Potentiation Of Dopamine Release Research Articles

Levodopa prevents the reinstatement of cocaine self-administration in rats via potentiation of dopamine release in the medial prefrontal cortex.

Dopamine agonists have been proposed as therapeutic tools for cocaine addiction. We have recently demonstrated that indirect dopamine agonists, including levodopa (L-DOPA), markedly increase cocaine-induced dopamine release in the medial prefrontal cortex (mPFC) of rats leading to the suppression of cocaine-seeking behavior. This study was aimed to understand the behavioral and neurochemical effects of L-DOPA on cocaine-taking and cocaine-seeking in rats. After reaching a stable pattern of intravenous cocaine self-administration under a continuous fixed ratio (FR-1) schedule of reinforcement, male rats were treated with L-DOPA at different steps of the self-administration protocol. We found that L-DOPA reduced cocaine self-administration under FR-1 schedule of reinforcement and decreased the breaking points and the amount of cocaine self-administered under the progressive ratio schedule of reinforcement. Levodopa also decreased cocaine-seeking behavior both in a saline substitution test and in the cue priming-induced reinstatement test, without affecting general motor activity. Importantly, L-DOPA greatly potentiated cocaine-induced dopamine release in the mPFC of self-administering rats while reducing their cocaine intake. In the same brain area, L-DOPA also increased dopamine levels during cue priming-induced reinstatement of cocaine-seeking behavior. The potentiating effect was also evident in the mPFC but not nucleus accumbens core of drug-naïve rats passively administered with cocaine. Altogether, these findings demonstrate that L-DOPA efficaciously reduces the reinforcing and motivational effects of cocaine likely potentiating dopamine transmission in the mPFC. Its ability to prevent cue priming-induced reinstatement of cocaine-seeking suggests that it might be effective in reducing the risk to relapse to cocaine in abstinent patients.

Cocaine Preferentially Potentiates Fast Releasable Vesicle Pool in Mouse Dopaminergic Striatum In Vivo

Cocaine, an addictive drug, increases extracellular dopamine (DA) concentration in basal ganglion. This effect has been commonly assumed mainly through the inhibition of the uptake activity of DA transporters (DAT), although other mechanisms such as cocaine potentiation of DA release is less examined under physiological conditions. Here we report that two kinetically distinct DA releasable vesicle pools, a fast releasable pool (FRP) and a prolonged releasable pool (PRP), existed following physiological field stimulations at medial forebrain bundle in mouse striatum in vivo. Surprisingly, cocaine selectively enhanced the DA release and replenishment from the FRP. using a cocaine-insensitive-DAT mouse model, cocaine-facilitated FRP (not PRP) release is mediated by DAT. In contrast, PRP (not FRP) release is selectively sensitive to D2 receptor (D2R). Thus, in addition to blocking DA reuptake, cocaine increases DA release through selectively activating DAT, increasing FRP size, and accelerating FRP replenishment in mouse striatum in vivo.

α7 neuronal nicotinic receptor agonist (TC-7020) reverses increased striatal dopamine release during acoustic PPI testing in a transgenic mouse model of schizophrenia

Genetic and post mortem evidence has implicated the α7 neuronal nicotinic receptor (NNR) in the etiology of schizophrenia and related disorders. In schizophrenia, enhanced subcortical dopamine (DA) correlates with positive and cognitive of the disease, including impairments in sensorimotor gating. We measured the levels of extracellular DA and DA metabolites during an acoustic test session of prepulse inhibition (PPI) of the startle response, a measure of sensorimotor gating, by microdialysis and HPLC-EC in a transgenic mouse model of schizophrenia. In th-fgfr1(tk−) mice, blockade of fibroblast growth factor receptor 1 (FGFR1) signaling during development in catecholaminergic neurons results in reduced size and density of midbrain DA neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). These mice displayed reduced PPI and enhanced startle response relative to control mice as well as a potentiation of DA release in the dorsal striatum during a 30minute PPI test session. Acute administration of a partial α7 NNR agonist TC-7020 (1.0mg/kg) normalized PPI and startle deficits and attenuated increases of DA release during acoustic PPI testing. These results provide direct evidence of elevated striatal dopaminergic transmission with impaired sensorimotor gating that may underlie cognitive and positive symptoms and motor deficits in schizophrenia and related disorders. Also, systemic targeting of alpha7 NNRs may ameliorate these deficits by functionally suppressing striatal DA activity.

Isoflurane anesthesia induces biphasic effect on dopamine release in the rat striatum

The effect of isoflurane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) modulated by pargyline, monoamine oxidase inhibitor, was studied using in vivo microdialysis techniques. A microdialysis probe was implanted into the right striatum of male SD rats. Each rat ( n = 5–6) was given saline or the same volume of 30 or 75 mg kg −1 pargyline intraperitoneally with or without 1 h isoflurane anesthesia (1 or 3%). Isoflurane anesthesia increased the extracellular concentration of DA in high dose (3%) and increased the metabolite concentrations in a dose-dependent manner. Pargyline administration increased the extracellular concentration of DA and 3-MT, and decreased that of other metabolites. After 30 mg kg −1 pargyline treatment, 1% isoflurane-induced DA release and increasing of 3-MT were preserved, whereas high dose isoflurane (3%) decreased the concentration of metabolites (DOPAC and HVA), despite of the increase by low dose isoflurane (DOPAC). When 75 mg kg −1 pargyline was administered, isoflurane anesthesia decreased the concentration of DA and DOPAC. The isoflurane-induced 3-MT increase was preserved in all experiments. Our results suggest that isoflurane anesthesia induced biphasic effect on DA regulation probably by the potentiation of DA release and the inhibition of DA synthesis. Isoflurane might modulate DA homeostasis presynaptically.

Potentiation of transmitter release from NMB human neuroblastoma cells by kappa-opioids is mediated by N-type voltage-dependent calcium channels

The selective kappa-opioid agonist trans-(±)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl) cyclohexyl] benzenacetamidemethansulfonate (U50,488) potentiates both basal and depolarization-evoked [ 3 H] dopamine release from NMB cells. The potentiation of dopamine release by U50,488 is mediated by N-type voltage-dependent calcium channels since it is blocked by omega-conotoxin, and is resistant to pertussis toxin (PTX)-treatment. When the stimulation of release by U50,488 is blocked by the N-channel antagonist omega-conotoxin, an inhibitory effect on dopamine release is revealed, suggesting that stimulatory and inhibitory effects of U50,488 are exerted in parallel.

Opioids potentiate transmitter release from SK-N-SH human neuroblastoma cells by modulating N-type calcium channels

Opioids induce dual (inhibitory and excitatory) regulation of depolarization-evoked [ 3H]dopamine release in SK-N-SH cells through either μ or δ receptors. The potentiation of dopamine release by opioid agonists is mediated by N-type voltage-dependent calcium channels and does not involve G i/G o proteins. Removal of the excitatory opioid effect by blockade with ω-conotoxin, an N-channel antagonist, reveals the inhibitiory effect of opioids on release, thus suggesting that both modulatory effects of opioids are exerted in parallel.

Long-term enhancement of dopamine release by high frequency tetanic stimulation via a N-methyl-D-aspartate-receptor-mediated pathway in rat striatum.

We studied the effects of high frequency tetanic stimulation of the striatum on the KCl (20 mM)-evoked dopamine release in rat striatal slices. The KCl-evoked dopamine release was potentiated by high frequency tetanic stimulation (10-20 Hz) of the striatum including the corticostriatal fibers, and this potentiation was observed until 3 h after high frequency tetanic stimulation. Potentiation of dopamine release after high frequency tetanic stimulation was induced not only by KCl but also by glutamate in Mg(2+)-free medium, N-methyl-D-aspartate in Mg(2+)-free medium, and by DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. 2-amino-5-phosphovalerate, 3-[(+/-)-2-carboxypiperazine-4-yl]-propyl-1-phosphonate or dibenzocycloheptaneimine, N-methyl-D-aspartate receptor inhibitors, abolished enhancement by tetanus, whereas, 6,7-dinitroquinoxaline-2,3-dione, an antagonist of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ionotropic receptors, or L-2-amino-4-phosphonobutyrate, an antagonist of glutamate metabotropic receptors, showed no effect. Moreover, pretreatment with glutamate or N-methyl-D-aspartate in the absence of Mg2+ also facilitated dopamine release evoked by KCl concentrations. When extracellular Ca2+ was removed from the medium during pretreatment, potentiation by glutamate disappeared. We conclude that activation of N-methyl-D-aspartate receptors on dopaminergic nerve terminals in the striatum produces the long-term changes in efficacy of the response to KCl or glutamatergic agents. That is, plastical phenomena could exist at presynaptic levels between glutamatergic neurons and dopaminergic neurons in striatum.

Dopamine re-uptake inhibitors show inconsistent effects on the in vivo release of dopamine as measured by intracerebral dialysis in the rat

The effects of the dopamine (DA) re-uptake blockers amfonelic acid and GBR 12909 on the in vivo release of DA were investigated. DA release was measured by means of a fully automated brain dialysis system. GBR 12909 induced a 3-fold increase in the output of DA; amfonelic acid was without effect. These results indicate a dissociation between the behavioural effects of DA re-uptake blockers and the effects on DA release. A strong synergistic rise of DA release was observed when haloperidol was co-administered with amfonelic acid or GBR 12909. The potentiation of DA release was completely prevented by infusion of 1 μM tetrodotoxin.

Is the muscarinic receptor that mediates potentiation of dopamine release negatively coupled to the cyclic GMP system?

Dopamine (DA) terminals in rat corpus striatum and frontal cortex possess muscarinic receptors that mediate enhancement of the depolarization-evoked release of the catecholamine. The effects of the membrane-permeating cyclic guanosine monophosphate (cyclic GMP) analog 8-Br-cyclic GMP and of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) on the muscarinic-induced increase of DA release were investigated in striatal synaptosomes prelabeled with [3H]DA and exposed in superfusion to 15 mM KCl and to acetylcholine (ACh). Preincubation of synaptosomes with 8-Br-cyclic GMP (10-200 microM) or with IBMX (200 microM) prevented the ACh-induced enhancement of [3H]DA release, without affecting the K+-evoked release of the [3H]amine. No significant decrease of the ACh effect was observed when 8-Br-cyclic GMP or IBMX were added concomitantly with ACh to the superfusion medium. The data suggest that stimulation of presynaptic muscarinic receptors on DA terminals may produce enhancement of 3H DA release through a decrease of the intraterminal cyclic GMP content.