Abstract
Recent studies have used conditional knockout mice to selectively delete the D2 autoreceptor; however, these approaches result in global deletion of D2 autoreceptors early in development. The present study takes a different approach using RNA interference (RNAi) to knockdown the expression of the D2 receptors (D2R) in the substantia nigra (SN), including dopaminergic neurons, which project primarily to the dorsal striatum (dStr) in adult rats. This approach restricts the knockdown primarily to nigrostriatal pathways, leaving mesolimbic D2 autoreceptors intact. Analyses of dopamine (DA) kinetics in the dStr reveal a decrease in DA transporter (DAT) function in the knockdown rats, an effect not observed in D2 autoreceptor knockout mouse models. SN D2 knockdown rats exhibit a behavioral phenotype characterized by persistent enhancement of locomotor activity in a familiar open field, reduced locomotor responsiveness to high doses of cocaine and the ability to overcome haloperidol-induced immobility on the bar test. Together these results demonstrate that presynaptic D2R can be depleted from specific neuronal populations and implicates nigrostriatal D2R in different behavioral responses to psychotropic drugs.
Highlights
Alterations in dopamine (DA) neurotransmission are associated with many neuropsychiatric conditions including schizophrenia, attention deficit hyperactivity disorder and drug addiction
enhanced green fluorescent protein (EGFP) expression was largely restricted to the substantia nigra (SN), and while both SN pars compacta (SNc) and SN pars reticulata (SNr) were transduced, the SNc had more prominent/dense signal
Real time qPCR analysis revealed an ∼90% reduction of D2 receptors (D2R) RNA expression when comparing rats infused with D2 short hairpin RNA (shRNA) virus (Figure 1B) and those infused with the SCR control virus (Figure 1C)
Summary
Alterations in dopamine (DA) neurotransmission are associated with many neuropsychiatric conditions including schizophrenia, attention deficit hyperactivity disorder and drug addiction. DA uptake via the presynaptic DA transporter (DAT) is essential for controlling synaptic DA concentrations. D2 receptors (D2R) located on presynaptic dopaminergic neurons participate in regulating synaptic DA concentrations by increasing DA uptake (Cass and Gerhardt, 1994; Dickinson et al, 1999; Wu et al, 2002), while inhibiting DA release (May and Wightman, 1989; Kawagoe et al, 1992; Wu et al, 2002) and synthesis (Budygin et al, 1999a,b) when activated. SN D2 Effects on Dopamine by excessive DA levels. These D2 autoreceptors may participate in DA-related pathologies and represent a potential therapeutic target. Being able to separate presynaptic D2 autoreceptor function from postsynaptic D2R in specific brain regions such as the striatum is essential in determining their roles in various neurological conditions
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