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      Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study

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          Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine. We characterized the impact of a wider range of perindopril doses on methamphetamine-induced effects in a larger group of non-treatment-seeking, methamphetamine-using volunteers.


          Before treatment, participants received 30mg methamphetamine. After 5 to 7 days of perindopril treatment (0, 4, 8, or 16mg/d), participants received 15 and 30mg of methamphetamine on alternate days. Before and after treatment, participants rated subjective effects and cardiovascular measures were collected.


          Prior to treatment with perindopril, there were no significant differences between treatment groups on maximum or peak subjective ratings or on peak cardiovascular effects. Following perindopril treatment, there were significant main effects of treatment on peak subjective ratings of “anxious” and “stimulated”; compared to placebo treatment, treatment with 8mg perindopril significantly reduced peak ratings of both anxious ( P=.0009) and stimulated ( P=.0070). There were no significant posttreatment differences between groups on peak cardiovascular effects.


          Moderate doses of perindopril (8mg) significantly reduced peak subjective ratings of anxious and stimulated as well as attenuated many other subjective effects produced by methamphetamine, likely by inhibiting angiotensin II synthesis. Angiotensin II is known to facilitate the effects of norepinephrine, which contributes to methamphetamine’s subjective effects. The lack of a classic dose-response function likely results from either nonspecific effects of perindopril or from between-group differences that were not accounted for in the current study (i.e., genetic variations and/or caffeine use). The current findings suggest that while angiotensin-converting enzyme inhibitors can reduce some effects produced by methamphetamine, more consistent treatment effects might be achieved by targeting components of the renin-angiotensin system that are downstream of angiotensin-converting enzyme.

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          Most cited references 46

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          There and back again: a tale of norepinephrine and drug addiction.

          Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine beta-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.
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            Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review.

            The discovery that all components of the renin-angiotensin system (RAS) are present in the central nervous system led investigators to postulate the existence of a local brain RAS. Supporting this, angiotensin immunoreactive neurons have been visualized in the brain. Two major pathways were described: a forebrain pathway which connects circumventricular organs to the median preoptic nucleus, paraventricular nucleus, and supraoptic nucleus, and a second pathway connecting the hypothalamus to the medulla oblongata. Blood-brain barrier deficient circumventricular organs are rich in angiotensin II receptors. By activating these receptors, circulating angiotensin II may act on central cardiovascular centers via angiotensinergic neurons, providing a link between peripheral and central angiotensin II systems. Among the effector peptides of the brain RAS, angiotensin II and angiotensin III have the same affinity for the two pharmacologically well-defined receptors: type 1 (AT1) and type 2 (AT2). When injected in the brain, these peptides increase blood pressure, water intake, and anterior and posterior pituitary hormone release and may modify memory and learning. The cloning of AT1 and AT2 receptor cDNAs has revealed that these receptors belong to the seven transmembrane domain receptor family. In rodents, two AT1 receptor subtypes, AT1A and AT1B, have been isolated. Using specific riboprobes for in situ hybridization histochemistry, recent studies mapped the distribution of AT1A, AT1B, and AT2 receptor mRNAs in the adult rat and found a predominant expression of AT1A and AT2 mRNA in the brain and of AT1B in the pituitary. Very limited overlap was found between the brain expression of AT1A and AT2 mRNAs. In several functional entities of the brain, such as the preoptic region, the hypothalamus, the olivocerebellary system, and the brainstem baroreflex arc, the colocalization of receptor mRNA, binding sites, and angiotensin immunoreactive nerve terminals suggests local synthesis and expression of angiotensin II receptors. In other areas, such as the bed nucleus of the stria terminalis, the median eminence, or certain parts of the nucleus of the solitary tract, angiotensin II receptors are likely of extrinsic origin. The neuronal expression of AT1A and AT2 receptors was demonstrated in the subfornical organ, the hypothalamus, and the lateral septum. By using double label in situ hybridization, AT1A receptor expression was localized in corticotropin releasing hormone but not in vasopressin containing neurons in the hypothalamus. The information is discussed together with functional data concerning the role of brain angiotensins, in an attempt to provide a better understanding of the physiological and functional roles of each receptor subtype.
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              Is Open Access

              Does Smoking Act as a Friend or Enemy of Blood Pressure? Let Release Pandora's Box

               Aurelio Leone (2011)
              In spite of the great number of observations which show the certainty of cardiovascular damage from smoking, the opinions on that are not yet unanimous. There is a discrepancy that could be attributed to the lack of reproducible data particularly in some epidemiological studies. On the contrary, experimental findings conducted on both animals and humans give evidence of exactly reproducible results of cardiovascular alterations and among these the course of Blood Pressure (BP). Findings identify an increase in BP of active smokers or non-smokers exposed to passive smoking, while a lot of others refer a lowering of BP due to smoking. This discrepancy could be explained as follows. Initially, a vasoconstriction mediated by nicotine causes acute but transient increase in systolic BP. This phase is followed by a decrease in BP as a consequence of depressant effects played chronically by nicotine itself. Simultaneously, carbon monoxide is acting directly on the arterial wall causing, in the long run, structurally irreversible alterations. At this time, there is a change in BP that increases again, and often constantly, its levels following chronic exposure. Changes in response to antihypertensive drugs have been observed in hypertensive smokers since smoking influences metabolic steps of the drugs.

                Author and article information

                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                July 2016
                7 April 2016
                : 19
                : 7
                Menninger Department of Psychiatry and Behavioral Sciences (Drs Verrico, Haile, De La Garza, Kosten, and Newton), Department of Pharmacology (Drs Verrico, De La Garza, Kosten, and Newton), and Department of Neuroscience (Drs De La Garza and Kosten), Baylor College of Medicine , Houston, TX; Department of Veterans Affairs Medical Center , Kansas City, Missouri (Dr Grasing); University of Kansas School of Medicine , Kansas City, Missouri (Dr Grasing).
                Author notes
                Correspondence: Christopher D. Verrico, PhD, Baylor College of Medicine, One Baylor Plaza: MS BCM350, Houston, TX 77030 ( verrico@ ). NCT01062451.
                © The Author 2016. Published by Oxford University Press on behalf of CINP.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact

                Page count
                Pages: 8
                Regular Research Article


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