

Acute: AM251 or THCV administered 45 min prior to training (AM251) or 30 min prior to training (THCV)

NOR Treatment starts: 8 weeks; treatment duration: 14 days; test: 24 h after final injection

CBD (CB1R/ CB2R indirect agonist)

2.5, 5 or 10 mg/ kg, i.p.

Acute: CBD 24 h administered immediately after the training session. Chronic: CBD administered daily for 14 days

Acute CBD treatment reverses NOR discrimination impairment induced by neonatal iron overload, a model of potential mechanisms in neurodegenerative disorders. Chronic CBD dosedependently reverse ironoverload induced NOR impairment.

Kunming strain of Male Swiss (background not specified)

5e6 weeks

NOR and NOL

HP (peptide CB1R antagonist), and RVD and VD (peptide CB1R agonists)

HP, RVD, VD: all 5 nmol, infusion speed: 2ml at 1 mL/min, i.c.v.

Acute: CB1R agonists/ antagonists administered 15 min prior to training

In a pharmacological mouse model of AD, where mice are chronically treated with Ab1-42, acute treatment with the CB1R peptide agonists RVD and VD reverses object location and object recognition impairments. The peptide CB1R antagonist HP did not reverse Ab1-42induced object recognition impairment but did reverse RVD and VD improvement of Ab1-42-induced impairment.

Fmr1 KO mice (FVB.129P2Pde6bþ Tyrc-ch Fmr1tm1Cgr/J) and WT littermates

Tissue collection: 12e16 weeks

NOR

Rimonabant 0.03, Rimonabant (CB1R antagonist/ 0.1, 0.3, and 1 mg/ inverse agonist), kg, i.p. NESS0327 (CB1R neutral antagonist)

Male

3 min

1 or 3 days after training

Acute rimonabant: 24 h after training. Subchronic rimonabant: daily for 7 days, or once every 2 days for 14 days. Acute NESS0327: after training. Subchronic NESS0327: daily for 7 days

Acute administration of THCV and the CB1R antagonist AM251 prior to training reverses phencyclidineinduced NOR and NOL impairment.

Frm1 KO mice exhibit NOR impairment and elevated hippocampal LTD induced by a group 1 metabotropic glutamate agonist. Elevated hippocampal LTD is reduced by subchronic rimonabant treatment.

Aso et al. (2015) APPxPS1 mice Male and WT littermates (mixed background)

NOR Treatment starts: 6 months; treatment duration: 5 weeks; test: 10 days after treatment cessation

THC (CB1R/CB2R partial agonist), CBD (CB1R/CB2R indirect agonist), THC þ CBD combination

Segal-Gavish et al. (2017a)

DISC1 KO mice Male and WT littermates (mixed C57BL/6 x CBA background)

NOR Treatment starts: PND 42; treatment ends: PND 51; test: PND 54þ

Bilkei-Gorzo et al. (2017)

C57BL/6J mice

Male

Treatment starts: 2 NOL (young), 12 (mature), 18 (old) months; treatment duration: 28 days; test: >5 days after treatment cessation

Alteba et al. (2016)

Rats (strain not specified)

NOR Male þ female Treatment: PND 45; treatment cessation: PND 60; test: PND 90þ; tissue collection: PND 114

Martin-Moreno Transgenic APP et al. (2012) mice and WT littermates (C57BL/6 background)

Male

Treatment starts: 7 months; treatment duration: 4 months; test: 11 months

NOR

Chronic: THC, CBD or THC þ CBD administered daily for 5 weeks; 10 day washout

24 h

NOR impairment in APPxPS1 mice reversed following chronic THC, CBD and THC þ CBD. Chronic treatment with THC, CBD or THC þ CBD reduces astrocytic markers around cortical Ab plaques in APPxPS1 mice; THC þ CBD reduces microglial markers around cortical Ab plaques in APPxPS1 mice and reduces soluble Ab1-42 protein in the hippocampus of APPxPS1 mice.

THC (CB1R/CB2R 10 mg/kg i.p. partial agonist)

Chronic: THC administered daily for 10 days

1h

Adolescent THC impairs NOR in DISC1 KO mice but not WTs.

THC (CB1R/CB2R 3 mg/kg, via partial agonist) minipumps

Chronic: 30 min continuous dosing of THC via minipumps for 28 days

Chronic low-dose THC reverses age-related decline in NOL memory.

WIN (CB1R agonist)

Chronic: WIN administered daily for 16 days

Chronic WIN treatment reverses early life stressinduced NOR and NOL impairment in male and female rats. Chronic WIN reverses stress-induced downregulation of CB1R protein levels in the basolateral amygdala in males, and stress-induced CB1R upregulation in the CA1 in females.

THC, 0.75 mg/kg; CBD, 0.75 mg/kg; THC þ CBD, 0.75 mg/kg each

1.2 mg/kg i.p.

0.2 mg/kg, in WIN (CB1R agonist) and JWH- drinking water 133 (CB2R selective antagonist)

30 min

Chronic: 24 h continuous dosing through drinking water for 4 months

Chronic JWH-133, but not chronic WIN, reversed impairments in NOR in transgenic APP mice. This was associated with decreased microglial activation in the cortex. JHW-133 and WIN decreased protein levels of inflammatory markers e.g., CB2R, COX-2, TNF-a. Continued

TABLE 31.5 Effects of Acute and Chronic Cannabinoid Treatment on NOL and NOR in Animal Models of Memory Impairmentdcont’d Species D Strain

Sex

Age

Arain et al. (2015)

SpragueeDawley rats

Male

Treatment starts: NOR PND 70; treatment ends: PND 76; test: PND 88

ACEA; CB1R agonist

Osborne et al. (2017)

SpragueeDawley rats

Male

NOR Treatment starts: PND 56, treatment ends: PND 80; test: PND 72

Cheng et al. (2014)

APPxPS1 mice Male and WT littermates (C57BL/6J x C3H/ HeJ mixed background)

Treatment starts: 24 weeks; treatment ends: 30 weeks; test: 30 weeks

Campos et al. (2015)

C57BL/6 mice

Treatment starts: 6e8 weeks old; treatment duration: 6 days; test: 5 days after treatment cessation

Female

Aso et al. (2016) APPxPS1 and WT Male littermates (mixed background), or C57BL/6J mice

Test

Cannabinoid Drug/s

References

Delay Between Training and Test Results Summary

Dose, Route

Dosing Regime

1 mg/kg, i.p.

Chronic: ACEA administered 1 mg/kg daily for 6 days

15 min or 24 h

The CB1R agonist ACEA reversed traumatic brain injury-induced impairment in NOR performance after a 15 min, but not a 24 h interval between training and test.

CBD (CB1R/CB2R 10 mg/kg i.p. indirect agonist)

Chronic: CBD administered twice daily for 24 days

1h

Chronic CBD reverses NOR impairment in poly I:C treated offspring, when animals are tested during treatment.

NOR

CBD (CB1R/CB2R 20 mg/kg indirect agonist)

Chronic: CBD administered daily for 8 weeks

1h

Chronic CBD reverses NOR impairment in APPxPS1 mice.

NOR

CBD (CB1R/CB2R 30 mg/kg, i.p. indirect agonist)

Subchronic: CBD administered daily for 3 or 7 days

24 h

Subchronic CBD reverses NOR impairment in a mouse model of cerebral malaria. This is associated with elevated hippocampal BDNF levels. There was no change to PFC BDNF or nerve growth factor in the hippocampus or PFC following subchronic CBD.

THC (CB1R/CB2R THC 0.75 mg/ partial kg þ CBD agonist) þ CBD 0.75 mg/kg, i.p. combination

Chronic: THC administered daily for 5 weeks

24 h

THC þ CBD combination reverses NOR impairment in aged APPxPS1 mice, but not WT aged or young WT mice. NOR impairment reversal is associated with reduced cortical protein levels of synaptosome associated protein-25 and glutamate receptor 2/3, but elevated GABA-A1R. THC þ CBD combination has no effect on cortical astrocyte or microglia concentration, or soluble Ab1-40 or Ab1-42 in the cortex and hippocampus.

NOR Treatment starts: 3 or 12 months treatment duration: daily for 5 weeks; test: 10 days after treatment cessation

NOR Hypoxiaischaemia induced at PND 7e10; subchronic treatment for 3 days; test: PND: 37-40

CBD (CB1R/CB2R 1 mg/kg s.c. indirect agonist)

Acute: CBD administered 10 min after hypoxiaischaemia procedure completion

1h

Hypoxia-ischaemia impairs NOR performance 30 days after the infarct; this is reversed by CBD treatment 10 min after the completion of the hypoxiaischaemia procedure. At PND 37þ, there was a reduction in N-acetylaspartate/choline levels in the parietal cortex following hypoxia-ischaemia; this was reversed following CBD treatment. Nacetylaspartate/choline levels inversely correlates with the severity of neuronal damage, suggesting CBD reduced neuronal damage.

DISC1 KO mice Female and WT littermates (mixed C57BL/6 x CBA background)

Tissue collection: 10 weeks old

NOR

n/a

n/a

1h

14 days voluntary access to running wheels reverses NOR in female DISC1 KO mice and increases CB1R protein in the hippocampus

Gomes et al. (2015)

C57BL/6 mice

Male

Treatment starts: 6 weeks

NOR

CBD (CB1R/CB2R 30 or 60 mg/kg, indirect agonist) i.p.

Chronic: CBD administered daily for 23 days

1h

Chronic CBD reverses NOR impairment in an MK-801 animal model of schizophrenia. In MK-801 treated animals, chronic CBD reduces the number of reactive microglia in the mPFC and CA1 region of the hippocampus, compared with‘ vehicle controls.

Abush and Akirav (2013)

SpragueeDawley rats

Male

Treatment: PND NOR 45; treatment cessation: PND 60; test: PND 91; tissue collection: 24 h, 10 or 30 days after final treatment

WIN (CB1R agonist)

Chronic: WIN administered daily for 14 days

30 min

Stress-induced impairment in NOR memory and LTP in the nucleus accumbens-ventral subiculum pathway is reversed following chronic adolescent WIN.

Pazos et al. (2012)

Wistar rats

Segal-Gavish et al. (2017b)

Male

None - running wheel access for 14 days

1.2 mg/kg, i.p.

2-AG, 2-arachidonoylglycerol; Ab1-40, amyloid-b 1-40; Ab1-42, amyloid-b 1e42; ACEA, arachidonyl-20 -chloroethylamide; AD, alzheimer’s disease; APPxPS1, amyloid precursor protein/presenilin 1; BDNF, brain-derived neurotrophic factor; CBD, cannabidiol; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; CP, CP55,940; COX-2, cyclooxygenase; DISC1, Disrupted in Schizophrenia 1; GABA, g-aminobutyric acid; HP, hemopressin; i.c.v., intracerebroventricular; i.p., intraperitoneal; KO, knockout; LTP, long-term potentiation; LTD, long-term depression; mPFC, medial prefrontal cortex; NMDAR, n-methyl-D-aspartate receptor; NOL, novel object location; NOR, novel object recognition; PEA, palmitoylethanolamide; PFC, prefrontal cortex; PND, postnatal day; RVD, (m)RVD-hemopressin(a); s.c., subcutaneous; THC, D9-tetrahydrocannabinol; THCV, tetrahydrocannabivarin; TNF-a, tumour necrosis factor a; VD, (m)VD-hemopressin(a); WIN, WIN-55,212-2; WT, wild type-like.

484

31. CANNABINOID MODULATION OF OBJECT RECOGNITION

CB1R peptide agonists RVD and VD or chronic treatment with THC reverses NOR impairment (Zhang et al., 2016; Aso et al., 2015, 2016). In contrast, chronic WIN does not reverse object recognition memory impairment in transgenic APP mice; however, the dose used in this study was low (0.2 mg/kg) (Martin-Moreno et al., 2012). Finally, in a mouse model for traumatic brain injury, chronic treatment with the CB1R agonist ACEA reverses object recognition impairment (Arain et al., 2015). It is possible that the ameliorative effects of cannabinoids on NOR impairment are due to anti-inflammatory properties of some cannabinoids, as chronic treatment with THC reduces astrocytic markers around cortical Ab plaques in APPxPS1 mice (Aso et al., 2015). Interestingly, targeting CB2R may also be beneficial in the treatment of neurodegenerative disorders, as chronic treatment of transgenic APP mice with the CB2R antagonist JWH-133 decreases cortical microglial activation as well as protein levels of inflammatory markers (e.g., CB2R, COX-2, TNF-a), and reverses NOR impairment in APP transgenic mice (Martin-Moreno et al., 2012). CBD appears to have protective effects in animal models of neurodegeneration, neuronal loss and neurological impairment. Acute CBD treatment reverses NOR impairment in a mouse model for neonatal iron overload, a mechanism involved in neurodegenerative disorders (Fagherazzi et al., 2012), as well as in a mouse model for hypoxiaischaemia (Pazos et al., 2012). Chronic CBD reverses NOR impairment in AD transgenic APPxPS1 mice (Aso et al., 2015; Cheng et al., 2014). Interestingly, chronic THC þ CBD also reverses NOR impairment in APPxPS1 mice (Aso et al., 2015, 2016). Finally, chronic CBD ameliorates object recognition deficits in a mouse model for cerebral malaria (Campos et al., 2015). CBD may protect against NOR impairment via modulation of inflammation and neuroprotective mechanisms. Chronic treatment of APPxPS1 mice with CBD or THC þ CBD reverses NOR impairment and reduces astrocytic markers around cortical Ab plaques in APPxPS1 mice, while chronic THC þ CBD reduces microglial markers around cortical Ab plaques and reduces soluble Ab42 protein in the hippocampus in APPxPS1 mice ((Aso et al., 2015) but see also (Aso et al., 2016)). CBD pretreatment prevents neuronal loss following hypoxia-ischaemia and reverses NOR impairment in this model (Pazos et al., 2012), while subchronic CBD reverses NOR impairment and elevates hippocampal brain-derived neurotrophic factor levels in a mouse model for cerebral malaria (Campos et al., 2015). Collectively, these studies support an anti-inflammatory and neuroprotective role for CBD in memory impairment in the presence of an increased neuroinflammatory state. There are also changes to receptor protein levels following chronic CBD treatment, which are associated with reversal of NOR impairment in APPxPS1 mice. Chronic combined THC and CBD treatment elevates cortical GABA-A1 protein levels and reduces mGlu2/3R cortical protein levels compared with vehicle-treated APPxPS1 mice (Aso et al., 2016), suggesting that cannabinoids alter the balance of excitatory versus inhibitory cortical neural activity in APPxPS1 mice. Shifting the balance of excitatory and inhibitory signalling may impact on processes such as synaptic plasticity, which is involved in NOR memory (discussed above) and is impaired in APPxPS1 mice (Liu et al., 2011).

7.2 Rodent Models of Schizophrenia In genetic and environmental animal models for schizophrenia, CB1R agonists worsen, and CB1R antagonists improve NOR impairment. Chronic THC impairs NOR in male Disrupted in Schizophrenia 1 (DISC1) KO mice, but not in WT controls (Segal-Gavish et al., 2017a). Conversely, acute treatment with AM251 or THCV, which both act as CB1R antagonists, reverses object location and recognition memory impairments in the schizophreniarelevant chronic phencyclidine model (Cascio et al., 2015). In female DISC1 KO mice, NOR impairment is reversed following 14 days of voluntary access to running wheels, and this is accompanied by increased CB1R protein in the hippocampus (Segal-Gavish et al., 2017b). It appears restoration of CB1R expression in key brain regions for learning and memory may improve NOR impairment in animal models of schizophrenia. There appears some potential for CBD to reverse cognitive impairment in animal models of schizophrenia, as chronic CBD reverses NOR impairment present in the offspring of dams treated with poly I:C, a model for prenatal infection relevant to schizophrenia (Osborne et al., 2017), and chronic CBD reverses NOR impairment in an MK-801 animal model for schizophrenia (Gomes et al., 2015). The ameliorating effects of CBD may be due in part to the antiinflammatory and neuroprotective properties of CBD, for MK-801-induced elevations in reactive microglia in the mPFC and CA1 region of the hippocampus are reduced following chronic CBD treatment (Gomes et al., 2015).

7.3 Rodent Models of Stress-Induced Cognitive Impairments CB1R agonism via chronic WIN treatment can improve stress-induced NOR impairment. Chronic adolescent WIN treatment reverses NOR and NOL impairment induced by early life stress (Alteba et al., 2016) or adolescent chronic stress (Abush and Akirav, 2013) when animals are tested in adulthood. Chronic adolescent WIN also

REFERENCES

485

reverses early-life stress-induced changes to CB1R protein levels in the basolateral amygdala and CA1 region of the hippocampus (Alteba et al., 2016) and reverses chronic stress-induced impairment to LTP in the nucleus accumbensventral subiculum pathway (Abush and Akirav, 2013). Acute administration of the CB2R antagonist AM630 has no effect on stress-induced NOR impairment (Busquets-Garcia et al., 2016), suggesting CB2R may not mediate NOR improvement. The mechanisms by which WIN treatment improves cognitive performance in stress-induced models of NOR impairment are unclear; however, it is possible that interactions between the eCB and stress systems may be involved (for reviews, see (Hillard, 2014; Senst and Bains, 2014)). WIN pretreatment can reduce stress-induced noradrenaline release in rats (Reyes et al., 2012), and noradrenaline can modulate stress-induced cognitive impairment (Birnbaum et al., 1999). It is possible that WIN reverses stress-induced impairment in NOR via noradrenergic mechanisms. WIN-induced cognitive impairment only appears to occur in the presence of cognitive impairment, and it is the balance between cannabinoid and adrenergic signalling, which appears to mediate cognition (for a discussion, see (Morilak, 2012)).

7.4 Intellectual Disability In the Fragile X Mental Retardation 1 (Fmr1) KO mice, a model for Fragile X syndrome, acute and chronic rimonabant treatment improves NOR, and a similar improvement in NOR memory in Frm1 KO mice is observed following chronic treatment with the CB1R neutral antagonist NESS0327 (Gomis-Gonzalez et al., 2016). NOR impairment is associated with elevated mGlu-LTD in Frm1 KO mice, and this is reversed following chronic rimonabant treatment (Gomis-Gonzalez et al., 2016), suggesting altered plasticity may account for cognitive impairment in Frm1 KO mice.

8. CONCLUSIONS The eCB system plays a critical role in the modulation of learning and memory, in particular, recognition memory. Targeting the eCB system may present a novel therapeutic avenue for disorders with prominent cognitive impairment in short- and long-term recognition memory (e.g., AD) (for reviews, see Karl et al., 2012; Bedse et al., 2015). From the literature reviewed, it appears that cannabinoids can have opposing effects on recognition memory based on the presence or absence of impairment: cannabinoids can exert beneficial effects on learning and memory function when impairment is present but can have neutral or detrimental effects when impairment is absent. Beneficial effects of cannabinoids on cognitive function in NOR and NOL paradigms appear related to the reversal of synaptic plasticity impairment or inflammation, as well as the normalization of forebrain receptor expression changes; these changes are dependent on the animal model and cannabinoid drug used. Importantly, our understanding of the molecular mechanisms driving cannabinoid-induced facilitation of memory processes is still quite limited, and future research should concentrate on the mechanisms by which cannabinoids improve memory processes in rodent models of disease. This type of research will help determine the utility of cannabinoids or endocannabinoidtargeting compounds as a treatment option for cognitive impairment in neurological disease.

References Abboussi, O., Said, N., Fifel, K., Lakehayli, S., Tazi, A., El Ganouni, S., 2016. Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence. Metab. Brain Dis. 31 (2), 321e327. Abush, H., Akirav, I., 2012. Short- and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats. PLoS One 7 (2), e31731. Abush, H., Akirav, I., 2013. Cannabinoids ameliorate impairments induced by chronic stress to synaptic plasticity and short-term memory. Neuropsychopharmacology 38 (8), 1521e1534. Albayram, O., Passlick, S., Bilkei-Gorzo, A., Zimmer, A., Steinhauser, C., 2016. Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons. Pflug. Arch. 468 (4), 727e737. Alteba, S., Korem, N., Akirav, I., 2016. Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood. Learn. Mem. 23 (7), 349e358. Antunes, M., Biala, G., 2012. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn. Process. 13 (2), 93e110. Arain, M., Khan, M., Craig, L., Nakanishi, S.T., 2015. Cannabinoid agonist rescues learning and memory after a traumatic brain injury. Ann. Clin. Transl. Neurol. 2 (3), 289e294.

486

31. CANNABINOID MODULATION OF OBJECT RECOGNITION

Arnold, J.C., Boucher, A.A., Karl, T., 2012. The yin and yang of cannabis-induced psychosis: the actions of Delta(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia. Curr. Pharm. Des. 18 (32), 5113e5130. Aso, E., Sanchez-Pla, A., Vegas-Lozano, E., Maldonado, R., Ferrer, I., 2015. Cannabis-based medicine reduces multiple pathological processes in AbetaPP/PS1 mice. J. Alzheimers Dis. 43 (3), 977e991. Aso, E., Andres-Benito, P., Ferrer, I., 2016. Delineating the efficacy of a cannabis-based medicine at advanced stages of dementia in a murine model. J Alzheimer’s Disease 54 (3), 903e912. Barbieri, M., Ossato, A., Canazza, I., Trapella, C., Borelli, A.C., Beggiato, S., et al., 2016. Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair novel object recognition in mice: behavioral, electrophysiological and neurochemical evidence. Neuropharmacology 109, 254e269. Barker, G.R., Warburton, E.C., 2008. NMDA receptor plasticity in the perirhinal and prefrontal cortices is crucial for the acquisition of long-term object-in-place associative memory. J. Neurosci. 28 (11), 2837e2844. Basavarajappa, B.S., Subbanna, S., 2014. CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations. Hippocampus 24 (2), 178e188. Battista, N., Di Tommaso, M., Bari, M., Maccarrone, M., 2012. The endocannabinoid system: an overview. Front. Behav. Neurosci. 6, 9. Bedse, G., Romano, A., Lavecchia, A.M., Cassano, T., Gaetani, S., 2015. The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer’s disease. J. Alzheimer’s Dis. 43 (4), 1115e1136. Bevins, R.A., Besheer, J., 2006. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nat. Protoc. 1 (3), 1306e1311. Bilkei-Gorzo, A., Albayram, O., Draffehn, A., Michel, K., Piyanova, A., Oppenheimer, H., et al., 2017. A chronic low dose of Delta9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat. Med. 23 (6), 782e787. Birnbaum, S., Gobeske, K.T., Auerbach, J., Taylor, J.R., Arnsten, A.F., 1999. A role for norepinephrine in stress-induced cognitive deficits: alpha1-adrenoceptor mediation in the prefrontal cortex. Biol. Psychiatry 46 (9), 1266e1274. Broyd, S.J., van Hell, H.H., Beale, C., Yucel, M., Solowij, N., 2016. Acute and chronic effects of cannabinoids on human cognition-a systematic review. Biol. Psychiatry 79 (7), 557e567. Burston, J.J., Woodhams, S.G., 2014. Endocannabinoid system and pain: an introduction. Proc. Nutr. Soc. 73 (1), 106e117. Busquets-Garcia, A., Gomis-Gonzalez, M., Srivastava, R.K., Cutando, L., Ortega-Alvaro, A., Ruehle, S., et al., 2016. Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation. Proc. Natl. Acad. Sci. U.S.A. 113 (35), 9904e9909. Campolongo, P., Ratano, P., Manduca, A., Scattoni, M.L., Palmery, M., Trezza, V., et al., 2012. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness. Front. Behav. Neurosci. 6, 11. Campolongo, P., Morena, M., Scaccianoce, S., Trezza, V., Chiarotti, F., Schelling, G., et al., 2013. Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity. Neuropsychopharmacology 38 (7), 1276e1286. Campos, A.C., Brant, F., Miranda, A.S., Machado, F.S., Teixeira, A.L., 2015. Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria. Neuroscience 289, 166e180. Capasso, A., Sobarzo-Sanchez, E., Nabavi, S.F., Rastrelli, L., 2016. Cannabinoids for the treatment of schizophrenia: an overview. Curr. Top. Med. Chem. 16 (17), 1916e1923. Cascio, M.G., Zamberletti, E., Marini, P., Parolaro, D., Pertwee, R.G., 2015. The phytocannabinoid, D9-tetrahydrocannabivarin, can act through 5-HT1A receptors to produce antipsychotic effects. Br. J. Pharmacol. 172 (5), 1305e1318. Cheng, D., Low, J.K., Logge, W., Garner, B., Karl, T., 2014. Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1D E9 mice. Psychopharmacology 231 (15), 3009e3017. Curran, H.V., Freeman, T.P., Mokrysz, C., Lewis, D.A., Morgan, C.J., Parsons, L.H., 2016. Keep off the grass? Cannabis, cognition and addiction. Nat. Rev. Neurosci. 17 (5), 293e306. De Laurentiis, A., Araujo, H.A., Rettori, V., 2014. Role of the endocannabinoid system in the neuroendocrine responses to inflammation. Curr. Pharm. Des. 20 (29), 4697e4706. Fagan, S.G., Campbell, V.A., 2014. The influence of cannabinoids on generic traits of neurodegeneration. Br. J. Pharmacol. 171 (6), 1347e1360. Fagherazzi, E.V., Garcia, V.A., Maurmann, N., Bervanger, T., Halmenschlager, L.H., Busato, S.B., et al., 2012. Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders. Psychopharmacology (Berl) 219 (4), 1133e1140. Ferre, S., Lluis, C., Justinova, Z., Quiroz, C., Orru, M., Navarro, G., et al., 2010. Adenosine-cannabinoid receptor interactions. Implications for striatal function. Br. J. Pharmacol. 160 (3), 443e453. Galanopoulos, A., Polissidis, A., Georgiadou, G., Papadopoulou-Daifoti, Z., Nomikos, G.G., Pitsikas, N., et al., 2014. WIN55,212-2 impairs nonassociative recognition and spatial memory in rats via CB1 receptor stimulation. Pharmacol. Biochem. Behav. 124, 58e66. Gomes, F.V., Llorente, R., Del Bel, E.A., Viveros, M.P., Lopez-Gallardo, M., Guimaraes, F.S., 2015. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr. Res. 164 (1e3), 155e163. Gomis-Gonzalez, M., Busquets-Garcia, A., Matute, C., Maldonado, R., Mato, S., Ozaita, A., 2016. Possible therapeutic doses of cannabinoid type 1 receptor antagonist reverses key alterations in fragile X syndrome mouse model. Genes (Basel) 7 (9). Hasanein, P., Teimuri Far, M., 2015. Effects of URB597 as an inhibitor of fatty acid amide hydrolase on WIN55, 212-2-induced learning and memory deficits in rats. Pharmacol. Biochem. Behav. 131, 130e135. Hillard, C.J., 2014. Stress regulates endocannabinoid-CB1 receptor signaling. Semin. Immunol. 26 (5), 380e388. Karl, T., Cheng, D., Garner, B., Arnold, J.C., 2012. The therapeutic potential of the endocannabinoid system for Alzheimer’s disease. Expert Opin. Ther. Targets 16 (4), 407e420. Kevin, R.C., Wood, K.E., Stuart, J., Mitchell, A.J., Moir, M., Banister, S.D., et al., 2017. Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA. J. Psychopharmacol. 31 (6), 757e769.

REFERENCES

487

Kirschmann, E.K., Pollock, M.W., Nagarajan, V., Torregrossa, M.M., 2017. Effects of adolescent cannabinoid self-administration in rats on addiction-related behaviors and working memory. Neuropsychopharmacology 42 (5), 989e1000. Klug, M., van den Buuse, M., 2012. Chronic cannabinoid treatment during young adulthood induces sex-specific behavioural deficits in maternally separated rats. Behav. Brain Res. 233 (2), 305e313. Klug, M., van den Buuse, M., 2013. An investigation into “two hit” effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice. Front. Behav. Neurosci. 7, 149. Korem, N., Zer-Aviv, T.M., Ganon-Elazar, E., Abush, H., Akirav, I., 2016. Targeting the endocannabinoid system to treat anxiety-related disorders. J. Basic Clin. Physiol. Pharmacol. 27 (3), 193e202. Kruk-Slomka, M., Dzik, A., Budzynska, B., Biala, G., 2017. Endocannabinoid system: the direct and indirect involvement in the memory and learning processes-a short review. Mol. Neurobiol. 54 (10), 8332e8847. Liu, H.L., Zhao, G., Cai, K., Zhao, H.H., Shi, L.D., 2011. Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation. Behav. Brain Res. 218 (2), 308e314. Lovelace, J.W., Corches, A., Vieira, P.A., Hiroto, A.S., Mackie, K., Korzus, E., 2015. An animal model of female adolescent cannabinoid exposure elicits a long-lasting deficit in presynaptic long-term plasticity. Neuropharmacology 99, 242e255. Lu, H.C., Mackie, K., 2016. An introduction to the endogenous cannabinoid system. Biol. Psychiatry 79 (7), 516e525. Lutz, B., Marsicano, G., Maldonado, R., Hillard, C.J., 2015. The endocannabinoid system in guarding against fear, anxiety and stress. Nat. Rev. Neurosci. 16 (12), 705e718. Martin-Moreno, A.M., Brera, B., Spuch, C., Carro, E., Garcia-Garcia, L., Delgado, M., et al., 2012. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflammation 9, 8. Morena, M., Campolongo, P., 2014. The endocannabinoid system: an emotional buffer in the modulation of memory function. Neurobiol. Learn. Mem. 112, 30e43. Morilak, D.A., 2012. Modulating the modulators: interaction of brain norepinephrine and cannabinoids in stress. Exp. Neurol. 238 (2), 145e148. Mouro, F.M., Batalha, V.L., Ferreira, D.G., Coelho, J.E., Baqi, Y., Muller, C.E., et al., 2017. Chronic and acute adenosine A2A receptor blockade prevents long-term episodic memory disruption caused by acute cannabinoid CB1 receptor activation. Neuropharmacology 117, 316e327. Osborne, A.L., Solowij, N., Babic, I., Huang, X.F., Weston-Green, K., 2017. Improved social interaction, recognition and working memory with cannabidiol treatment in a prenatal infection (poly I: C) rat model. Neuropsychopharmacology 42 (7), 1447e1457. Pazos, M.R., Cinquina, V., Gomez, A., Layunta, R., Santos, M., Fernandez-Ruiz, J., et al., 2012. Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology 63 (5), 776e783. Pertwee, R.G., 2008. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol. 153 (2), 199e215. Puighermanal, E., Busquets-Garcia, A., Gomis-Gonzalez, M., Marsicano, G., Maldonado, R., Ozaita, A., 2013. Dissociation of the pharmacological effects of THC by mTOR blockade. Neuropsychopharmacology 38 (7), 1334e1343. Rabbani, M., Vaseghi, G., Hajhashemi, V., 2012. AM281, cannabinoid antagonist/inverse agonist, ameliorates scopolamine-induced cognitive deficit. Iran J. Basic Med. Sci. 15 (5), 1106e1110. Renard, J., Krebs, M.O., Jay, T.M., Le Pen, G., 2013. Long-term cognitive impairments induced by chronic cannabinoid exposure during adolescence in rats: a strain comparison. Psychopharmacology (Berl) 225 (4), 781e790. Reyes, B.A., Szot, P., Sikkema, C., Cathel, A.M., Kirby, L.G., Van Bockstaele, E.J., 2012. Stress-induced sensitization of cortical adrenergic receptors following a history of cannabinoid exposure. Exp. Neurol. 236 (2), 327e335. Rodriguez, G., Neugebauer, N.M., Yao, K.L., Meltzer, H.Y., Csernansky, J.G., Dong, H., 2017. Delta9-tetrahydrocannabinol (Delta9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice. Pharmacol. Biochem. Behav. 159, 6e11. Rosenberg, E.C., Patra, P.H., Whalley, B.J., 2017. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav. 70 (Pt B), 319e327. Saito, A., Ballinger, M.D., Pletnikov, M.V., Wong, D.F., Kamiya, A., 2013. Endocannabinoid system: potential novel targets for treatment of schizophrenia. Neurobiol. Dis. 53, 10e17. Segal-Gavish, H., Gazit, N., Barhum, Y., Ben-Zur, T., Taler, M., Hornfeld, S.H., et al., 2017. BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction. Hum. Mol. Genet. 26 (13), 2462e2471. Segal-Gavish, H., Barzilay, R., Rimoni, O., Offen, D., 2017. Voluntary exercise improves cognitive deficits in female dominant-negative DISC1 transgenic mouse model of neuropsychiatric disorders. World J. Biol. Psychiatry 1e10. Senst, L., Bains, J., 2014. Neuromodulators, stress and plasticity: a role for endocannabinoid signalling. J. Exp. Biol. 217 (Pt 1), 102e108. Sticht, M.A., Jacklin, D.L., Mechoulam, R., Parker, L.A., Winters, B.D., 2015. Intraperirhinal cortex administration of the synthetic cannabinoid, HU210, disrupts object recognition memory in rats. Neuroreport 26 (5), 258e262. Subbanna, S., Shivakumar, M., Psychoyos, D., Xie, S., Basavarajappa, B.S., 2013. Anandamide-CB1 receptor signaling contributes to postnatal ethanol-induced neonatal neurodegeneration, adult synaptic, and memory deficits. J. Neurosci. 33 (15), 6350e6366. Swartzwelder, N.A., Risher, M.L., Abdelwahab, S.H., D’Abo, A., Rezvani, A.H., Levin, E.D., et al., 2012. Effects of ethanol, Delta(9)tetrahydrocannabinol, or their combination on object recognition memory and object preference in adolescent and adult male rats. Neurosci. Lett. 527 (1), 11e15. Thanos, P.K., Clavin, B.H., Hamilton, J., O’Rourke, J.R., Maher, T., Koumas, C., et al., 2016. Examination of the addictive and behavioral properties of fatty acid-binding protein inhibitor SBFI26. Front. Psychiatry 7, 54. Vaseghi, G., Rabbani, M., Hajhashemi, V., 2013. The effect of AM281, a cannabinoid antagonist, on memory performance during spontaneous morphine withdrawal in mice. Res. Pharm. Sci. 8 (1), 59e64. Zamberletti, E., Vigano, D., Guidali, C., Rubino, T., Parolaro, D., 2012. Long-lasting recovery of psychotic-like symptoms in isolation-reared rats after chronic but not acute treatment with the cannabinoid antagonist AM251. Int. J. Neuropsychopharmacol. 15 (2), 267e280.

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31. CANNABINOID MODULATION OF OBJECT RECOGNITION

Zamberletti, E., Prini, P., Speziali, S., Gabaglio, M., Solinas, M., Parolaro, D., et al., 2012. Gender-dependent behavioral and biochemical effects of adolescent delta-9-tetrahydrocannabinol in adult maternally deprived rats. Neuroscience 204, 245e257. Zamberletti, E., Beggiato, S., Steardo Jr., L., Prini, P., Antonelli, T., Ferraro, L., et al., 2014. Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiol. Dis. 63, 35e47. Zamberletti, E., Gabaglio, M., Prini, P., Rubino, T., Parolaro, D., 2015. Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats. Eur. Neuropsychopharmacol. 25 (12), 2404e2415. Zhang, R.S., He, Z., Jin, W.D., Wang, R., 2016. Effects of the cannabinoid 1 receptor peptide ligands hemopressin, (m)RVD-hemopressin(alpha) and (m)VD-hemopressin(alpha) on memory in novel object and object location recognition tasks in normal young and Abeta1-42-treated mice. Neurobiol. Learn. Mem. 134 (Pt B), 264e274.