C Pharmacology & Toxicology 2003, 93, 42–47. Copyright C Printed in Denmark . All rights reserved ISSN 0901-9928 Pimozide Injections into the Nucleus accumbens Disrupt Maternal Behaviour in Lactating Rats Maria Rita P. Silva, Maria M. Bernardi, Pablo E. Cruz-Casallas and Luciano F. Felicio Department of Pathology, School of Veterinary Medicine, University of Sa ˜o Paulo, SP, Brazil (Received August 26, 2002; Accepted February 20, 2003) Abstract: In rodents ongoing maternal behaviour requires activation of dopamine receptors. Therefore, it is possible that some motor components of maternal behaviour might be mediated by concurrent dopaminergic stimulation. It has been previously demonstrated that peripheral injections of some antipsychotic drugs such as pimozide have disruptive effects on maternal behaviour. The present experiments were designed to verify the effects of pharmacological blockade of limbic dopamine receptors on ongoing maternal behaviour in lactating rats. The hypothesis that central injections of the drug pimozide would have an effect on maternal behaviour was tested. We investigated the effects of central bilateral intra- accumbens microinjections of the dopamine D2 receptor antagonist pimozide (1.5 and 3.0 mg) on maternal behaviour. Animals treated with 3.0 mg of pimozide showed significantly longer latencies for all parameters of maternal behaviour compared to controls. These results suggest that dopamine receptors in the nucleus accumbens play a role in ongoing maternal behaviour. Dopamine has been implicated in the expression of motiv- ated behaviours (Robbins & Everitt 1996; Parkinson et al. 2000). The mesolimbic dopaminergic pathway, which orig- inates from neurones of the ventral tegmental area, innerv- ates the ventral striatum, i.e. the nucleus accumbens and the olfactory tubercle. Among the projections of the mesol- imbic system, those to the nucleus accumbens are particu- larly important because of the extensive connections of this nucleus to other limbic structures. The nucleus accumbens receives and integrates inputs from the amygdala, hippo- campus, entorhinal area, anterior cingulate area, and parts of the temporal lobe. The mesolimbic dopaminergic projec- tion to the nucleus accumbens is thought to modulate these inputs and thereby influence the output of the nucleus ac- cumbens to its target regions, i.e. the hypothalamus, ventral pallidum and frontal lobes (Kandel 2000), which are in- volved in emotional and motivational aspects of behaviours (Koob 1998 & 1992). With respect to maternal behaviour, it has been shown that the mesolimbic dopaminergic system of maternal rats is activated by cues from newborns (Lonstein et al. 1998; Felton et al. 1999; Lee et al. 1999 & 2000; Vernotica et al. 1999). For example, during the re- union with the pups after a lengthy separation extracellular concentrations of dopamine and its metabolites increase in the ventral striatum of maternal rats (Hansen et al. 1993). 6-Hydroxydopamine-induced lesions in the ventral tegmen- tal area during mid-pregnancy impair normal nest building and retrieval immediately after parturition (Hansen et al. 1991a; Hansen 1994). Furthermore, dopamine receptor Author for correspondence: Luciano F. Felicio, Department of Pathology, School of Veterinary Medicine, University of Sa ˜o Paulo, Orlando M. de Paiva, 87, 05508-900 Sa ˜o Paulo, SP, Brazil (fax π55 11 3091 7829, e-mail lfelicio/usp.br). blockade in the nucleus accumbens with cis-flupenthixol in- hibits maternal pup retrieval and licking but not nursing (Keer & Stern 1999). Systemic injections of the dopamine receptor antagonist haloperidol (Giordano et al. 1990; Stern & Taylor 1991; Stern & Keer 1999; Silva et al. 2001; Lonstein 2002) and raclopride (Hansen et al. 1991b) increase latencies for mat- ernal care. In addition, since dopamine antagonists for spe- cific receptor subtypes (D1, D2) alter maternal behaviour, both types of dopamine receptors seem to be involved in the control of this behaviour (Silva et al. 2001). The present study was designed to verify the effects of ventral intra-accumbens injections of the D2 receptor an- tagonist pimozide in lactating rats on maternal behaviour. Materials and Methods Animals. Nulliparous female rats from our own colony (Wistar ori- gin, 200–250 g) were used. At 90–100 days of age, they were bred by placing two females with a male of the same strain for 4 days. Housing and maintenance. Animals were housed in polypropylene cages measuring 32¿40¿18 cm that contained wood shavings as bedding material. Food and water were available ad libitum and the animals were maintained on a 12:12 hr day/night cycle (lights on at 6 a.m.) at a controlled temperature of 22∫2 æ. At the end of preg- nancy, the females were individually housed and allowed to give birth. Their neonates were culled to six pups the first day after par- turition which was considered as day 1 of lactation. No animal was subjected to more than one kind of behavioural test. The animals used in this study were maintained in accordance with the guidelines of the Committee on Care and Use of Laboratory Animal Re- sources, National Research Council, USA. Stereotaxic surgery, microinfusions, and histology . On days 14–17 of pregnancy, female rats were anaesthetised with 0.6 mg/kg of a keta- mine/xylazine mixture (ketamine – Ketaset A ; Fort Dodge Labora- tories SP, Brazil and xylazine – Rompun A ; Bayer SP, Brazil) and