Neonatal nitric oxide synthase inhibition: social interaction deficits in adulthood and reversal by antipsychotic drugs.

Nitric oxide synthase (NOS) is thought to migrate improperly during development in the brains of schizophrenic patients. Also it is known that nitric oxide (NO) effects synaptogenesis during development of the CNS. Previously we have shown that neonatal treatment with a NOS inhibitor effects an animal's sensitivity to amphetamine and PCP. In the present study, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine, 10mg/kg, s.c.) daily on post-natal days (PD) three, four and five. L-Nitroarginine (L-NoArg) treated male rats at adulthood (PD56 and older) had a deficit in social interaction (SI) when placed in an environment with another foreign male rat and this deficit was reproducible on a weekly basis for at least five weeks. Haloperidol failed to significantly reverse this deficit before pronounced secondary effects on general behavior were seen at high doses. However, the atypical antipsychotics, clozapine and olanzapine, were able to significantly reverse this deficit at doses which did not effect baseline SI values. In a separate cohort of animals the effect of DOI was investigated, this was done to ascertain if there was a differential sensitivity of serotonergic pathways in this model. There was no difference in the behavioral score elicited from control or NoArg-treated rats. It is suggested that the SI deficits seen here may be more sensitive to atypical antipsychotics rather than haloperidol.

Repair of isolated multiple muscular ventricular septal defects: the septal obliteration technique.

BACKGROUND: Isolated multiple ventricular septal defects (mVSDs) remain a surgical challenge. The dilemma of whether to perform a complete repair ultimately rests with the surgeon, who must decide if all significant septal defects can be located. Avoidance of a pulmonary arterial band (as part of a two-stage repair) will negate the need for future pulmonary arterial reconstruction and will reduce the incidence of late right ventricular diastolic dysfunction. METHODS: We performed a retrospective analysis of hospital and echocardiographic data of eight children who underwent a septal obliteration technique (SOT) as part of their correction of mVSDs (with and without coarctation of the aorta). RESULTS: Eight children with a mean age of 10.5 months (range 1.5 to 36 months), and weight of 6.2 kg (range 2.1 to 13.5 kg), respectively, underwent correction of mVSDs. All had a single, large, perimembranous defect, additional VSDs within the muscular trabecular septum (juxtaposed to the moderator band), and apical mVSDs. All VSDs were repaired via the right atrium, with avoidance of either a right or left ventriculotomy. The posterior and apical defects were excluded from the right ventricular cavity with a pericardial patch (SOT). The follow-up period remains limited to a mean of 20.9 months (8 to 39 months). Two children repaired with SOT had previous pulmonary artery bands (neonatal coarctation repair). All children were successfully discharged home with a mean postoperative Qp:Qs of 1.09:1. One pacemaker was required, but this child has since reverted back to normal sinus rythm. CONCLUSIONS: Our initial experience using the SOT in the treatment of apical VSDs as a component of isolated mVSDs has been rewarding. All children are currently alive, in normal sinus rhythm, and have no residual significant left-to-right shunts.

Isolated origin of the left subclavian artery from the left pulmonary artery.

We describe two children with isolated origin of the left subclavian artery from the left pulmonary artery detected by echocardiography during the assessment of their congenital cardiac malformations. Both patients demonstrated pre-operative evidence of subclavian steal. This entity results from persistence of the dorsal segment of the sixth left arch, with regression of the left fourth arch and interruption of the left dorsal arch distal to the origin of the seventh left intersegmental artery. The significance of this finding relates to the potential for pulmonary overcirculation, which could have significant post-operative ramifications if not detected prior to surgical repair of an associated cardiac malformation. This entity differs from cases with a right aortic arch and aberrant left subclavian artery which has the potential to form a vascular ring, unlike cases with isolated origin of the left subclavian artery from the pulmonary artery that do not cause compression of the airway.

Effect of AMPA receptor modulators on hippocampal and cortical function.

Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA.

Does the degree of cyanosis affect myocardial adenosine triphosphate levels and function in children undergoing surgical procedures for congenital heart disease?

OBJECTIVE: The outcome of children with cyanosis after cardiac surgical procedures is inferior to that of children who are acyanotic. Animal studies indicated detrimental effects of chronic hypoxia on myocardial metabolism and function. We studied whether the presence or the degree of cyanosis adversely affected myocardial adenosine triphosphate, ventricular function, and clinical outcome in children. METHODS: Forty-eight children who underwent repair of tetralogy of Fallot were divided according to their preoperative saturation: group I, 90% to 100% (n = 14 patients); group II, 80% to 89% (n = 16 patients); and group III, 65% to 79% (n = 18 patients). Adenosine triphosphate was measured from right ventricular biopsy specimens taken before ischemia, at 15 minutes of ischemia, at end-ischemia, and at 15 minutes of reperfusion. Ejection fraction was measured by echocardiography. RESULTS: Even before surgical ischemia, compared with groups I and II, group III had lower preoperative ejection fraction (59% +/- 2.9% vs 67% +/- 1.7% and 68% +/- 1.0%; P <.01) and lower preischemic adenosine triphosphate levels (15.1 +/- 2.1 vs 19.1 +/- 1.9 and 21.4 +/- 1.5 micromol/g dry weight; P <.01). After 15 minutes of ischemia, group III had lower adenosine triphosphate levels (11.2 +/- 1.8 vs 14.77 +/- 2.3 and 17. 6 +/- 3.1 micromol/g dry weight; P <.01). With reperfusion, both cyanotic groups lost further adenosine triphosphate compared with partial recovery in the acyanotic group (-22% +/- 3.8%, -20% +/- 3. 1% vs +18% +/- 1.8%; P <.01). Children in group III had a more complicated postoperative course as evidenced by longer ventilatory support (85 +/- 25 hours vs 31 +/- 15 and 40 +/- 21 hours; P =.07), inotropic support (86 +/- 23 hours vs 38 +/- 12 and 36 +/- 4 hours; P <.01), and intensive care unit stay (160 +/- 35 hours vs 60 +/- 10 and 82 +/- 18 hours; P =.02). CONCLUSIONS: The degree of cyanosis adversely affects myocardial adenosine triphosphate, function, and clinical outcome of children who undergo cardiac operation. Children with cyanosis should be identified as a higher risk group that could be targeted for supportive interventions.

Single coronary artery and complete transposition of the great arteries: a technical challenge resolved?

BACKGROUND: The origin of the coronary arteries from a single aortic sinus remains a rare congenital anomaly, once regarded as having little clinical significance. Contemporary surgical practice, however, frequently demands precise coronary reimplantation. In this article we emphasize a prophylactic surgical technique found especially helpful in the repair of D-transposition of the great arteries (D-TGA)/single coronary artery. METHODS: We reviewed the institutional cardiac registry. RESULTS: Since 1985, 398 neonates with D-TGA were repaired with the arterial switch procedure. A mortality rate of 38% was encountered in "simple" D-TGA (n = 174)/single coronary (2.9% left facing sinus (IRLCx), 7.5% right facing sinus (IIRLCx)) and 41% in neonates with D-TGA (n = 224)/single coronary (3.6% IRLCx, 12% IIRLCx). During the past 3.5 years the surgical mortality rate of neonates (n = 6) treated with origin of the coronary arteries from a single aortic sinus has dropped to 0%. CONCLUSIONS: The surgical repair of D-TGA/single coronary artery continues to trouble surgeons. The implantation of a well-mobilized coronary "button" into a previously anastomosed neoaorta remains a key prophylactic technique in the achievement of good technical results.

Preservation of the pulmonary valve complex in tetralogy of fallot: how small is too small?

BACKGROUND: Surgical repair of congenital lesions associated with right ventricular outflow tract obstruction frequently requires the destruction of pulmonary valve (PV) components including the valve annulus. The resultant pulmonary insufficiency may lead to late functional deterioration of right ventricular performance. Acute right ventricular dysfunction has been associated with poor pulmonary runoff, tricuspid valve regurgitation, and pulmonary hypertension. Preservation of PV competence may prevent both early and late right ventricular failure. However, the recent trend towards earlier repair of tetralogy of Fallot (TOF) may preclude preservation of the PV in favor of a transannular patch. We reviewed our experience with surgical repair of TOF to determine if age and/or body size affected the ability to repair the PV. METHODS: We reviewed the clinical records of 50 consecutive children who underwent surgical repair of TOF by one surgeon. The latter 27 patients underwent repair with an intention to preserve their pulmonary valve. In total, 28 patients underwent repair with preservation of their pulmonary valve, and form the basis of this study. Serial echocardiographic assessments were performed early (3 to 6 months) and late (12 months) after surgery. RESULTS: Pulmonary valve preservation was possible in the majority of children (89%) in whom it was intended. Pulmonary valve competence was observed in 68% of children, with only 5 (16%) children demonstrating severe insufficiency at follow-up. Residual right ventricular outflow tract obstruction was present in only 1 child who underwent repair with pulmonary valve preservation at greater than 2 years of age. CONCLUSIONS: Our data suggest that earlier repair of TOF does not preclude preservation of the pulmonary valve and may indeed facilitate repair. The pulmonary valve remains competent at 12 months, with acceptable gradients, and should participate in somatic growth. Pulmonary valve preservation during repair of TOF may prevent free pulmonary insufficiency, progressive right ventricular dilation, and the need for future prosthetic pulmonary valve replacement.

Minimally invasive surgery with cardioscopy for congenital heart defects.

BACKGROUND: Minimally invasive cardiac surgery remains a burgeoning discipline lacking adequate instrumentation and perfusion circuitry, particularly for the pediatric population. Cardioscopy, utilizing first generation imaging equipment with a variety of different angled lenses, provides a unique opportunity to expand the realm for the diagnosis and treatment of congenital heart disease. METHODS: Sixty-eight children with a mean weight of 23 +/- 11 kg (range 8-62 kg) who underwent repair of atrial septal defects (ASD) using a minimally invasive approach (MINI group) were compared to 25 consecutive children undergoing ASD repair via a full median sternotomy (CONT group). In addition, mini-sternotomy with or without cardioscopy allowed for the diagnosis and treatment of more complex congenital lesions in 24 children. RESULTS: The mean age in the MINI group was 7 +/- 3 years (range 1-15 years) compared to 4 +/- 4 years in the CONT group (p = 0.009). The mean body surface area of the MINI group (0.8 +/- 0.2 m2; range 0.4-1.6 m2) was larger than the CONT group (mean 0.6 +/- 0.3 m2; range 0.2-1.6 m2; p = 0.04). Ischemic times and cardiopulmonary bypass times were similar in both groups. Postoperative hospital stay was shorter in the MINI group (3 +/- 2 versus 4 +/- 1 days; p = 0.014). CONCLUSIONS: Minimally invasive cardiac surgery can be performed safely even in small children with congenital heart defects. In addition to improved cosmetic results, these techniques can reduce the utilization of hospital resources. Future advances in cardioscopic technology should permit minimally invasive repair of most complex congenital heart lesions and should obviate the need for full sternotomy in the majority of children undergoing cardiac surgery.

Pediatric heparin-induced thrombocytopenia: management with Danaparoid (orgaran).

Heparin-induced thrombocytopenia is a rare and serious complication of anticoagulation therapy. There remains a paucity of information pertaining to alternative anticoagulation strategies for use during cardiopulmonary bypass concomitant with heparin-induced thrombocytopenia, especially in children. We report the successful treatment of heparin-induced thrombocytopenia and subsequent hemorrhagic complications postoperatively in a 2-year-old child with Danaparoid (orgaran). Emergent conduit revision with cardiopulmonary bypass was required for a thrombosed systemic-venous to pulmonary-arterial connection (completion modified Fontan procedure). Required doses of Danaparoid were consistently twofold that previously reported for adults.

Extended aortic root replacement with aortic allografts or pulmonary autografts in children.

OBJECTIVES: To evaluate the early results and effectiveness of left ventricular outflow tract enlargement with aortic allograft or pulmonary autograft in children with complex left ventricular outflow tract obstruction. METHOD: The records of 30 children who underwent aortic root enlargement and replacement with either an aortic allograft (22 patients) or pulmonary autograft (8 patients) between January 1987 and June 1997 were reviewed. The predominant diagnosis was complex left ventricular outflow tract obstruction (n = 19), associated with aortic incompetence in 11 children. Before root enlargement, 27 children underwent surgical valvotomy (14 patients), balloon dilatation (10 patients), or both interventions (3 patients). Mean age at root enlargement was 5.4 +/- 3.5 years (range, 2 days-16 years). Most of the children (27 patients) underwent a Konno aortoventriculoplasty. Concomitant septal myectomy was performed in 4 children, mitral valve procedure in 5 children, and endocardial fibroelastosis resection in 1 child. RESULTS: Five children (17%) died in hospital. Four of these were infants less than 2 months old. All had acute aortic incompetence as the result of recent intervention necessitating urgent operation. The fifth child, aged 10 years, died of myocardial failure 2 weeks after the operation. During the follow-up period (mean length, 4.1 +/- 2.8 years), sudden death occurred in 1 child 3 months after the operation. Follow-up echocardiograms (obtained for 23 of the surviving 24 children within 3 +/- 2.3 years) showed a left ventricular outflow tract gradient reduced from a mean of 65 to 11 mm Hg (P =.001); Z value increased from a mean of -0.5 to 4.1 (P <. 001), and aortic incompetence was trivial or mild except in 2 children. CONCLUSION: Urgent aortic root enlargement in decompensating neonates carries higher mortality rates. In older children, the early results of root enlargement and implantation of allograft or autograft are good.

On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia.

NADPH-d (nicotinamide-adenine dinucleotide phosphate-diaphorase) neurons are thought to migrate improperly during development in the brains of schizophrenic patients. This enzyme is a nitric oxide synthase (NOS). Nitric oxide (NO) is known to affect neurodevelopmental processes in the CNS. Therefore, we hypothesized that interference of NO generation during development may produce some aspects of schizophrenia symptomatology in a rat model. In these experiments, neonatal rats were challenged with a NOS inhibitor (L-nitroarginine 1-100 mg/kg s.c.) daily on post-natal days 3-5. L-Nitroarginine (L-NoArg) treated male rats developed a hypersensitivity to amphetamine in adulthood versus vehicle treated controls, whereas female rats did not. However, L-NoArg treated female rats developed a hypersensitivity to phencyclidine (PCP) at juvenile and adult ages versus vehicle treated controls, whereas male animals did not. L-NoArg treated male rats also had deficits in pre-pulse inhibition of startle whereas adult female rats did not. The results are discussed in terms of a new neurodevelopmental model of schizophrenia and male/female differences inherent in this disease.

Factors associated with outcomes of persistent truncus arteriosus.

OBJECTIVES: The purpose of this study was to identify trends and factors associated with outcomes of persistent truncus arteriosus (PTA). BACKGROUND: Although there have been significant improvements, PTA continues to be associated with significant morbidity and mortality. METHODS: We undertook a review of all consecutive cases of PTA (n = 205) presenting at our institution from 1953 to 1997. Data were collected regarding demographics, anatomy, management (surgical palliation and repair) and outcomes (mortality and reoperation). RESULTS: Significant trends (p < or = 0.001) related to groups defined by year of birth were as follows: number of cases (1953-1967, n = 13; 1968-1977, n = 42; 1978-1987, n = 69; 1988-1997, n = 81), median age at first assessment (8 months, 42 days, 7 days and 2 days, respectively), proportion who did not have any surgery (58%, 27%, 22% and 11%), proportion who had an initial palliative procedure (25%, 37%, 6% and 2%), proportion who underwent PTA repair (31%, 59%, 72% and 88%), median age at PTA repair (11.2 years, 1.1 years, 1.6 months and 12 days) and proportion dying before hospital discharge after repair (50%, 63%, 56% and 41%). Since 1995, mortality before hospital discharge after repair has further decreased to 2/11 (18%). Increasing time to initial conduit replacement in hospital survivors was significantly related to larger sized conduit at repair (p = 0.02) and use of pulmonary homografts (vs. aortic homografts or xenografts; p = 0.002). Interventional catheterization to address conduit obstructions significantly increased conduit longevity. CONCLUSIONS: Significant improvements in PTA outcomes are evident with trends toward earlier age at assessment and complete repair.

Effect of the dopaminergic neurotoxin MPTP on cocaine-induced locomotor sensitization.

The blockade of dopamine (DA) uptake via the dopamine transporter (DAT) in the nucleus accumbens (NAC) and striatum by cocaine has a major role in the reinforcing and psychomotor stimulating effects of the drug. Here we investigated the effect of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the expression and induction of sensitization to the locomotor stimulating effect of cocaine. MPTP (20 mg/kg x 4) caused 72 and 76% depletion of DAT sites in the NAC and striatum, respectively, in C57BL/6 mice. The magnitude of this depletion 3 and 19 days after MPTP administration was the same. To determine the effect of MPTP on the expression of the sensitized response to cocaine, cocaine-experienced mice (20 mg/kg for 5 days) received MPTP 3 days before a challenge cocaine injection was given on day 15. Cocaine/MPTP mice were significantly more sensitive to the challenge cocaine injection than the cocaine/saline-pretreated mice. To determine whether depletion of NAC and striatal DAT affects the induction of sensitization to cocaine, mice were pretreated with MPTP 3 days before the administration of cocaine (20 mg/kg for 5 days). The magnitude of the sensitized response of MPTP/cocaine-pretreated mice to cocaine challenge was the same as the sensitized response of mice treated with saline/cocaine, while the number of DAT binding sites in the MPTP/cocaine group was significantly lower than the saline/cocaine group. The present study indicates that MPTP exacerbates the expression of locomotor sensitization to cocaine, but it had no effect on the induction of sensitization. We conclude that the expression, but not the induction, of locomotor sensitization to cocaine may be dependent on the level of DAT binding sites.

Direct neonatal ventriculo-arterial connections (REV): early results and future implications.

BACKGROUND: Is the time-honored supposition correct that insertion of a competent prosthetic conduit or homograft is necessary to achieve right ventricular (RV) to pulmonary artery continuity in neonates? A direct ventriculo-arterial connection, or réparation à l'étage ventriculaire (REV), has been successfully used to achieve RV to pulmonary artery continuity in neonates without mortality or major morbidity. Acute RV function is preserved even in the face of free pulmonary insufficiency, but scrupulous preservation of pulmonary artery patency (unobstructed pathway) must be achieved. METHODS: We retrospectively reviewed the cases of 6 neonates who underwent direct ventriculo-arterial connection to achieve RV to pulmonary artery continuity during open heart procedures in the last 3 years. RESULTS: The 6 neonates had a mean age of 12.3 days (range, 2 days to 6 weeks) and a mean weight of 3.2 kg (range, 2.7 to 3.6 kg) at operation. Two of them had a diagnosis of aortic atresia + ventricular septal defect and successfully achieved an in-series circulation. Two had pulmonary atresia + ventricular septal defect and 2, double-outlet right ventricle + transposition of the great arteries + ventricular septal defect + pulmonary atresia. Follow-up is a mean of 16 months (range, 6 to 22 months). Surgical reintervention was required in 3 neonates and resulted in excellent hemodynamics in 2 of them. In the other patient, who had bilateral long-segment branch pulmonary artery hypoplasia, stents were placed without hemodynamic benefit. All children are currently alive with preserved RV function even in the presence of free pulmonary insufficiency. CONCLUSIONS: Although the creation of a direct ventriculo-arterial connection has routinely been used for children older than 1 year with satisfactory initial results, its application in neonate is very limited. Why have neonates been denied this viable alternative? Perhaps the answer involves legitimate concerns about the consequent free pulmonary insufficiency and the presumed acute RV diastolic dysfunction.

Aortic atresia with a ventricular septal defect: modified single-stage neonatal biventricular repair.

BACKGROUND: The spectrum of hypoplastic left heart disease is diverse but the surgical repair is strictly dichotomous, culminating in either a univentricular or a biventricular surgical repair. Although aortic atresia with a ventricular septal defect historically has been managed by conversion to a univentricular physiology, a biventricular repair occasionally has been attempted in stages or in conjunction with the implantation of multiple allografts or prosthetic conduits. Our repair strategy recently has evolved to the use of a modified single-stage biventricular repair using only autologous tissues without conduits. METHODS: Retrospective analysis (1989 to 1997) of neonates with aortic atresia with a ventricular septal defect. RESULTS: Five neonates underwent repair of aortic atresia with a ventricular septal defect. One died in the hospital. The mean age and weight of the neonates who underwent repair were 7.8 days (range, 2 to 17 days) and 3.2 kg (range, 3 to 3.6 kg), respectively. Three neonates had a univentricular repair and 2 had a modified biventricular repair. The latter two procedures were successful and the patients were discharged from the hospital. CONCLUSIONS: Long-term results are lacking to attest to this surgical modification's superiority over either the standard multistage univentricular operation or the single-stage biventricular repair using multiple conduits. However, we are optimistic that routine use of this modification will enable a greater percentage of neonates to undergo a biventricular repair without the need for serial conduit revisions or future aortoplasty.

Surgical treatment of aortic arch hypoplasia in infants and children with biventricular hearts.

BACKGROUND: Results of aortic arch reconstruction in the setting of biventricular physiology are well documented in the adult population, however, in children, surgical outcome of this subgroup of patients is less clear. METHODS: We studied the clinical outcomes of 37 children aged 8 days to 15 years (median 26 months), who underwent aortic arch reconstruction for arch hypoplasia from 1982 to 1997. The children were divided into three groups: Group 1 (20 patients) had isolated aortic arch lesions, Group 2 (13 patients) had associated intra-cardiac pathology yet conserving a biventricular physiology, Group 3 (4 patients) had Williams Syndrome. Previous interventions for coarctation had been performed in 30 patients (81%). Arch repair consisted of a patch aortoplasty in the majority of patients (35 of 37 children). RESULTS: Operative mortality occurred in 5 children, 4 in Group 2 (31%), 1 in Group 3 (25%) and none in Group 1. Permanent neurological complications occurred in 2 children (5 %). During the follow-up, which ranged from 1 month to 8 years, balloon angioplasty for arch obstruction was required in 1 child. There was one late death, associated with a subsequent intra-cardiac repair. CONCLUSIONS: Aortic arch surgery in children with isolated arch hypoplasia, is associated with excellent early and late survival in addition to a low reintervention rate. Alternative perfusion and operative strategies must be implemented in infants with associated intra-cardiac anomalies to improve results.

Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH-induced locomotor sensitization, the protective effect of melatonin observed in the present study may be due primarily to diminishing METH-induced hyperthermia.