ORIGINAL ARTICLE
Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid
exposure during adolescence
Oualid Abboussi1&Nadia Said2&Karim Fifel3&Sara Lakehayli2&Abdelouahhab Tazi2&
Soumaya El Ganouni1
Received: 4 June 2015 / Accepted: 21 October 2015
#Springer Science+Business Media New York 2015
Abstract
Chronic exposure to cannabinoids during adoles- cence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the seroto- ninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were admin- istered separately at 1 mg/kg and 20 mg/kg, and in combina- tion at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor ag- onist WIN55,212–2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like mem- ory in the open field and novel object recognition tests respec- tively 30 minutes after the last drug administration. Chronic WIN55,212–2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute ad- ministration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses.
However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212–2. These findings give
further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophre- nia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease.
Keywords
Adolescence . Cannabinoids . 5-HT4 receptors . D3 receptors . Anxiety . Memory
Introduction
Cannabis is one of the most commonly used illicit drug world- wide, especially among adolescents and young adults (UNODC
2013). Accumulating clinical evidence emphasizedthe risks of psychiatric disorders related to cannabis use, par- ticularly among early onset users (Degenhardt et al.
2013). Ithas been reported that cannabinoids exposure during adoles- cence produces anxiety and deficits of attentional processing and working memory (Schreiner and Dunn
2012). These ob-servations have their counterparts in animal model studies showing that chronic exposure to cannabinoids during adoles- cence induces long-lasting neurobehavioral dysfunctions in emotional control and cognitive functions (Bambico et al.
2010; Trezza et al.2012).
Cannabinoids mediate their pharmacological effects main- ly through two G-protein coupled receptors CB1 and CB2 (Herkenham et al.
1991). Numerous autoradiographic studiesof the mammalian brain showed that the largest concentrations of CB1 receptors were found in the central nervous system particularly in the cortex, striatum, amygdala and the hippo- campus while the CB2 receptors were more abundant in im- mune cells (Burns et al.
2007; Devane et al.1992). The can-nabinoid receptors are involved in the release of various key neurotransmitters such as GABA, glutamate, acetylcholine
* Oualid Abboussi [email protected]
1 Laboratory of Biochemistry and Neurosciences, Faculty of Sciences and Technics, Hassan 1er University, B.P. 577, Route of Casablanca, Settat, Morocco
2 Department of Pharmacology, Faculty of Medicine, Hassan II University, 19 Rue Tarik Bnou Ziad, Casablanca, Morocco
3 Laboratory of Neurophysiology, Department of Molecular Cell Biology, Leiden University, Medical Center, PO Box 9600, Mailbox S5-P, 2300 RC Leiden, The Netherlands
DOI 10.1007/s11011-015-9753-2
and monoamines (Köfalvi et al.
2005). Interestingly, it hasbeen shown that cannabinoid CB1 receptors are expressed on neurite extensions and over cell bodies of serotonergic and dopaminergic neurons (Lau and Schloss
2008), whichsuggest a cross-talk with these monoaminergic systems.
Thus, in regards to the neurobehavioral effects of cannabi- noids, chronic exposure to cannabinoids during adolescence in rats has been suggested for modelling some symptomato- logic aspects of schizophrenia (for review (Stone and Hsi
2011a)), in particular, anxiety and cognitive deficits includingthe episodic-like memory (Casadio et al.
2011; Saykin et al.1991; Stone and Hsi2011b). Indeed, this animal model was
used to test the efficiency of new schizophrenia therapies (Leweke and Schneider
2011; Schneider and Koch2003;Zarrindast et al.
2010).On the basis of this background, we hypothesised that the long-lasting behavioral alterations induced by chronic expo- sure to cannabinoids during adolescence can be improved through modulation of serotoninergic and or dopaminergic systems. Interestingly, the 5-HT4 serotonin and D3 dopamine receptors seem to be the potential therapeutic target since they are highly abundant in the limbic system which is involved in mnemonic processes. It has been recently suggested that acti- vation of 5-HT4 receptor exert a rapid anxiolytic-like effect and improve deficits in multiple domains of cognition, includ- ing declarative memory (David
2013; Meneses1998; Orsettiet al.
2003). These beneficial effects of 5-HT4 activation werecorrelated to neuroplastic-associated changes, such as adult hippocampal neurogenesis, and increase in the expression of neuroplasticity-related proteins (BDNF, CREB, AKT) (Orsetti et al.
2003; Matsumoto et al. 2001; King et al.2008). On other hand, D3 receptor antagonists were suggested
as effective antipsychotic agents for the treatment of the neg- ative and cognitive symptoms of schizophrenia (Joyce and Millan
2005; Gross et al.2013). It has been reported thatselective blockade of D3 receptors versus D2 receptors facil- itates frontocortical cholinergic transmission, improves cogni- tion and display a low potential for extrapyramidal side-effect in rats (Millan et al.
2007; Gross et al.2012).Therefore, in this study, we attempted to prove that using U-99194A as a D3 dopamine receptor antagonist and RS67333 as a selective 5-HT4 receptor agonist, may improve the cognitive and emotional functions in rats pre-treated chronically during adolescence by the WIN55,212–2.
Materials and methods
AnimalsA total of 57 adolescent (27–30 PND) male Wistar rats were used in all the experiments (Fig.
1). The animals were housedin groups of four per cage, with free access to food and water,
and kept at a constant temperature (22 ± 2 °C) under a 12/12 h light-dark cycle (light beginning at 7:00 a.m.). All experi- ments were carried out during the light phase between 9 a.m. and 5 p.m. All efforts were made to minimise animal suffering (Prut and Belzung
2003).All experimental procedures were approved by the local ethical committee of Hassan 1er university and were in com- pliance with the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No.
8023, revised 1978).
Drug treatments
All drugs and control vehicle injections were given intraperi- toneally (i.p) in a volume of 5 ml/kg. The following drugs were used: WIN55,212–2, a potent aminoalkylindole CB1 receptors agonist (Tocris Bioscience, France); the partial high- ly selective 5-HT4 receptors agonist RS67333 [1-(4-amino-5- chloro-2-methoxyphenyl)-3-(1-butyl-4-piperidinyl)-1- propanone] hydrochloride (Tocris Bioscience, France); and the preferential dopamine D3 antagonist U-99194A [5,6- dimethoxy-2-(di-n-propyl-amino)] indan maleate salt (Sigma–Aldrich Canada) (20 times higher preferential affinity to D3 over D2). All drugs were dissolved in 0.1 % Tween 80 and diluted in saline 0.9 %.
Different groups of rats were injected with either WIN55, 212–2 (1 mg/kg) (n = 47) or its vehicle (V/V,V;
n= 10). Each day the rats received one, two or no injection (10 times one injection, five times two injections and 10 times no injection per day) in order to mimic the irregularity in human cannabis users (Schneider and Koch
2003).The last WIN55,212–2 treatment was followed by a 20 day drug washout period, first to allow the adolescent groups to reach adulthood, and then to exclude the confounding effects of drug withdrawal (Fig.
1). After this period, rats fromWIN55,212–2 group were randomized and divided into four subgroups, which were injected with RS67333 (1 mg/kg) (W/RS,V;
n= 11); U-99194A (20 mg/kg) (W/U,V;
n= 12);
both RS67333 and U-99194A in combination at 0.5 mg/kg and 10 mg/kg, respectively (W/RS,U;
n= 12); or vehicle (W/V,V;
n= 12) 30 min before behavioral testing (Fig.
1).Behavioral assays Open field test
The open field apparatus consisted of a 100 × 100 cm rectan-
gular arena surrounded by 40 cm high walls made of grey
plexiglass. The floor of the open field was virtually divided
into 25 equal squares (20 × 20 cm each, 16 peripherals and 9
centrals) brightly illuminated by a white light lamp (100 W)
suspended 2 m above the open field arenas. Rats were each
gently placed at the centre of the arena and left to get
accustomed to the apparatus for one minute before a behav- ioral recording of five minutes, performed after drug or vehi- cle administration.
Anxiety-like behavior was measured by the frequency and total duration of central squares visits using an automated activity monitoring system (AnyMaze, Stoelting). The in- crease in central locomotion without modification of total lo- comotion (i.e. the total number of the central and peripheral squares visited) along with the increased vertical exploration can be interpreted as anxiolytic-like effects and the decrease of these variables is associated with anxiogenic-like effects (Antunes and Biala
2012). On the other hand, an increase intotal locomotion can reflect a stimulant effect while decreased vertical (rearing) activity and locomotion can reveal a sedative effect (Antunes and Biala
2012). This experiment is the first ofthe three sessions of habituation to the memory test that follow.
Novel object recognition test
The object recognition task is conducted in the open field apparatus to test long-term memory in rats during adulthood.
This task evaluates the ability of the animal to discriminate between novel and familiar objects. Non treated rats usually spend more time exploring a novel than a familiar object (O’Shea et al.
2004). The test procedure consisted in threesessions: familiarization, acquisition, and retention. During the first 3 days, rats were familiarized to the apparatus for 5 min per day. During the acquisition session, two objects (A1 and A2) were placed 15 cm from the sidewall in diagonal corners opposite each other. The rat was placed in the middle of the open field arena. Each rat was allowed to explore the apparatus and objects for five minutes. At the end of the trial, the rat was removed from the apparatus and returned to its home cage. After 24 h inter-trial interval, the rat was returned to the open field (retention session) that contained the familiar object (a duplicate of A2 from retention session) in the same location as in the acquisition session and a new object B re- placed A1.
Objects of various shapes ranging in size from about 9 × 7 × 5 cm to 9 × 10 × 7 cm were used. Each object was available in quadruplicate. Object A1 (to be replaced in trial 2)
was counter balanced for each group of animals. Object A2 (to remain the same for trial 2) was the same for all animals to avoid the possibility of aversion and/or preference to the ob- ject. The new object B was similar in size to A1 to reduce preference for either of the objects. All objects and the appa- ratus were cleaned using 70 % ethyl alcohol to eliminate ol- factory stimuli. The behaviors scored included approaches to each object: directing the nose to the object at a distance of
<1 cm and/or touching it with the nose; and time spent with each object sniffing or climbing the object) (O’Shea et al.
2004).
The discrimination index (DI) [(time spent exploring the novel object - time spent exploring the familiar object)/total exploration time] was calculated for the retention trials (Schneider and Koch
2007).Statistical data analysis
Data were presented as mean (±SEM) and analysed by one- way analyses of variance (ANOVA) for the open field test and two-way ANOVA for the novel object recognition test. This detected the main effect of drug treatment, the main effect of the task, and the interaction between drug treatment and object exploration. When a significant effect was found, further anal- ysis by Benferroni post-hoc test was performed. The discrim- ination indexes were further compared to the reference value of 0 (indicating no discrimination), by a univariate t-test. The significance level was set at
p< 0.05. For all analysis Graphpad-prism 5 software was used.
Results
Open field measurements
The open field assessments showed that WIN55,212
–2 treated rats exhibited an anxiogenic-like behavior. One-way ANOVA revealed a main effect of treatments on the number of visits (F
(4,53)= 3.410,
p= 0.0149) and the time spent in central squares (F
(4,53)= 13.18,
p< 0.001). Bonferroni post-hoc com- parisons showed that chronic exposure to WIN55, 212–2 (1 mg/kg) during adolescence significantly decreased the
Fig. 1 Schematic representation of the experimental design used toassess the behavioral effects of 5-HT4 and D3 receptors modulation in rats undergoing chronic WIN55,212–2 (1 mg/kg) treatment during
adolescence. Win: WIN55,212–2; RS: RS67333; U-99: U-99914A;
NOR: Novel object recognition test; PND: post-natal days
number of visits and the time spent in the central squares when compared with vehicle group (p < 0.05, Fig.
2b, c).Compared to WIN55,212
–2 treated rats (W/V,V), acute administration of RS67333 (1 mg/kg) 5-HT4 receptors ago- nist increased the time spent in central squares (p < 0.05, Fig.
2c). However, administration of U-99194A (20 mg/kg)D3 receptors antagonist (alone) or in combination with RS67333 at 0.5 mg/kg and 10 mg/kg, respectively, did not increase the number of visits and the time spent in central squares (p > 0.05, Fig.
2b, c). This suggests that unlikeU-99194A, RS67333 may have an anxiolytic-like effect (Fig.
2b). On the other hand, WIN55,212–2 induced a slightbut non-significant decrease in locomotor activity (p = 0.075, Fig.
2a), and a non-significant effect on rearing scores(p > 0.05 Fig.
2d). Also, acute administration of RS 67333(1 mg/kg), U-99194A (20 mg/kg) or both in combination does not affect the locomotor activity when compared with vehicle group (p > 0.05, Fig.
2c).Novel object recognition measurements
The acquisition session results indicated no significant effect of treatment on the total time of exploration [ANOVA:
F
(4102)= 0.885,
p= 0.476] neither a difference in exploration
time of the object A1 versus object A2 in all the treatment groups [Bonferroni post-hoc test (p > 0.05)] (Fig.
2).During the second session of the novel object recognition test (Fig.
3), WIN55,212–2 (1 mg/kg) treated animals werenot able to discriminate new vs familiar object compared to the reference value 0 (p > 0.05). Acute administration of RS67333 (1 mg/kg) 5-HT4 receptors agonist, U-99194A (20 mg/kg) D3 receptors antagonist or both in combination at 0.5 mg/kg and 10 mg/kg, respectively, significantly in- creased the discrimination index compared to the WIN55, 212–2 treated group (p < 0.05). Interestingly, when comparing co-administered group with RS67333 and U-99194A (W/RS, U) to vehicle group (V/V, V) and to the reference value 0, we observed that co-administration of RS67333 (0.5 mg/kg) and U-99194A (10 mg/kg) reversed the deleterious effect of the WIN55,212–2 on object recognition performances (p > 0.05) (Fig.
4).Discussion
In the present study, we showed that the deleterious effects of WIN55,212–2 exposure during adolescence on anxiety and cognition were significantly reversed by acute administration of RS76333 (1 mg/kg) and co-administration of RS76333 and
V/V, V
W/V,V W/RS,V
W/V,U W/RS,U 0
10 20 30
*
b
Number of central squares visited
V/V/V W/V,V
W/RS,V W/V,U W/RS,U 0
10 20 30 40 50
a
Total squares visted
V/V,V W/V,V W/RS, V
W/V,U W/RS,U 0
10 20 30 40 50
d
Rearing (seconds)
V/V,V W/V,V W/RS,V W/V,U W/R
S,U 0
20 40 60 80
***
c
***
##
**
Time spent in central squares (%)
Fig. 2 Effects of acute intraperitoneal administration of RS67333, U-99194A or both in combination at lower doses to rats undergoing chronic WIN55,212–
2 (1 mg/kg) treatment (i.p) during adolescence on locomotor activity (a), anxiety-like behavior (b,c), and rearing (d) during the open- field test. Data are presented as mean ± SEM. ***p< 0.0001,
**p< 0.01, *p< 0.05 compared with vehicle (V) group;
##p< 0.01compared with WIN55,212–2 (W) group.
(Bonferroni post-hoc test)
U-99194A at lower doses, respectively. Locomotor activity was not affected by the treatments suggesting that the obtained results cannot be attributed to a locomotor impairment or an overall lack of exploration.
To our knowledge, no study has yet been interested in the pharmacological modulation of the behavioral disorders in- duced by cannabinoids exposure during adolescence through activation or deactivation of 5-HT4 and/or D3 receptors.
Chronic exposure to WIN55,212–2 during adolescence re- sulted in an anxiogenic-like behavior and impaired episodic- like memory evaluated respectively in the open field and the novel object recognition tests that were carried out 20 days after the last treatment. These findings are in agreement with previous reports demonstrating that cannabinoids induce long-lasting working memory impairments and increased anx- iety in adolescent rats (Schneider and Koch
2007; Bossongand Niesink
2010). Cannabis use during adolescence has beenassociated with increased vulnerability to develop neuropsy- chiatric disorders later in life especially schizophrenia (Fernandez-Espejo et al.
2009). Hence, chronic adolescentWIN55,212–2 administration has often been proposed as a valid model for this disease (Leweke and Schneider
2011;Mendez-David et al.
2014).Without normalizing the performances of WIN55,212–2 pre-treated animals, acute injection of RS67333 at 1 mg/kg 30 min before behavioral testing decreased the anxiety and improved the episodic-like memory when administered in combination at lower doses with U-99,194 in rats when com- pared to WIN55,212–2 pre-treated rats. These effects are in line with the anxiolytic-like properties of the RS67333 report- ed in several previous studies. For example, Mendez-David et al. showed that the 5-HT4 receptor agonists RS67333 has a rapid anxiolytic effect mediated by a neurogenesis indepen- dent mechanism in an animal model of anxiety (Lamirault and Simon
2001). Furthermore, Lamirault and Simon have shownthat RS67333 administered at a similar dose (1 mg/kg) im- proves episodic-like memory in the novel object recognition test (Laszy et al.
2005). More recently, it has also been dem-onstrated that 5-HT4 receptor agonists can improve attention processes which is one of the primary cognitive deficits asso- ciated with schizophrenia disease (Orsetti et al.
2003).Similarly, acute administration of the D3 receptor antago- nists U-99194A also partially restored the cognitive perfor- mances in the novel object recognition test, but did not have any significant effect on anxiety-like behavior in rats pre- treated with WIN55,212–2 during adolescence. In agreement with these results, acute administration of U-99194A at a similar dose (20 mg/kg) has been shown to improve the learning performance in memory-impaired rats tested in in the Morris water maze and in social recognition tests (Reavill et al.
2000). It has also been demonstrated thatD3 receptor antagonists improve recognition perfor- mance and attention processes associated with schizo- phrenia that share similar neural substrates underlying the behavioral impairments induced by chronic exposure to cannabinoids during adolescence (Luedtke and Mach
2003; Bockaert et al. 2006).More importantly, our findings show that the co- administration of RS67333 and U-99194A at lower doses (0.5 mg/kg and 10 mg/kg, respectively) restores the object recognition performances in WIN55,212–2 pre-treated rats chronically during adolescence, suggesting that RS67333 and U-99194A may act synergistically and in complementar- ity. The beneficial effects of co-modulation of these molecular regulators 5-HT4 and D3 receptors might be related to the fact that both play a major role in the control of cell signalling and particularly hippocampal neurogenesis (Liu et al.
2009; Chenet al.
2006; Abboussi et al.2014) which is severely alteredunder the effect of chronic cannabinoids exposure during ad- olescence as we have demonstrated in a previous study (Bockaert et al.
2006).Actually, it has been shown that 5-HT4 and D3 receptors are present at high densities and co-expressed post-
V/V,V W/V,V W/RS
,V
W/V,U W/RS,U 0
5 10 15
20 A1
A2
Time of exploration (seconds)
Fig. 3 Effects of chronic WIN55,212–2 (1 mg/kg) exposure (i.p) during Adolescence (W), and subsequent acute intraperitoneal administration of RS67333 (n= 11), U-99194A (n= 12) or both in combination at lower doses (n= 12) during adulthood on the duration of exploring objects A1 and A2 during the first session of the novel object recognition test. Data are presented as mean ± SEM. (Bonferroni post-hoc test)
V/V,V W/V,V W/RS,V W/V,U W/RS,U -0.2
0.0 0.2 0.4
0.6
***
***
* *
##
###
Discrimination index
Fig. 4 Effects of chronic exposure to WIN55,212–2 (1 mg/kg) during Adolescence, and subsequent acute intraperitoneal administration of RS67333, U-99194A or both in combination at lower doses during adult- hood on episodic-like memory. Data are presented as mean ± SEM.
***p < 0.0001, *p < 0.05 compared with vehicle (V) group;
###p< 0.0001,##p< 0.01 compared with WIN55,212–2 (W) group.
(Bonferroni post-hoc test)
synaptically with CB1 receptors in the hippocampus [43–45], suggesting a cross talk between these neurotransmitter sys- tems. Furthermore, the 5-HT4 receptors are coupled to Gs proteins whereas the D3 receptors are associated to Gi protein (Kim et al.
2001; Neves et al.2002). Thus, the blockade of D3receptors and the activation of 5-HT4 receptors respectively take off inhibition and stimulate the adenylate cyclase leading to a local increase of cAMP that improves the PK activity necessary for both signal transduction and the different mo- lecular steps of learning and memory processing (Cavalli et al.
2008). Thus, the obtained results suggest that targeting differ-
ent neuronal systems, using lower doses from each com- pound, could be considered as a more beneficial pharmaceu- tical approach for treating the cognitive dysfunctions associ- ated with cannabis use. This multi-target pharmacological ap- proach captures and merges the benefits of each compound, which may further enhance their efficacy and safety in com- parison to traditional antipsychotics (Morphy and Rankovic
2006; Costantino and Barlocco2012).In conclusion, the present study has shown that chronic cannabinoids exposure during adolescence induced episodic- like memory deficit, a memory that is precociously altered in schizophrenic patients. Co-modulation of 5-HT4 and D3 re- ceptors significantly reversed the induced behavioral deficits, giving further support for the multiple medication therapy recommended by numerous clinical studies (Costantino and Barlocco
2012; Kroeze and Roth2012). More profound in-vestigations will be necessary to identify the detailed mecha- nisms underlying the beneficial effects of this combination on the long-lasting behavioral alterations associated with canna- binoids intake during adolescence.
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