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-AR) are primarily localized at presynaptic elements in the ventral midbrain. Studies from several brain regions have shown that presynaptic α1-AR activation enhance 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 and increased spontaneous EPSCs frequencies but not their amplitudes suggesting a presynaptic locus of action. No changes in miniature EPSCs (0.5 µM TTX) were observed after phenylephrine’s application which suggest 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+ ACSF and depletion of intracellular Ca2+ stores with thapsigargin (10 µM) failed to increase the AMPA EPSCs amplitude . Chelerythrine (1 µM, 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-ARs activation modulates glutamatergic inputs that affect VTA-DA neurons excitability. α1-ARs 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 to the neuroadaptations occurring in the mesocorticolimbic circuitry during the addiction process.
The increased activity and stereotyped behaviors that result from repeated administration of cocaine is called cocaine sensitization. This sensitized response has been postulated as one of the basic pathophysiological mechanisms in drug addiction. Recent evidence indicates that noradrenergic neurotransmission might be implicated in some of the behavioral effects of cocaine. The present article examined the role of alpha-adrenergic receptor agonists and antagonists in the development and expression of cocaine sensitization. Rats were injected once per day, for 7 consecutive days, with the alpha-1 receptor antagonist prazosin (0.5 mg/kg, i.p.) 15 min before cocaine administration (15 mg/kg, i.p.). After 8 days, animals received a cocaine challenge (15 mg/kg, i.p.) and were tested for locomotion. Following a 7-day withdrawal period rats received a second cocaine challenge. One day after the last challenge, rats were reinstated to the initial protocol for 1 day. In another set of experiments, rats were injected twice per day with the alpha-2 receptor antagonists yohimbine (5 mg/kg, i.p.), idazoxan (0.25 mg/kg, i.p.), or with the alpha-2 agonist clonidine (0.025 mg/kg, i.p.), followed by cocaine injections (15 mg/kg, i.p.), for 7 consecutive days. Thereafter, the protocol was similar to that following prazosin administration. The results demonstrated that the alpha-1 receptor antagonist prazosin blocked the development and expression of cocaine sensitization. On the other hand, both alpha-2 antagonists failed to inhibit the development or the expression of cocaine sensitization. Instead, they produced an increase in locomotor activity during the first day of experimentation. The alpha-2 agonist clonidine attenuated the acute response to cocaine on day 1 and retarded the increased locomotor activity on the following 2 days. There was a dramatic increase in the level of sensitization after the first cocaine challenge. However, it inhibited the expression of cocaine sensitization during the reinstatement protocol. These results suggest that alpha adrenoreceptors play an important role in modulating different stages of cocaine sensitization and probably cocaine addiction.
Alterations in the state of excitability of midbrain dopamine (DA) neurons from the ventral tegmental area (VTA) may underlay changes in the synaptic plasticity of the mesocorticolimbic system. Here, we investigated norepinephrine's (NE) regulation of VTA DA cell excitability by modulation of the hyperpolarization-activated cation current, I h in whole cell recordings. Current clamp recordings show that NE (40 µM) hyperpolarizes spontaneously firing VTA DA cells (11.23 ±4 mV; n = 8). In voltage clamp, NE (40 µM) induces an outward current (100 ± 24 pA; n = 8) at − 60 mV that reverses at about the Nernst potential for potassium (−106 mV). In addition, NE (40 µM) increases the membrane cord conductance (179 ± 42%; n = 10) and reduces I h amplitude (68 ± 3% of control at −120 mV; n = 10). The noradrenergic alpha-1 antagonist prazosin (40 µM; n = 5) or the alpha-2 antagonist yohimbine (40 µM; n = 5) did not block NE effects. All NE-evoked events were blocked by the D 2 antagonists sulpiride (1 µM) and eticlopride (100 nM) and no significant reduction of I h took place in the presence of the potassium channel blocker BaCl 2 (300 µM). Therefore, it is concluded that NE inhibition of I h was due to an increase in membrane conductance by a non-specific activation of D 2 receptors that induce an outward potassium current and not a result of a second messenger system acting on h-channels. The results also suggest that I h channels are mainly located at dendrites of VTA DA cells and thus their inhibition may facilitate the transition from single spike firing to burst firing and vice versa.
The ventral tegmental area (VTA) plays an important role in reward and motivational processes involved in drug addiction. Previous studies have shown that alpha1-adrenoreceptors (α1-AR) are primarily found presynaptically at this area. We hypothesized that GABA released onto VTA-dopamine (DA) cells is modulated by presynaptic α1-AR. Recordings were obtained from putative VTA-DA cells of male Sprague-Dawley rats (28–50 days postnatal) using whole-cell voltage clamp technique. Phenylephrine (10µM; α1-AR agonist) decreased the amplitude of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) evoked by electrical stimulation of afferent fibers (n=7; p<0.05). Prazosin (1µM, α1-AR antagonist), blocked this effect. Paired-pulse ratios were increased by phenylephrine application (n=13; p<0.05) indicating a presynaptic site of action. Spontaneous IPSCs frequency but not amplitude, were decreased in the presence of phenylephrine (n=7; p<0.05). However, frequency or amplitude of miniature IPSCs were not changed (n=9; p>0.05). Phenylephrine in low Ca2+ (1mM) medium decreased IPSC amplitude (n=7; p<0.05). Chelerythrine (a protein kinase C inhibitor) blocked the α1-AR action on IPSC amplitude (n=6; p<0.05). Phenylephrine failed to decrease IPSCs amplitude in the presence of paxilline, a BK channel blocker (n=7; p<0.05). Taken together, these results demonstrate that α1-ARs at presynaptic terminals can modulate GABA release onto VTA-DA cells. Drug-induced changes in α1-AR could contribute to the modifications occurring in the VTA during the addiction process.
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