Reduced Presynaptic Dopamine Activity in Adolescent Dorsal Striatum

Abstract

Adolescence coincides with symptomatic onset of several psychiatric illnesses including schizophrenia and addiction. Excess limbic dopamine activity has been implicated in these vulnerabilities. We combined molecular and dynamic indices of dopamine neurotransmission to assess dopamine function in adolescent rats in two functionally distinct striatal subregions: nucleus accumbens (NAc) and dorsal striatum (DS). In adolescents, we find an overall reduction in dopamine availability selective to the DS. Dopamine release in the DS, but not in the NAc, was less responsive to amphetamine in adolescents compared to adults. The dopamine transporter (DAT) inhibitor, nomifensine, similarly inhibited basal and amphetamine-induced dopamine release in either regions of both the age groups, suggesting that the reduced effectiveness of amphetamine is not due to differences in DAT function. Furthermore, DAT and vesicular monoamine transporter-2 expressions were similar in the DS and NAc of adolescent rats. In contrast, expression of tyrosine hydroxylase (TH) was reduced in the DS, but not in the NAc, of adolescents compared to adults. Behaviorally, adolescents were less sensitive to amphetamine but more sensitive to a TH inhibitor. These data indicate that, in contrast to the general notion that dopamine is hyperactive in adolescents, there is diminished presynaptic dopamine activity in adolescents that is selective to the DS and may result from attenuated TH activity. Given recent reports of altered dopamine activity in associative/dorsal striatum of individuals at a clinically high risk of psychosis, our data further support the idea that dorsal, as opposed to ventral, regions of the striatum are a locus of vulnerability for psychosis.

Evaluating long-term consequences of adolescent antipsychotic exposure

“…Chapter 1 4 Studies in adolescent rodents have complemented investigations in humans and enabled further identification of multiple neural maturation processes at both structural and functional levels during this period ( Figure 1-1(b)); in particular, maturation of dopaminergic (DA) (Andersen et al 2000;Matthews et al 2013;McCutcheon et al 2012;McCutcheon and Marinelli 2009;Tarazi et al 1998;Teicher et al 1995;Tseng and O'Donnell 2007;Yetnikoff et al 2014) and endocannabinnoid systems (de Fonseca et al 1993;Klugmann et al 2011) in major brain regions such as striatum, nucleus accumbens (NAc), ventral tegmental area (VTA) and prefrontal cortex (PFC) have been explored. Recently, adolescent maturation of gamma-amino butyric acid (GABA)-secreting interneurons of the PFC has also been reported (Caballero et al 2014).…”

“…Given the role of the NAc in control of locomotor activity (Beninger 1983;Kelly et al 1975;Staton and Solomon 1984), this brain region may be a target for long-lasting effects of atypical APDs given to adolescents. The adolescent NAc undergoes major maturation changes in dopaminergic receptors (Tarazi and Baldessarini 2000;Tarazi et al 1998) and transporters (Matthews et al 2013). In addition, functional interaction of dopaminergic (D1 and D2) and receptor-mediated modulation of NAc medium spiny neurons also functionally matures from adolescence to adulthood (Benoit-Marand and O'Donnell 2008).…”

“…Blockade of striatal dopamine neurotransmission by APDs is tightly correlated with their cataleptic effect (Wadenberg et al 2000;Wadenberg et al 2001b). Therefore, ongoing maturation processes in both pre-and post-synaptic dopamine systems of the adolescent striatum [See, for examples, (Matthews et al 2013;Teicher et al 1995)] may perhaps play a role in differential ondrug cataleptic response. Long-term cataleptic responses after a drug-free interval are yet to be investigated with APD administration to adolescents.…”

“…For instance, a recent report indicates that the dopamine synthesis capacity of adolescent dorsal striatum is still immature with lower levels of TH and DAT proteins, compared to adult counterparts (Mathews et al 2009;Matthews et al 2013). The effects of adolescent APDs on this major maturation change have not been investigated yet.…”

“…an increase in cataleptic effect with daily injection, has been reported with repeat haloperidol treatment in adult rats despite the lack of such cataleptic response with the initial exposure to this drug (Banasikowski and haloperidol. Alternately, although dopaminergic firing is highly active at this age, presynaptic dopamine innervation of the adolescent dorsal striatum is incomplete compared with adults (Matthews et al 2013;Stamford 1989). Therefore if the synaptic machinery of the subcortical dopamine synapse is still under development perhaps the anti-dopaminergic effects of risperidone or haloperidol may not be fully experienced.…”