Investigation of gender differences in the cardiovascular actions of direct and indirect sympathomimetic stimulants including cathinone in the anaesthetized rat

Abstract

We have studied gender differences in the direct and indirect sympathomimetic cardiovascular effects of the stimulant cathinone (from Khat) (and for comparison methylenedioxymethamphetamine [MDMA]) and the archetypal indirect sympathomimetic agent tyramine, employing male and female Wistar rats. Animals were sympathectomized by treatment with 6-hydroxydopamine or treated with vehicle. In male and female vehicle-treated pentobarbitone-anaesthetized rats, all three agonists (0.001-1 mg/kg) produced significant tachycardia, tyramine produced large pressor, and in high doses small depressor responses, MDMA produced small pressor responses, and cathinone produced only minor pressor effects. In sympathectomized rats, pressor responses, even those to tyramine, were virtually abolished, and depressor responses to tyramine were abolished. In vehicle-treated rats, the tachycardia to tyramine, but not the tachycardia to cathinone or MDMA, was significantly greater in male than female rats. This may suggest that the mechanism of the tachycardia to tyramine differs from those of the stimulants cathinone and MDMA. Following sympathectomy, there were no differences between male and female rats in the tachycardia to any agent. Hence, there were gender differences in the tachycardia response for tyramine, but no gender differences in the cardiovascular responses to the widely used recreational stimulants cathinone and MDMA. Cardiac stimulant actions of cathinone and MDMA were similar in male and female rats.

Sex and Gender Differences in the Effects of Novel Psychoactive Substances

“…However, men and women differ for reasons for quitting use of synthetic cathinones, as female users perceive the fear of consequences (i.e., increasing amounts/frequency of use) as more important reasons with respect to the male users’ perceptions [ 122 ]. In animals, the cardiovascular effects of the stimulant cathinone (from khat) were similar in males and females [ 123 ] while adolescent exposure to methylone was found to induce higher anxiety-related behavior in female than male rats [ 124 ]. Similar to (+)-amphetamine- and (+)-methamphetamine [ 125 ], cathinone also induced significantly higher increases in motor activity in females than in males, and when administered in combination with caffeine, it significantly elevated body temperature acutely in male but not female rats [ 126 ].…”

Cardiovascular and temperature adverse actions of stimulants

“…Indirect actions by the release of monoamine or transporter blockade should be most important where there is dense innervation, such as the heart or CNS, but less important where there is sparse innervation, for instance, the vasculature (see Alsufyani & Docherty, 2016). One of the most densely innervated tissues is the sino‐atrial node of the heart that controls heart rate, and many stimulants including cocaine and MDMA tend to have more marked cardiac than vasoconstrictor actions.…”

“…MDMA can cause major cardiovascular complications and sudden death. MDMA is reported to increase heart rate (Hayner & McKinney, 1986) and blood pressure (Gouzoulis et al, 1993; Vollenweider et al, 1998) in humans and at similar doses per kilogram in rats (Alsufyani & Docherty, 2016; O'Cain et al, 2000). MDMA increases both systolic and diastolic blood pressure by action at α 1 ‐ and α 2 ‐adrenoceptors and 5‐HT 2 receptors in rats (McDaid & Docherty, 2001) and α 1 ‐adrenoceptors in humans (Hysek et al, 2013).…”

“…In humans, the selective SERT inhibitor citalopram reduced the cardiac and blood pressure actions of MDMA (Liechti & Vollenweider, 2000). Cardiovascular actions, both in terms of heart rate and blood pressure, of MDMA were greatly attenuated by chemical sympathectomy with 6‐hydroxydopamine (6‐OHDA) in rats suggesting a predominantly indirect agonist action and a peripheral site of action as 6‐OHDA poorly passes the blood‐brain barrier (Alsufyani & Docherty, 2016). Indeed, MDMA (1 mg·kg −1 ) produces α 1 ‐adrenoceptor‐mediated rises in blood pressure in the pithed rat, an effect that can hardly be central but must be due to direct or indirect (presumably mainly indirect) peripheral actions on vascular α 1 ‐adrenoceptors (McDaid & Docherty, 2001).…”

“…Cathinone is the main and most active component of khat and has been shown to act as a weak amphetamine‐like agonist (Brenneisen et al, 1986; Kalix, 1991), causing tachycardia and hypertension and increasing the force of cardiac contraction in dogs (Kalix, 1991) and rats (Yanagita, 1979). In rats, cathinone has weaker pressor actions than MDMA but induced marked tachycardia, and this was attenuated by sympathectomy and hence is largely indirect by the release of noradrenaline (Alsufyani & Docherty, 2016).…”