Safety and immunogenicity of the anti-cocaine vaccine UFMG-VAC-V4N2 in a non-human primate model.

A promising strategy for cocaine addiction treatment is the anti-drug vaccine. These vaccines induce the production of anticocaine antibodies, capable of linking to cocaine, and decrease the passage of cocaine throughout the blood-brain barrier, decreasing drug activity in the brain. Our research group developed a new vaccine candidate, the UFMG-V4N2, to treat cocaine use disorders (CUD) using an innovative carrier based on calixarenes. This study assessed the safety and immunogenicity of the anti-cocaine vaccine UFMG-VAC-V4N2 in a non-human primate toxicity study using single and multiple vaccine doses. The UFMG-VAC-V4N2 yielded only mild effects in the injection site and did not influence the general health, feeding behavior, or hematological, renal, hepatic, or metabolic parameters in the vaccinated marmosets. The anti-cocaine vaccine UFMG-VAC-V4N2 presented a favorable safety profile and induced the expected immune response in a non-human primate model of Callithrix penicillata. This preclinical UFMG-VAC-V4N2 study responds to the criteria required by international regulatory agencies contributing to future anticocaine clinical trials of this anti-cocaine vaccine.

Cardiovascular responses evoked by activation or blockade of GABA(A) receptors in the hypothalamic PVN are attenuated in transgenic rats with low brain angiotensinogen.

Previous evidence indicates that a balance between inhibitory gabaergic and excitatory angiotensinergic factors in the PVN is important for cardiovascular control. We investigated the cardiovascular response evoked from activation or blockade of GABA(A) receptors in the paraventricular nucleus (PVN), in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)]. Brain Ang II and Ang-(1-7) levels were also determined. In functional experiments, TGR(ASrAOGEN) and Sprague-Dawley rats (SD, control) were anesthetized with urethane and blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. Brain Ang II and Ang-(1-7) levels were largely reduced in TGR(ASrAOGEN) compared with SD rats. Inhibition of PVN neurons with the GABA(A) agonist, muscimol (1 nmol/100 nL), resulted in an attenuated fall in all cardiovascular variables in TGR(ASrAOGEN) compared with SD rats. This difference was particularly pronounced in HR (TGR Mus -23±6 bpm vs. -77±9 bpm SD Mus; P<0.05) and RSNA (TGR -3±10% vs.-29±8% SD; P<0.05). Furthermore, the sympathetic response evoked by blockade of GABA(A) receptors in the PVN of TGR(ASrAOGEN) was also largely suppressed. The present data indicate that the sympathetic outflow mediated by PVN neurons under basal conditions is suppressed in TGR(ASrAOGEN) rats corroborating the functional significance of brain angiotensin production in the central regulation of sympathetic output to the cardiovascular system.

Baroreflex control of heart rate and renal sympathetic nerve activity in rats with low brain angiotensinogen.

The main objective of the present study was to evaluate baroreceptor control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in transgenic rats (TG) with low angiotensinogen production in glial cells, TGR(ASrAogen)-680. In addition, the sympathetic and vagal autonomic tonus to the heart was investigated. As previously shown, TG rats presented a lower arterial pressure (AP) and HR. However, TG rats had decreased AP variability during the night (8.9+/-0.4 mmHg vs 9.8+/-0.3 mmHg, in SD) accompanied by an increase in HR variability (39+/-1 beats/min vs 35+/-1 beats/min, in SD) and augmented locomotor activity during the night (3.5+/-0.3 counts/min vs 2.5+/-0.2 counts/min, in SD). In addition, TG rats presented increased baroreflex sensitivity for the RSNA (slope of line that correlates decreases in RSNA and increases in AP=1.36+/-0.18 vs 0.77+/-0.1, in SD) and an increased sensitivity for both the baroreflex bradycardia (0.79+/-0.04 ms/mmHg vs 0.52+/-0.04 ms/mmHg, in SD) and tachycardia (1.46+/-0.1 ms/mmHg vs 0.93+/-0.01 ms/mmHg, in SD). Further, TG rats had increased vagal tonus (25+/-3 beats/min vs 11+/-4 beats/min in SD) without significant change in the sympathetic tonus to the heart. These results confirm and extend previous observations showing that glial angiotensinogen, the main source of brain RAS peptides, importantly modulates sympathetic tonus, at least to the renal nerve, and vagal tonus to the heart.