TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia

Abstract

A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the alpha4beta2, ganglionic (alpha3beta4) and muscle subtypes. The transgenic th(tk-)/th(tk-) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.

Fig. 1

Effects of TC-5619 on alpha7 NNRs expressed in oocytes. Dose–response for TC-5619-evoked currents in human alpha7 receptors expressed in Xenopus oocytes. Data were normalized to the net charge of control 300 µM ACh responses obtained 5 min before the experimental agonist-evoked responses. Each point represents the Mean ± SEM of the normalized responses of at least four oocytes.

Fig. 2

Effects of TC-5619 or TC-5619 and clozapine together on pre-pulse inhibition in mice. TC-5619 alone (0.1 and 0.3 mg/kg), clozapine alone (3.0 mg/kg) or both drugs together were administered i.p. PPI was measured in age-matched controls (Panel A) and in transgenic th(tk−)/th(tk−) mice (Panel B) as described in Section 2. Results are expressed as Mean ± SEM. ^*Significant difference from control group receiving same treatment at individual stimulus intensity (post hoc; p < 0.05, after significant main effect of genotype F value; ANOVA). ^#Significant difference within genotype from vehicle group at individual stimulus intensity (post hoc LSD; p < 0.05, after significant main effect of drug F value; ANOVA).

Fig. 3

Effects of TC-5619 or TC-5619 and clozapine together on startle response in mice. TC-5619 alone (0.1 and 0.3 mg/kg), clozapine alone (3.0 mg/kg) or both drugs together were administered i.p. Startle response was measured in age-matched controls (Panel A) and th(tk−)/th(tk−) mice (Panel B) as described in Section 2. Results are expressed as Mean ± SEM. *Significant difference from control group receiving same treatment (p < 0.05, significant main effect of genotype F value; ANOVA). ^#Significant difference within genotype from vehicle group (p < 0.05, significant main effect of drug F value; ANOVA).

Fig. 4

Effects of TC-5619 or TC-5619 and clozapine together on social investigation in mice. In the absence of drug (baseline and vehicle groups), control mice spend more time investigating stimulus animals than transgenic th(tk−)/th(tk−) mice. Treatment with TC-5619 (0.3 mg/kg) increased the time subjects of both genotypes spent investigating the stimulus animal. There was no difference in investigation time between drug-treated control mice and drug-treated th(tk−)/th(tk−) mice. Low doses of clozapine (3.0 mg/kg) or TC-5619 (0.1 mg/kg) alone had no effect on investigation time of either a female or male stimulus animal. These behaviorally inactive doses of TC-5619 and clozapine administered together increase social investigation of female stimulus animals in both genotypes. With a male stimulus animal, however, treatment with clozapine and TC-5619 (low dose) increased investigation time in th(tk−)/th(tk−), but not control mice. ^†Significantly different from other groups of the same genotype (p < 0.05). ^*Significantly different from control group of the same treatment (p < 0.05).

Fig. 5

Effects of TC-5619 on locomotor activity in the open-field test and elevated plus maze in mice. (Panel A) The time control or th(tk−)/th(tk−) mice spent in the periphery or center zone of the open-field. Although th(tk−)/th(tk−) mice spent significantly more time in the center (and consequently significantly less time in the periphery) than controls, there was no effect of TC-5619 (0.3 mg/kg). ^*Significantly different from controls (p < 0.05). (Panel B) TC-5619 had no effect on time spent in the open and the closed arms of the elevated plus maze. As expected, subjects of both genotypes spent significantly more time in the closed arms than in the open arms. The th(tk−)/th(tk−) mice spent significantly more time in the open arms than controls. There was no effect of drug. ^*Significantly different from controls (p < 0.05).

Fig. 6

Effects of TC-5619 on apomorphine-induced impairment of pre-pulse inhibition in rats. To examine pre-pulse (PP) inhibition in rats, the PP trials involved either a pre-pulse of 75 dB (=10 dB over background) or 85 dB (=20 dB over background) of 20 ms duration with onset 100 ms prior to a 120-dB pulse of 40 ms duration. The average inter-trial interval was set to 40 s with a range of 20–60 s, and the inter-trial interval length was randomized. The startle response was measured for 100 ms from the onset of the 120-dB pulse presentation. The magnitude of the “flinch” of a startled rat was measured. The level of PPI was calculated as a percentage score for each acoustic pre-pulse trial type as follows: %PPI = 100 − {[(startle response for pre-pulse + pulse)/(startle response for pulse-alone)] × 100}. Data are expressed as Mean ± SEM. ^†p < 0.001 vs. saline/vehicle; ^**p < 0.001 vs. saline plus apomorphine.

Fig. 7

Effects of TC-5619 on cognition in a novel object recognition paradigm in rats. (Panel A) TC-5619 was administered p.o. (0.3 mg/kg) and the exploration times were determined at 0.5, 2, 6, 18 and 24 h post-administration as described in Section 2. Data are expressed as Mean ± SEM. ^*p < 0.05 vs. vehicle controls. (Panel B) A % recognition index was calculated (%RI = [(time investigating novel object)/(total time investigating both novel + familiar objects)] ×100) at various times following administration of TC-5619 (0.3 mg/kg p.o.). Results represent the recognition index (RI) as a function of time following administration of TC-5619 and are expressed as Mean ± SEM. ^*p < 0.05 vs. vehicle controls.