Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: Persisting effects on locomotor activity, learning and nicotine self-administration

Abstract

Dopaminergic innervation of the frontal cortex in adults is important for a variety of cognitive functions and behavioral control. However, the role of frontal cortical dopaminergic innervation for neurobehavioral development has received little attention. In the current study, rats were given dopaminergic lesions in the frontal cortex with local micro-infusions of 6-hydroxydopamine (6-OHDA) at one week of age. The long-term behavioral effects of neonatal frontal cortical 6-OHDA lesions were assessed in a series of tests of locomotor activity, spatial learning and memory, and intravenous (IV) nicotine self-administration. In addition, neurochemical indices were assessed with tissue homogenization and HPLC in the frontal cortex, striatum, and nucleus accumbens of neonatal and adult rats after neonatal 6-OHDA lesions. In neonatal rats, frontal 6-OHDA lesions as intended caused a significant reduction in frontal cortical dopamine without effects on frontal cortical serotonin and norepinephrine. The frontal cortical dopamine depletion increased serotonin and norepinephrine levels in the nucleus accumbens. Locomotor activity assessment during adulthood in the Figure-8 maze showed that lesioned male rats were hyperactive relative to sham lesioned males. Locomotor activity of female rats was not significantly affected by the neonatal frontal 6-OHDA lesion. Learning and memory in the radial-arm maze was also affected by neonatal frontal 6-OHDA lesions. There was a general trend toward impaired performance in early maze acquisition and a paradoxical improvement at the end of cognitive testing. Nicotine self-administration showed significant lesion × sex interactions. The sex difference in nicotine self-administration with females self-administering significantly more nicotine than males was reversed by neonatal 6-OHDA frontal cortical lesions. Neurochemical studies in adult rats showed that frontal cortical dopamine and DOPAC levels significantly correlated with nicotine self-administration in the 6-OHDA lesioned animals but not in the controls. Frontal cortical serotonin and 5HIAA showed inverse correlations with nicotine self-administration in the 6-OHDA lesioned animals but not in the controls. These results show that interfering with normal dopamine innervation of the frontal cortex during early postnatal development has persisting behavioral effects, which are sex-specific.

Simvastatin reverses the downregulation of M1/4 receptor binding in 6-hydroxydopamine-induced parkinsonian rats: The association with improvements in long-term memory

“…Similar to previous reports (Rezvani et al, 2008), 6-OHDA lesioned rats in the current study showed deficits in long-term memory as indicated by the longer total distance travelled to reach the platform and the shorter duration in the west arena of the water maze. It is important that simvastatin treatment significantly increased the reduced total distance travelled in the MWM and the duration of the 6-OHDAinduced PD rats in the west arena of the water maze (Fig 2), demonstrating the ability of simvastatin to produce a profound improvement in impaired memory effects in the 6-OHDA lesioned PD rats.…”

Differential Response of Central Dopaminergic System in Acute and Chronic Unpredictable Stress Models in Rats

“…A decrease in behavioral locomotor activity was observed in our study when rats were subjected to AS and CUS as evaluated in terms of decreased horizontal activity, stereotypy counts and total distance traveled. In rodents, the meso-striatal and meso-cortico-limbic dopaminergic pathways are known to modulate spontaneous and DA induced motor activity [9,[48][49][50]. The role of DA in the fronto-striatal circuitry in the expression of stereotypy is also proposed [51].…”

Sex differences in the acquisition and maintenance of cocaine and nicotine self-administration in rats

“…In the literature on sex differences in the acquisition of nicotine self-administration, females acquired nicotine self-administration faster than males (Lynch 2009), but one study indicated no sex differences (Feltenstein et al 2012). Post-acquisition, females maintained significantly higher levels of nicotine infusions than males during maintenance (Grebenstein et al 2013; Rezvani et al 2008; Chaudhri et al 2005; Donny et al 2000; but see Feltenstein et al 2012). …”