Stimulation of the ventral tegmental area enhances the effect of vasopressin on blood pressure in conscious rats

Abstract

The mesolimbic dopamine system projects to a large number of forebrain areas and plays an important role in the regulation of locomotor activity, cognition and reward. We previously found evidence for a functional interaction between the mesolimbic dopamine system and circulating vasopressin and the present study was performed to test the hypothesis that mesolimbic dopamine stimulation modulates the cardiovascular effects of vasopressin. Sprague-Dawley rats were stereotaxically implanted with a guide cannula into the region of origin of the mesolimbic system, the ventral tegmental area, and instrumented with catheters into the abdominal aorta and jugular vein. One week later, separate groups of conscious rats were injected intravenously with 1, 3 or 10 ng kg(-1) of arginine-vasopressin or other vasopressor drugs before and after intra-ventral tegmental area injection of 10 nmol of neurotensin. Intra-ventral tegmental area injections of neurotensin had no significant effect on mean arterial pressure and heart rate but significantly potentiated the pressor response to intravenous administration of vasopressin when compared to saline-injections. However, the vasopressin-induced bradycardia was unaffected. Intravenous pretreatment with raclopride blocked the ability of neurotensin, injected into the ventral tegmental area, to potentiate the vasopressin-induced pressor response. Intra ventral tegmental area injections of neurotensin had no effect on the pressor response and bradycardia induced by intravenous angiotensin II or methoxamine. In conclusion, these results suggest that the mesolimbic dopamine system, in addition to its well-known role in the regulation of behaviour, modulates cardiovascular control by potentiating the effects of vasopressin on mean arterial pressure. British Journal of Pharmacology (2000) 129, 29 - 36

Figure 1

Left panel: The effect of micro-injection of saline or 10 nmol of the substance P analogue DiMe-C7 or neurotensin into the ventral tegmental area on mean arterial pressure (MAP, top) and heart rate (bottom) of conscious rats (n=10 rats per group). ANOVA showed that there was an overall significant effect of treatment (F_(2,269)=17.l, P<0.0001) and of time after injection (F_(8,269=3.6, P=0.0005). Between-group analysis showed that the changes in mean arterial pressure after treatment with DiMe-C7 were significantly different from those after saline or neurotensin treatment which were not different from each other. Further between-group analysis showed that the change in mean arterial pressure after treatment with DiMe-C7 was significantly greater than that after treatment with saline at 10, 15, 20, 25, 30, and 40 min after injection (P<0.05, Bonferroni-corrected t-test). At none of the time-points was the small increase in mean arterial pressure in rats treated with neurotensin significantly different from that in rats treated with saline. No significant differences in heart rate were observed. Right panel: The effect of micro-injection of saline (n=7), DiMe-C7 (n=10) or neurotensin (n=6) into the ventral tegmental area on plasma vasopressin concentration at 10 min after stimulation. Data are mean±s.e.mean. ^*P<0.05 for difference with saline-injected controls.

Figure 2

Typical traces of blood pressure recordings showing the mean arterial pressure (MAP) responses to intravenous injections of 1, 3, or 10 ng kg⁻¹ of arginine-vasopressin before (left panels) and after (right panels) micro-injection of 10 nmol of neurotensin into the ventral tegmental area of conscious rats. Arrows indicate the moment of vasopressin injections. Numbers wth the arrows refer to the vasopressin doses in ng kg⁻¹.

Figure 3

Maximal changes in mean arterial pressure (MAP, mmHg, top panels) and heart rate (beats min⁻¹, bottom panels) following intravenous injection of arginine-vasopressin before and after micro-injection of neurotensin or saline into the ventral tegmental area of conscious rats. The rats were either not pretreated (left panels) or pretreated with raclopride (right panels). For pressor responses in controls, ANOVA yielded a significant effect of neurotensin treatment (F_(1,59)=18.0, P<0.0022) and of vasopressin dose (F_(2,59)=66.3, P<0.0001). After injection of saline into the ventral tegmental area, ANOVA yielded a significant effect of vasopressin dose only (F_(2,59)=65.6, P<0.0001). For heart rate responses, ANOVA yielded significant effects of vasopression dose only (F_(2,59)=11.0, P=0.0008 and F_(2,59)=23.1, P<0.0001 after neurotensin- or saline injection, respectively). Similarly, for pressor responses in raclopride-pretreated rats, ANOVA yielded only a significant effect of vasopressin dose (F_(2,53)=83.1, P<0.0001 and F_(2,41)=48.6, P<0.0001 after neurotensin- or saline injection, respectively). For heart rate responses in raclopride-pretreated rats again there was only a significant effect of vasopressin dose (F_2,53)=25.9, P<0.0001, and F_(2,41)=17.0, P=0.0003, respectively). Data are mean change in mean arterial pressure (mmHg) or heart rate (beats min⁻¹) ±s.e.mean of n=10 for saline- and neurotensin-treated controls and n=7 and 9 for the saline and neurotensin-treated raclopride groups, respectively