Neurotoxicology and Teratology 22 (2000) 357–368 0892-0362/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0892-0362(99)00084-7 The influence of route of administration on the acute cardiovascular effects of cocaine in conscious unrestrained pregnant rats Charles F. Mactutus a,b,c,d, *, Rosemarie M. Booze c,e , Russell T. Dowell d,e a Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40546 USA b Department of Psychology, College of Arts and Sciences, University of Kentucky, Lexington, KY 40546 USA c Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40546 USA d Tobacco and Health Research Institute, University of Kentucky, Lexington, KY 40546 USA e Departments of Anatomy and Neurobiology and Medicine, College of Medicine, University of Kentucky, Lexington, KY 40546 USA Received 10 November 1997; accepted 7 December 1999 Abstract The intravenous route of administration, accessed via a subcutaneous vascular access port, has been recently suggested as an animal model for studying the developmental effects of maternal cocaine abuse in the pregnant and/or group-housed rat. The present study (1) assessed the cardiovascular effects of intravenous (IV) cocaine, delivered via bolus injection, in chronically catheterized near-term preg- nant rats, and (2) compared the IV cardiovascular responses to those following cocaine delivered via the commonly employed subcutane- ous (SC) and intragastric (IG) routes of administration. Pregnant gestation day 15 (GD15) young adult female Sprague–Dawley rats (n 5 21) were anesthetized and catheters surgically implanted into the carotid artery, jugular vein, fundus of the stomach, and a subcutaneous pouch. On GD17–19, heart rate (HR) and mean arterial pressure (MAP) were assessed, using a within-subjects design, prior and subse- quent to IV (3 mg/kg), IG (60 mg/kg), and SC (40 mg/kg) cocaine. An interval of 6 h separated IV and IG cocaine administration and an interval of 18 h separated IG and SC cocaine administration. The peak responses of HR (23%↓) and MAP (37%↑) following IV cocaine were noted within 0.5 min. In contrast, the peak responses of HR (4%↓, 6%↓) and MAP (2%↑, 15%↓) after IG (23 min) or SC (26 min) cocaine, respectively, were significantly smaller and markedly delayed. No significant change in aortic blood flow velocity was detected following cocaine via any route of administration, although phasic flow velocities (PFV) were differentially sensitive to route of adminis- tration (PFV dias not PFV sys ); IV cocaine increased (55%↑) whereas IG or SC cocaine decreased z35%↓) PFV dias . The pressor effects of an equimolar dose of IV cocaine methiodide (3.9 mg/kg) were indistinguishable from those of IV cocaine (38%↑ vs. 37%↑), as were the ef- fects on PFV dias (83%↑ vs. 55%↑). The lack of an effect of cocaine methiodide on HR was consistent with the bradycardia effect of co- caine attributable to central mediation of the baroreflex. Finally, the pressor effects of IV cocaine paralleled the rapidly peaking arterial plasma levels of cocaine noted within 30 s after the initiation of drug injection. In sum, prominent effects of IV cocaine on maternal car- diovascular physiology are noted; as such, the recent reports of a lack of maternal/fetal toxicity following daily (3–6mg/kg) IV cocaine during GD8–21 are not due to use of an ineffective drug dose. It was equally clear that the SC and IG routes of exposure did not repro- duce the cardiovascular component(s) of the expected physiological response to cocaine. © 2000 Elsevier Science Inc. All rights re- served. Keywords: Heart rate; Mean arterial pressure; Drug administration routes; Sprague–Dawley; Intravenous; Intragastric; Subcutaneous 1. Introduction Cocaine use during pregnancy has been associated with an increased rate of spontaneous abortions, premature labor and delivery, abruptio placentae, intrauterine growth retar- dation (decreased weight, length and head circumference), neurobehavioral and neurological abnormalities, cerebral infarction, cardiac, respiratory, and ocular complications, as well as an increased incidence of congenital malformations and sudden infant death syndrome (SIDS) [13,66]. How- ever, conflicting reports of a lack of association of maternal cocaine use with intrauterine growth retardation [53], ter- atogenicity [40] or SIDS [4] have also been noted. Prospec- tive population-based studies, which provide a more accu- rate estimate of risk, have also failed to define any specific pathogonomic outcome (e.g., [25,73]). In sum, these con- flicting data are reminders that we know little about the par- ticular conditions surrounding cocaine abuse that represent the greatest risk for adverse developmental outcome. The multiple pharmacological effects of cocaine which, most notably, cause stimulation of the central nervous sys- * Corresponding author. Tel.: 606-257-4788; fax: 606-323-1077. E-mail address: cfmact1@pop.uky.edu (C.F. Mactutus).