Activation of alpha1-adrenoceptors enhances glutamate release onto ventral tegmental area dopamine cells

The ventral tegmental area (VTA) plays an important role in reward and motivational processes that facilitate the development of drug addiction. Glutamatergic inputs into the VTA contribute to dopamine (DA) neuronal activation related to reward and response-initiating effects in drug abuse. Previous investigations indicate that alpha1-adrenoreceptors (α1-ARs) are primarily localized at presynaptic elements in the ventral midbrain. Studies from several brain regions have shown that presynaptic α1-AR activation enhances glutamate release. Therefore, we hypothesized that glutamate released onto VTA-DA neurons is modulated by pre-synaptic α1-AR. Recordings were obtained from putative VTA-DA cells of male Sprague–Dawley rats (28–50 days postnatal) using voltage clamp techniques. Phenylephrine (10 μM) and methoxamine (80 μM), both α1-AR agonists, increased AMPA receptor-mediated excitatory postsynaptic currents’ (EPSCs) amplitude evoked by electrical stimulation of afferent fibers (p < 0.05). This effect was blocked by the α1-AR antagonist prazosin (1 μM). Phenylephrine decreased the paired-pulse ratio (PPR) and increased spontaneous EPSCs’ frequencies but not their amplitudes suggesting a presynaptic locus of action. No changes in miniature EPSCs (0.5 μM, tetrodotoxin [TTX]) were observed after phenylephrine’s application which suggests that α1-AR effect was action potential dependent. Normal extra- and intracellular Ca2+ concentration seems necessary for the α1-AR effect since phenylephrine in low Ca2+ artificial cerebrospinal fluid (ACSF) and depletion of intracellular Ca2+ stores with thapsigargin (10 μM) failed to increase the AMPA EPSCs’ amplitude. Chelerythrine (1 μM, protein kinase C (PKC) inhibitor) but not Rp-cAMPS (11 μM, PKA inhibitor) blocked the α1-AR activation effect on AMPA EPSCs, indicating that a PKC intracellular pathway is required. These results demonstrated that presynaptic α1-AR activation modulates glutamatergic inputs that affect VTA-DA neuronal excitability. α1-AR action might be heterosynaptically localized at glutamatergic fibers terminating onto VTA-DA neurons. It is suggested that drug-induced changes in α1-AR could be part of the neuroadaptations occurring in the mesocorticolimbic circuitry during the addiction process.

► Presynaptic α1-ARs activation enhances glutamate release onto VTA DA neurons.
► This effect involves a selective activation of the PKC intracellular pathway.
► Presynaptic α1-AR-mediated effect requires extra- and intracellular calcium.