The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions

Abstract

1. In order to explore potential therapeutic implications of cannabinoid antagonists, the effects of the prototypical cannabinoid antagonist SR141716A on monoamine efflux from the medial prefrontal cortex and the nucleus accumbens of the rat were investigated by in vivo microdialysis. 2. SR141716A moderately increased serotonin efflux and concentrations of its metabolite 5-HIAA, both in the medial prefrontal cortex and the nucleus accumbens, and increased norepinephrine, dopamine and their metabolites in the medial prefrontal cortex. In contrast, it had no effect on norepinephrine, dopamine and their metabolites in the nucleus accumbens. 3. At the same doses, SR141716A increased acetylcholine efflux in the medial prefrontal cortex, in agreement with previous studies; contrary to the effects in cortex, SR141716A had no effect on acetylcholine efflux in the nucleus accumbens. 4. The efficacy of SR141716A in the psychostimulant-induced hyperlocomotion and the forced swimming paradigms was also explored in mice. SR141716A attenuated phenylcyclidine- and d-amphetamine-induced hyperlocomotion, without affecting locomotor activity when administered alone, and decreased immobility in the forced swimming test. 5. These results suggest that the cortical selectivity in the release of catecholamines, dopamine in particular, induced by the cannabinoid antagonist SR141716A, its procholinergic properties, together with its mild stimulatory effects on serotonin and norepinephrine efflux make similar compounds unique candidates for the treatment of psychosis, affective and cognitive disorders.

Figure 1

SR141716A increases 5-HT (a,d), DA (b,e) and NE (c,f) efflux in the prefrontal cortex of the rat. (a,b, and c) Represent time course effects after i.p. administration of SR141716A at 3 and 10 mg kg⁻¹. (d,e and f) Represent the average effects of SR141716A (1, 3, 10 mg kg⁻¹; i.p.) over the course of the experiment (overall effects). Data represent mean±s.e.mean of n=5–8 rats per experimental group and are expressed as multifold change from baseline, which is the average of the five basal values immediately before SR141716A administration. Asterisks indicate P<0.05 as compared to the vehicle-receiving group. (a,b,c) Statistical significance for each time point is indicated with an asterisk only for the 10 mg kg⁻¹ dose.

Figure 2

SR141716A increases 5-HIAA (a, d), DOPAC (b, e) and HVA (c, f) efflux in the prefrontal cortex of the rat. (a, b, and c) Represent time course effects after i.p. administration of SR141716A at 3 and 10 mg kg⁻¹. (d, e and f) Represent the average effects of SR141716A (1, 3, 10 mg kg⁻¹; i.p.) over the course of the experiment (overall effects). Data represent mean±s.e.mean of n=5–8 rats per experimental group and are expressed as multifold change from baseline, which is the average of the five basal values immediately before SR141716A administration. Asterisks indicate P<0.05 as compared to the vehicle-receiving group. (a, b, c) Statistical significance for each time point is indicated with an asterisk only for the 10 mg kg⁻¹ dose.

Figure 3

SR141716A increases 5-HT (a, c) and 5-HIAA (b, d) efflux in the n.Acc. of the rat. (a and b) Represent time course effects after i.p. administration of SR141716A at 10 mg kg⁻¹. (c and d) Represent the average effects of SR141716A (3, 10 mg kg⁻¹; i.p.) over the course of the experiment (overall effects). Data represent mean±s.e.mean of n=5–8 rats per experimental group and are expressed as multifold change from baseline, which is the average of the five basal values immediately before SR141716A administration. Asterisks indicate P<0.05 as compared to the vehicle-receiving group.

Figure 4

SR141716A increases ACh efflux in the prefrontal cortex (a, c) but does not affect ACh efflux in the n.Acc. (b, d) of the rat. (a and b) Represent time course effects after i.p. administration of SR141716A. (c and d) Represent the average effects of SR141716A over the course of the experiment (overall effects). Data represent mean±s.e.mean of n=5–8 rats per experimental group and are expressed as multifold change from baseline, which is the average of the five basal values immediately before SR141716A administration. (a) Statistical significance for each time point is indicated with an asterisk only for the 10 mg kg⁻¹ dose. Asterisks indicate P<0.05 as compared to the vehicle-receiving group.

Figure 5

SR141716A attenuates d-amphetamine (a) and PCP (b) induced hyperlocomotion without affecting basal locomotor activity in the mouse. Data (ambulations over a 60 min period after concurrent i.p. administration of each of the drug combinations) represent mean±s.e.mean of n=8–12 mice per experimental group. Closed asterisks indicate P<0.05 as compared to the vehicle-receiving group and open asterisks P<0.05 as compared to the d-amphetamine- (a) or PCP- (b) receiving group.

Figure 6

SR141716A reduces immobility in the forced swimming test in the mouse. Data (immobility for the last 4 min of a 6 min trial) represent mean±s.e.mean of n=7–8 mice per experimental group. Asterisks indicate P<0.05 as compared to the vehicle-receiving group.