Abstract Rationale: AZT treatment of seropositive pregnant women and their neonates has been widely used due to its effectiveness in reducing vertical trans- mission of HIV, but medium- and long-term effects of AZT on neurobehavioural development and adult re- sponding are still poorly described. Objective: The aim of the present study was to evaluate the long-term effects of prenatal AZT treatment on aggressive behaviour of adult male mice. Methods: Pregnant CD-1 mice were given saline vehicle, 0.4, or 0.8 mg/ml AZT in their drinking water from gestation day 10 to delivery. Social- aggressive types of interaction were assessed in their male offspring following a 4-week isolation period. Two groups of subjects were used, each undergoing a differ- ent type of test: test 1 consisted of a single 20-min en- counter with an isolated same-strain opponent on postna- tal day (PND) 90, while in test 2 (PND 150) subjects were paired for 10 min for 5 consecutive days with a non-isolated opponent. Results: Slight changes in both aggressive and defensive components of the male-specif- ic agonistic pattern were evident only in test 1, AZT mice displaying a limited increase of aggressive behav- iour compared to their controls. Conclusions: Although the long-term effects of prenatal AZT on social behav- iour are limited, they may be of some relevance for pae- diatricians in order to plan a follow-up of infants, chil- dren and adolescents exposed in utero to antiretroviral drugs. Key words AZT · AIDS · Aggressive behaviour · Behavioural teratology · Animal model · Mouse Introduction As recently as 1993, one-third of the children born to HIV-infected mothers became seropositive or developed AIDS within 3 years, and had about a 20% chance of dy- ing within the same period (CDC 1994). They contracted HIV during pregnancy, labour or delivery (Connor et al. 1994). Since the beginning of 1994, HIV-infected preg- nant women have been treated in the perinatal period with zidovudine (3’-azido-3’-deoxythymidine, AZT). This treatment, which reduces the mother-neonate virus transmission rate to 8.3%, has became widely used in Europe and it is now a standard procedure in the United States (CDC 1994). The fast adoption of AZT treatment has not been par- alleled by a thorough evaluation of its medium- and long-term effects on both non-infected and infected in- fants. Short-term toxic and teratogenic effects of AZT have been reported. They include a reduction of haemo- globin values in pre- and postnatally treated human neo- nates (Connor et al. 1994) and a reduction in body growth in prenatally treated human (Sperling et al. 1992) and macaque monkey (Ha et al. 1994, 1998) neonates, but not in mice (Taylor et al. 1992). Toltzis et al. (1993) characterised a critical period of toxicity (resulting in re- sorption and reduced fertility) for murine embryos be- tween ovulation and implantation, while Greene et al. (1996) located this critical period in the early stages of pregnancy. Animal models of prenatal AZT exposure have been used to evidence potential teratological effects of this drug on behaviour (short-, medium-, and long-term). Ha et al. (1994) reported no impairment in learning tasks in- volving search for hidden food in macaques, while visu- al-based tasks were significantly impaired. In rats, no significant effect of AZT on reflex development, open field exploration or water maze escape was found C. Rondinini · I. Branchi · E. Alleva ( ✉ ) Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e Sistema, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Roma, Italy e-mail: alleva@iss.it Fax: +39-06-4957821 A. Venerosi · G. Calamandrei Section of Comparative Psychology, Laboratorio di Fisiopatologia di Organo e Sistema, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Roma, Italy Psychopharmacology (1999) 145:317–323 © Springer-Verlag 1999 ORIGINAL INVESTIGATION Carlo Rondinini · Aldina Venerosi · Igor Branchi Gemma Calamandrei · Enrico Alleva Long-term effects of prenatal 3’-azido-3’-deoxythymidine (AZT) exposure on intermale aggressive behaviour of mice Received: 1 November 1998 / Final version: 10 March 1999