Developmental Brain Research, 51 (1990) 237-240 237 Elsevier BRESD 51011 Changes in brain dopaminergic indices induced by perinatal exposure to cannabinoids in rats F. Rodriguez de Fonseca, M. Cebeira, M.L. Hern~indez, J.A. Ramos and J.J. Fern~indez-Ruiz Department of Biochemistry, Faculty of Medicine, Complutense University, Madrid (Spain) (Accepted 8 August 1989) Key words: Dopaminergic neuron; Dopamine receptor; Tyrosine hydroxylasc; Cannabinoid; Development Perinatal exposure to cannabinoid derivatives has been shown to produce effects on brain development. In this study, we evaluated the changes induced by maternal exposure to hashish crude extract (HCE) during gestation and lactation in several biochemical indices of dopamine activity in the striatum and the limbic forebrain of offspring. Studies were performed either during the HCE exposure or after drug withdrawal. Perinatal exposure to HCE reduced the number of striatal D t binding sites in females and increased the L-3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio, whereas an increase in the number of striatal D 2 binding sites, with a reduction in their affinity, and a decrease in the activity of tyrosine hydroxylase (TH) were observed in males. The DOPAC/DA ratio was also increased in the limbic forebrain in HCE-exposed females, but there were no changes in binding site parameters. Most of these effects disappeared after cessation of cannabinoid treatment, but the decrease in striatal TH activity in males was maintained during drug withdrawal. Interestingly, the affinity of D 2 receptors in the striatum of females, the number of striatal D 1 receptors in males, and the limbic TH activity in males increased after the cessation of drug treatment. These results allow us to conclude that: (1) the effects of perinatal exposure to HCE were different depending on the sex and the specific brain area studied; and (2) most of the effects disappeared after cessation of cannabinoid treatment, although some new changes then appeared. INTRODUCTION It is well established that 6-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabinoid derivatives, is able to alter several biochemical indices of neurotransmitter systems in the brain (for review see ref. 2). These changes have been related to the effects of this drug on several processes, such as decreases in anterior pituitary hormone release x°'24, antidystonic effects 22, enhancement of psychotic disorders 1, and others 15. Moreover, perinatal exposure to THC has been reported to produce effects on brain development and learning ability3'25. This perinatal effect of THC can be produced because it can be transferred from the mother to the offspring through the placental blood during gestation 16 and through the maternal milk during lactationll.The purpose of the present study was to investigate the effects of maternal cannabis exposure on the development and maturation of brain dopaminergic neurotransmission. To this end, we measured L-3,4-dihydroxyphenylacetic acid/ dopamine (DOPAC/DA) ratio, the tyrosine hydroxylase (TH) activity and the number and affinity of D 1 and D 2 DA binding sites in the striatum and limbic forebrain, two of the main areas of dopaminergic neurotransmis- sion, of offspring of mothers exposed daily to hashish crude extract (HCE) from the 5th day of gestation to the 24th day of lactation. Studies were performed with animals sacrificed either during HCE exposure (20th day of life) or after 6 days of drug withdrawal (30th day of life) in order to observe the maintenance or disappear- ance of the HCE-induced changes and the possible appearance of new changes due to cessation of drug exposure. MATERIALS AND METHODS Animals Female virgin rats of the Wistar strain were housed from birth in a room with controlled photoperiod (8.00-20.00 h light) and temperature (23 + 1 °C). They had free access to standard food (Panlab, Barcelona, Spain) and water. At adult age (> 8 weeks of life, 150-200 g), daily vaginal smears, taken between 10.00 and 12.00 h, were done, and only those animals exhibiting 3 or more consistent 4-day cycles were used in this study. Females in the proestrous phase were allowed to stay with a male, and a new vaginal smear was done on the next day. Those animals showing the presence of sperm cells were accepted as probably pregnant and used for the cannabinoid exposure studies. Cannabinoid treatment Hashish was obtained from the Spanish Administration (Servicio de Restricci6n de Estupefacientes y Psic6tropos, Direcci6n General Correspondence: J.J. Fern~indez-Ruiz, Department of Biochemistry, Faculty of Medicine, Complutense University, 28040-Madrid, Spain. 0165-3806/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)