Abstract
Hypocretins (hcrt), also known as orexins, play a critical role in reward-seeking behavior for natural rewards and drugs of abuse. The mesolimbic dopamine pathway that projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is critically involved in the neural mechanisms underlying reward-seeking and motivation. Hcrt immunopositive fibers densely project to the shell of the nucleus accumbens (NAcSh), suggesting that the NAcSh might be a site for the interaction between hcrt and dopaminergic modulation of reward-seeking behavior. While it is known that hcrt action in the VTA can increase dopamine in the NAc, it has not been determined if hcrt released locally at dopaminergic terminals in the NAcSh can modulate dopamine concentration. Here, we use fast scan cyclic voltammetry (FSCV) in forebrain slices containing the NAcSh to determine whether hcrt can alter evoked dopamine concentration. We found bath application of hcrt-1 increases phasically evoked dopamine release, without altering reuptake at dopamine terminals in the NAcSh. Hcrt-1-induced potentiation of dopamine concentration was inhibited by SB334867, a hcrt receptor 1 antagonist, as well as ionotropic glutamate receptor antagonists, AP-5, CNQX and DNQX. Taken together, these results suggest that local hcrt-1 can modulate dopamine in the NAcSh and may play a role in reward-seeking and appetitive behaviors.
Highlights
The hypocretins, known as orexins, are neuropeptides produced solely in the lateral hypothalamic and perifornical areas (de Lecea et al, 1998; Sakurai et al, 1998)
While glutamatergic and dopaminergic inputs converge on the same MSNs, direct synaptic contacts between dopaminergic and glutamatergic axon terminals have not been observed in the nucleus accumbens (NAc) (Sesack and Pickel, 1990, 1992; O’Donnell and Grace, 1995; Mulder et al, 1998)
While several studies have demonstrated that hcrt-1 administered into the ventral tegmental area (VTA) can increase dopamine concentration in the NAcSh (Vittoz et al, 2008), NAc core (España et al, 2011) or both (Narita et al, 2006), our data suggests an additional mechanism by which hcrt-1 can modulate dopamine concentrations in the NAcSh
Summary
The hypocretins (hcrt), known as orexins, are neuropeptides produced solely in the lateral hypothalamic and perifornical areas (de Lecea et al, 1998; Sakurai et al, 1998). They are comprised of two distinct peptides; hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2). Dopamine neurons of the ventral tegmental area (VTA) project to the nucleus accumbens (NAc) via the medial forebrain bundle (Nauta et al, 1978). Hypocretin neurons make dense projections to both dopamine neurons of the VTA as well as the medial NAcSh (Peyron et al, 1998; Baldo et al, 2003) where both hcrt-R1 and R2 are expressed (Marcus et al, 2001; Martin et al, 2002)
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