| The mesolimbic and mesocortical dopamine systems share a complex and interactive relationship. It is widely held that mesocortical DA serves an inhibitory function over mesolimbic DA activity; impairment of this function is believed to contribute to disordered states including schizophrenia and substance abuse, via permission of mesolimbic sensitisation, a maladaptive form of neuroplasticity that leaves the mesolimbic dopamine system overactive. Previous experiments examining the effects of neurotoxin-induced depletion of prefrontal dopamine (PFC-DA) have only partially supported these hypotheses, as results have been mixed. Moreover, these experiments did not take into account the preponderance of evidence suggesting that the pathogenesis of both schizophrenia and substance abuse is, in part, congenital.;The experiments presented here tested the hypothesis that neonatal insult to PFC-DA-neurons leads to a state of mesolimbic dopaminergic overactivity in adulthood. Rats were given 6-OHDA to deplete PFC-DA on PND11 and were tested for locomotor response and behavioural sensitisation to amphetamine, and responding for conditioned reinforcement after amphetamine challenge in adulthood. Dopamine release in the nucleus accumbens (NAcc) after two doses of amphetamine was also measured. These rats demonstrated hypersensitivity to systemic amphetamine, increased responding for conditioned reward, and elevated dopamine release in the NAcc, all of which suggest excess mesolimbic dopamine activity.;As well, a group of rats lesioned on PND11 were tested for behavioural sensitisation to amphetamine both pre- and post-adolescence. These rats were no different from controls during the pre-adolescent tests, but were found post-adolescence to be more susceptible to amphetamine sensitisation than sham-lesioned rats, implying that this deficit does not manifest until adulthood. Two groups of rats were given the PFC-DA-depleting lesion in adulthood (PND60); these rats did not display increased response to or sensitisation by amphetamine, or greater responding for conditioned reinforcers.;Together these data indicate that the effects of early depletion of PFC-DA include behavioural symptoms consistent with excess mesolimbic dopamine activity, and that these effects do not emerge until post-adolescence, while adult PFC-DA depletion has no such effects. This research has implications for the study of schizophrenia and substance abuse, both of which are often modeled using lesions of adult rats, and both of which have suspected neurodevelopmental underpinnings. |
