In zebrafish, the ventilatory response to hypoxia first develops at 3 days post-fertilization (d.p.f.) before O2-chemoreceptive neuroepithelial cells (NECs) of the gill appear at 7 d.p.f. This indicates the presence of extrabranchial chemoreceptors in embryos and a developmental transition to primarily gill O2 sensing. This thesis examined the skin NECs, which reach peak density in embryos but decline as gill NECs appear. Exposure of embryos and larvae to chronic hypoxia prevented the loss of skin NECs, shifted peak basal ventilation to a later developmental stage, and induced a hypoventilatory response to acute hypoxia. Chronic exposure to hyperoxia rapidly diminished skin NECs, shifted peak ventilation to earlier stages and eliminated the response to acute hypoxia. Administration of the neurotoxin 6-hydroxydopamine degraded nerve terminals that contact skin NECs and reduced both basal ventilation frequency and the hypoxic ventilatory response. Thus, skin NECs are candidates for extrabranchial O2 chemoreceptors in developing zebrafish.

In zebrafish, the ventilatory response to hypoxia first develops at 3 days post-fertilization (d.p.f.) before O2-chemoreceptive neuroepithelial cells (NECs) of the gill appear at 7 d.p.f. This indicates the presence of extrabranchial chemoreceptors in embryos and a developmental transition to primarily gill O2 sensing. This thesis examined the skin NECs, which reach peak density in embryos but decline as gill NECs appear. Exposure of embryos and larvae to chronic hypoxia prevented the loss of skin NECs, shifted peak basal ventilation to a later developmental stage, and induced a hypoventilatory response to acute hypoxia. Chronic exposure to hyperoxia rapidly diminished skin NECs, shifted peak ventilation to earlier stages and eliminated the response to acute hypoxia. Administration of the neurotoxin 6-hydroxydopamine degraded nerve terminals that contact skin NECs and reduced both basal ventilation frequency and the hypoxic ventilatory response. Thus, skin NECs are candidates for extrabranchial O2 chemoreceptors in developing zebrafish.

In zebrafish, the ventilatory response to hypoxia first develops at 3 days post-fertilization (d.p.f.) before O2-chemoreceptive neuroepithelial cells (NECs) of the gill appear at 7 d.p.f. This indicates the presence of extrabranchial chemoreceptors in embryos and a developmental transition to primarily gill O2 sensing. This thesis examined the skin NECs, which reach peak density in embryos but decline as gill NECs appear. Exposure of embryos and larvae to chronic hypoxia prevented the loss of skin NECs, shifted peak basal ventilation to a later developmental stage, and induced a hypoventilatory response to acute hypoxia. Chronic exposure to hyperoxia rapidly diminished skin NECs, shifted peak ventilation to earlier stages and eliminated the response to acute hypoxia. Administration of the neurotoxin 6-hydroxydopamine degraded nerve terminals that contact skin NECs and reduced both basal ventilation frequency and the hypoxic ventilatory response. Thus, skin NECs are candidates for extrabranchial O2 chemoreceptors in developing zebrafish.

In zebrafish, the ventilatory response to hypoxia first develops at 3 days post-fertilization (d.p.f.) before O2-chemoreceptive neuroepithelial cells (NECs) of the gill appear at 7 d.p.f. This indicates the presence of extrabranchial chemoreceptors in embryos and a developmental transition to primarily gill O2 sensing. This thesis examined the skin NECs, which reach peak density in embryos but decline as gill NECs appear. Exposure of embryos and larvae to chronic hypoxia prevented the loss of skin NECs, shifted peak basal ventilation to a later developmental stage, and induced a hypoventilatory response to acute hypoxia. Chronic exposure to hyperoxia rapidly diminished skin NECs, shifted peak ventilation to earlier stages and eliminated the response to acute hypoxia. Administration of the neurotoxin 6-hydroxydopamine degraded nerve terminals that contact skin NECs and reduced both basal ventilation frequency and the hypoxic ventilatory response. Thus, skin NECs are candidates for extrabranchial O2 chemoreceptors in developing zebrafish.

To determine whether behavioral sensitization produced by prolonged D-amphetamine administration affects susceptibility of nigrostriatal dopaminergic neurons to the neurotoxic actions of 6-hydroxydopamine (6-OHDA), rats were treated daily from the 23 rd day after birth for 11 consecutive days with D-amphetamine (1.0 mg/kg s.c.) or saline. On the last day of treatment, one group primed with D-amphetamine and one control group of rats were tested to confirm behavioral sensitization development. The remaining animals were additionally treated on the 34 th day (one day after the last D-amphetamine injection) with 6-OHDA HBr (300 μg in 10 μl i.c.v., salt form, half in each lateral ventricle) or its vehicle. Four weeks later the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-metoxytyramine (3-MT), as well as 5-hydroxytrypatmine (5-HT) and its metabolite 5-hydroxyindoleacteic acid (5-HIAA) were assayed in the striatum, by HPLC/ED. In rats with behavioral sensitization, 6-OHDA reduced endogenous dopamine and its metabolites content to a comparable degree in comparison to controls. This finding indicates that presumed up-regulation of the dopamine transporter in the behaviorially sensitized rats did not increase the neurotoxicity of a high dose of 6-OHDA.

Since prolyl-leucyl-glycinamide (MIF-1) modifies the behavior of adult rats after treatment with neuroleptics, we examined whether MIF-1 would also modify adult behavior after treatment of neonatal rats with 6-hydroxydopamine (6-OHDA). Rats received 6-OHDA (100 μg i.c.v.) or diluent at 3 days after birth and either MIF-1 (2.0 mg/kg per day s.c. × 10 days) or diluent beginning at 28 or 29 days after birth. At 5 weeks, a low dose (0.1 mg/kg s.c.) of apomorphine increased the distance traveled, time in ambulation, number of stereotypic movements, and number of movements per time in stereotypy, but decreased the time in stereotypy in the 6-OHDA group. MIF-1 (× 7 or 8 days) showed a tendency to attenuate the increased number of movements and significantly (P < 0.05) reduced all of the other effects of neonatal 6-OHDA. Behavior induced by higher doses of apomorphine in the 6-OHDA group (reduced licking and head nodding; increased paw treading, taffy pulling and self-biting) were not attenuated by MIF-1. At 38 or 39 days, total in vitro binding of [3H]SCH-23390 and [3H]spiroperidol to striatal homogenates was not altered in any of the groups. The findings demonstrate that specific early developmental alterations in apomorphine-induced behaviors can be modified by treatment of adult rats with MIF-1, even in the absence of overt changes in the binding of striatal dopamine D-1 and D-2 receptors.

To determine whether prolonged supersensitization of dopamine D-1 receptors could be produced during ontogeny, rats were treated daily, from birth, for 33 consecutive days with the D-1 receptor agonist, SKF 38393 HC1 (3.0 mg/kg per day i.p.). These rats were additionally treated at 3 days after birth with the neurotoxin, 6-hydroxydopamine HBr (6-OHDA; 200 μg, i.c.v., half in each lateral ventricle) or its vehicle. At 6 to 7 weeks from birth a challenge dose of SKF 38393 HCl (3.0 mg/kg i.p.) increased stereotypy scores for a number of behaviors in 6-OHDA-lesioned rats that were treated repeatedly during ontogeny with SKF 38393. These accentuated behaviors included licking, grooming, taffy pulling, jumping, paw treading and locomotion. Although the findings demonstrate an increased sensitivity of D-1 receptors to an agonist, there was no change in the Bmax or Kd for D-1 receptors in the striatum. In rats that were treated during postnatal development with SKF 38393, but not lesioned with 6-OHDA, SKF 38393-induced stereotyped behaviors were not substantially different from control. The neonatally primed rat model may be useful for probing mechanisms of receptor supersensitivity.