Jana Kučerová

Therapeutic Potential of Cannabinoids in Schizophrenia

Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuanas psychoactive principle Δ(9)-tetrahydrocannabinol), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time- and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizophrenia.

Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behavior after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5–10 mg/kg), did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg) did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2) reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens (NAc) of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive-like state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats.

The effects of methamphetamine self-administration on behavioural sensitization in the olfactory bulbectomy rat model of depression

Depression is frequently comorbid with a drug addiction and may seriously complicate its treatment. Currently, there is no routinely used animal model to investigate this comorbidity. In this study the effect of repeated administration of methamphetamine on i.v. drug self-administration in an olfactory bulbectomy model of depression in rats was investigated in order to propose and validate a rat model of comorbid depression and addiction. Male Wistar rats were either olfactory-bulbectomized (OBX) or sham-operated. They subsequently underwent a methamphetamine sensitization regime, which consisted of daily i.p. injections of methamphetamine for a 14-d period; controls received Sal injections at the same frequency. The i.v. self-administration of methamphetamine (0.08 mg/kg in one infusion) paradigm on a fixed ratio schedule of reinforcement was performed using operant chambers. A significant decrease of the drug intake was recorded in sham-operated animals pretreated with methamphetamine when compared to the unpretreated group. This was not apparent in the OBX groups. Both groups of OBX animals exhibited a higher intake of methamphetamine compared to the corresponding sham-operated groups, thus confirming the hypothesis of higher drug intake in depressive conditions in this rodent model. The procedure of behavioural sensitization to methamphetamine decreased the number of self-administered drug doses per session in the sham-operated rats. It is hypothesized that this phenomenon resulted from increasing efficacy of the drug after behavioural sensitization caused by repeated methamphetamine intermittent administration.

P.3.a.005 Structural and behavioural changes in a rodent developmental disruption model of schizophrenia

as processing speed [F(1.253) = 6.81; p = 0.010] as compared to MetS−. Linear regression analyses revealed that WAIS IQ scores (b =−0.18; p = 0.003) and immediate recall (b =−0.22; p< 0.001) were associated with waist circumference. In the school performance subscale of the PAS the MetS+ group scored significantly worse than the MetS− group in the age epoch 12−16 [F(1,246) = 7.51; p = 0.007]. Discussion: At a mean age of 30 years old, patients with schizophrenia and an additional diagnosis of MetS have poorer cognitive performance as compared to those without MetS. This indicates that, even in the early stages of the disease, metabolic abnormalities are related to poor cognition in schizophrenia. Furthermore, in schizophrenia premorbid cognitive deficits, independently of SES, predict the presence of MetS later in life. This suggests that prevention of MetS should focus in particular on those patients with recent onset schizophrenia, who have poor cognitive performance.

P.6.d.003 Acute administration of full 5-HT1B agonist suppresses methamphetamine intake in IV self-administration rat model

5-HT1B full agonist CGS12066B was shown to dose-dependently suppress MET intake in the IVSA model.

P.4.06 Aripiprazole impact on methamphetamine i.v. self-administration in the olfactory-bulbectomy model of depression in rats

In the present study the effect of aripiprazole on methamphetamine (MET) I.V. self-administration in olfactory-bulbectomy model of depression in conditions of behavioural sensitization to MET in rats was investigated.

P.2.22 Impact of behavioural sensitization to methamphetamine on i.v. selfadminitration of the drug in male and female rats

The female animals were already recorded to respond differently to methamphetamine (MET) abuse than males. This gender dissimilarity may be caused by the influence of estral cycles and different susceptibility to behavioural sensitization. In this study the model of i.v. self-administration of MET (or saline as control) combined with fourteen days (14 D) of intermittent pretreatment with MET (or saline) was used hypothesizing possible influence of behavioral sensitization to the drug on the spontaneous intake in i.v. self-administration sessions was used in male and female rats.

P.6.d.005 Impact of behavioural sensitization and estrogen levels on i.v. self-adminitration of methamphetamine in rats

All the animals experienced previously with effects of MET in the phase of pretreatment showed the lower self-administered intake of MET. This might indicate that MET produced more profound rewarding effects in rats previously sensitized to the drug. The female groups in estrus-like conditions self-administered higher doses of MET than male groups with the same treatment however the females in anestrus self-administererd even lower doses than males. This indicates certain enhancing effect of estrogens on MET addiction in laboratory rodent model which is in accordance with other findings from animal and human studies.

P.6.d.001 Are there gender or seasonal variabilities in mouse behavioral response to acute and chronic ecstasy

In this study we summarized and statistically processed results of four experiments of the same design proceeded during aproximately one year to evaluate gender differences on larger groups of mice treated with MDMA, and the females included were intact animals, but also ovariectomized females without or with estrogen substitution in the last experiment. A possibility of seasonal impact on behavioral variabilities was also evaluated.