Extracellular dopamine and norepinephrine in the developing rat prefrontal cortex: transient effects of early partial loss of dopamine

Abstract

Early developmental abnormalities affecting mesocortical dopamine (DA) neurons may result in later functional deficits that play a role in the emergence of psychiatric illness in adolescence/early adulthood. Little is known about the functional maturation of these neurons under either normal or abnormal conditions. In the present study, 6-hydroxydopamine was infused into the rat medial prefrontal cortex (mPFC) on postnatal day (PN) 12-14. On PN30-35, 45-50, and 60-65, mPFC extracellular DA and norepinephrine (NE) concentrations were monitored in intact and lesioned rats using in vivo microdialysis. Extracellular DA and NE concentrations in the intact mPFC remain fairly stable across development; one exception being a trend for acute tailshock-evoked DA concentrations to increase as a function of age. Lesioned rats sustained a persistent (approximately 50%) decrease in mPFC tissue DA concentrations. Tailshock-evoked increases in mPFC extracellular DA were attenuated in lesioned rats tested on PN30-35, but not PN45-50 or 60-65. Basal and evoked extracellular NE was unaffected in lesioned rats tested at any age, despite a persistent (approximately 25%) decrease in tissue NE content. Horizontal locomotor activity was also assessed in the present study. Results of previous studies suggest this behavior is modulated by mesoprefrontal DA neurons. Although not significant, acute tailshock- and acute amphetamine-evoked horizontal locomotor activity tended to be attenuated in lesioned rats tested on PN30-35 and augmented in lesioned rats tested on PN60-65. The present data suggest that early partial loss of mesoprefrontal DA nerve terminals, resulting in a persistent decrease in tissue DA concentrations, is unlikely to result in persistent alterations in local DA release.

Figure 1

Tissue DA, NE, and DOPAC concentrations in the mPFC of PN30-35, 45-50, and 60-65 control rats and rats previously sustaining local 6-OHDA infusions on PN12-14 (panels A, B, and C, respectively; n=5–9/group). Local 6-OHDA decreased mPFC tissue DA and DOPAC concentrations by ~50% and NE by ~25% relative to age-matched control rats. Tissue NE concentrations were increased in PN60-65 control and lesioned rats relative to treatment-matched PN30-35 rats. Data are presented as group mean ± S.E.M. *Significantly different from age-matched control (t tests, p≤0.05). **Significantly different from treatment-matched PN30-35 rats (t tests with layered Bonferroni correction, p≤0.017–0.05).

Figure 2

Basal and tailshock-evoked extracellular DA concentrations in the mPFC of control rats and rats previously sustaining partial loss of tissue mPFC DA and NE (~50 and 25%, respectively) on PN12-14 and subsequently tested on PN30-35, 45-50, and 60-65 (panels A, B, and C, respectively; n=5–6/group). Relative to age-matched controls, PN30-35 lesioned rats exhibited a trend for lower basal and evoked extracellular DA. Tailshock increased extracellular DA in PN30-35 control rats, but not lesioned rats. Basal and evoked extracellular DA concentrations in the mPFC of PN45-50 and 60-65 lesioned rats did not differ from age-matched controls. Tailshock increased extracellular DA in the mPFC of lesioned and control rats tested on PN45-50 and 60-65. Data are presented as group mean ± S.E.M. *Significantly different from baseline sample immediately preceding tailshock, collapsed across treatment condition (t tests with layered Bonferroni correction, p≤0.006–0.05). **Significantly different within-group baseline sample immediately preceding tailshock (t tests with layered Bonferroni correction, p≤0.006–0.05).

Figure 3

Basal and tailshock-evoked extracellular NE concentrations in the mPFC of control rats and rats previously sustaining partial loss of mPFC DA and NE (~50 and 25%, respectively) on PN12-14 and subsequently tested on PN30-35, 45-50, and 60-65 (panels A, B, and C, respectively; n=5–6/group). Basal and stress-evoked extracellular NE concentrations in the mPFC of lesioned rats did not differ from age-matched controls. Tailshock increased extracellular NE in the mPFC of PN30-35, 45-50, and 60-65 rats. Data are presented as group mean ± S.E.M. *Significantly different from baseline sample immediately preceding tailshock, collapsed across treatment condition (t tests with layered Bonferroni correction, p≤0.006–0.05).

Figure 4

Effects of tailshock on horizontal locomotor activity in control rats and rats previously sustaining partial loss of mPFC DA and NE (~50 and 25%, respectively) on PN12-14 and subsequently exposed to 30 min of tailshock on PN30-35, 45-50, and 60-65 (panels A, B, and C, respectively; n=5–9/group). The total number of photocell beam interruptions per 15-min interval was determined for each rat. Tailshock evoked similar increases in motor activity in PN30-35, 45-50, and 60-65 lesioned and age-matched control rats. Each point represents the group mean ± S.E.M. *Significantly different from the baseline sample immediately preceding tailshock, collapsed across treatment condition (t tests with layered Bonferroni correction, p≤0.006–0.05).

Figure 5

Effects of d-amphetamine sulfate (1.5 mg/kg, i.p.) on horizontal locomotor activity in control rats and rats previously sustaining 6-OHDA lesions of the mPFC on PN12-14 and subsequently tested on PN30-35 or 60-65 (n=6–10/group). Local administration of 6-OHDA resulted in ~40% loss of mPFC tissue DA and no significant loss of tissue NE on PN12-14 (A) The total number of photocell beam interruptions per 15-min interval was determined for each subject. Amphetamine increased motor activity in control and lesioned rats tested on PN30-35 (B) and PN60-65 (C) and these effects did not differ as a function of treatment condition. Each point represents the group mean ± S.E.M. *Significantly different from the baseline sample immediately preceding d-amphetamine (t tests with layered Bonferroni correction, performed on data collapsed across treatment condition, p≤0.006–0.05). **Significantly different from age-matched control (t tests, p≤0.05).