Reversal of apomorphine locomotor sensitization by a single post-conditioning trial treatment with a low autoreceptor dose of apomorphine: a memory re-consolidation approach.

Sensitization is a common feature of psychostimulants and sensitization effects are generally considered to be linked to the addictive properties of these drugs. We used a conventional paired/unpaired Pavlovian protocol to induce a context specific sensitization to the locomotor stimulant effect of a high dose of apomorphine (2.0mg/kg). Two days following a 5 session sensitization induction phase, a brief 5min non-drug test for conditioning was conducted. Only the paired groups exhibited locomotor stimulant conditioned response effects. Immediately following this brief test for conditioning, the paired and the unpaired groups received injections of 0.05mg/kg apomorphine, 2.0mg/kg apomorphine or vehicle designed to differentially impact memory re-consolidation of the conditioning. Two days later, all groups received a sensitization challenge test with 2.0mg/kg apomorphine. The 2.0mg/kg apomorphine post-trial treatment potentiated sensitization while the 0.05mg/kg eliminated sensitization. These effects were only observed in the paired groups. The activation of dopaminergic systems by the high dose of apomorphine strengthened the drug/environment association whereas the inhibition of dopamine activity by the low auto-receptor dose eliminated this association. The results point to the importance of conditioning to context specific sensitization and targeting memory re-consolidation of conditioning as a paradigm to modify sensitization.

Role of the 5-HT(1A) somatodendritic autoreceptor in the dorsal raphe nucleus on salt satiety signaling in rats.

We investigated the possible role of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus (DRN) on salt intake response during basal conditions and following natriorexigenic challenge aroused by sodium depletion in rats. Acute systemic administration (76-1520 nmol/kg s.c.) of 8-OH-DPAT, a selective 5-HT(1A) somatodendritic autoreceptor agonist, induced a clear and dose-dependent preference for salt intake through free choice between water and 0.3 M NaCl simultaneously offered under basal conditions. Acute intra-DRN microinjection (7.5 nmol/rat) of 8-OH-DPAT significantly mimicked the acute systemic protocol in sodium-replete rats. Interestingly, microinjection of 8-OH-DPAT into the DRN raised an additional long-lasting increase of 0.3 M NaCl intake in sodium-depleted rats despite a high volume ingested 30 min after central injection. Conversely, chronic systemic treatment (1520 nmol/kg s.c.) with 8-OH-DPAT for 2 and 3 weeks or repeated intra-DRN microinjection (7.5 nmol/rat) evoked a significant long-term decrease in 0.3 M NaCl intake in sodium-depleted rats given only water and a sodium-deficient diet over the course of 24 h after furosemide injection. These results show a clear-cut involvement of the DRN 5-HT(1A) somatodendritic autoreceptors in sodium satiety signaling under basal conditions and during the consummatory phase of salt intake in sodium-depleted rats.

Modulation of acetylcholine release by presynaptic muscarinic autoreceptors.

The existence of a modulatory system controlling the acetylcholine (ACh) release was first proposed for the nicotinic subtype in 1962. Following the first observation of a possible positive feedback loop activated by the released Ach, many studies were oriented in the investigation of the involved presynaptic autoreceptors. Most of the data have been obtained at the motor end-plate, commonly defined as the simplest model of peripheral synapse. The characterization of the chemical transmission since its first proposal showed a more complex pattern involving both the cholinergic and the adrenergic systems. It is now evident that this regulation is widespread both in the central and in the peripheral nervous system. The evidence that the release of ACh can be up- or down-regulated by the transmitter itself (autoregulation) or other neuromediators (heteroregulation) is now proved. In the last decades the attention was focused to the identification of the receptor subtypes located on the releasing nerve terminal. For the purpose, different techniques were used in the various laboratories. The functional approach was based mainly on the electrophysiological characterization of the events evolved prior, during and after the activation of the motor endplate nicotinic receptor. On the other hand, the overflow studies were carried out using radiolabeled ACh (rACh) obtained treating muscle fibers with radioactive choline (rCh). Many scientific papers proposed common data indicating a clear positive (nicotinic) or negative (muscarinic) modulation of the ACh release. Temporally, the description of the muscarinic regulation followed the discovery of the nicotinic one. However, by a pure pharmacological point of view it represents a challenge due to the more complex organization and function. In the peripheral nervous system, i.e. neuromuscular, the meaning of both the muscarinic and nicotinic modulations may appear as free of function. Conversely, in the central systems some effects, such as antinociception and others, could represent the basis of a functional activity such as proposed by Corrado group. The complete characterization of this phenomenon by a physiological and a pharmacological point of view could represents the goal for future uses and therapeutic potential. The present review illustrates the know how and the efforts in the characterisation of the muscarinic regulation of transmitter release from the beginning of its discovery trying to order the numerous scientific data published in this field. Furthermore, our personal data obtained with the Loose Patch Clamp (LPC) technique will be briefly presented and discussed. Our work was built up using agonists and antagonists of the muscarinic receptor subtype in the aim of better characterize the modulation function of the mediator Ach. We used carbachol (Cch), oxotremorine (Oxo) and dl-muscarine as agonists and 1-hyoscyamine, pirenzepine, ipratropium, 11[[2-1[(diethylamino) methyl-1-piperidinyl]-acetyl]-5, 11-dihydro-6H-pyrido [2,3-b][1,4] benzodiazepine-6-one (AFDX-116), methoctramine and 1,1-dimethyl-4 diphenylacetoxy-N-methylpiperidine (4-DAMP) as antagonists.

Dopaminergic systems. Dopamine receptors.

This article describes D1 and D2 receptor subfamilies, their neuroanatomic localizations and the possibility of their neuronal co-localization and relation to the other dopamine autoreceptors and those coupled to G-proteins as well as the actions of antipsychotic drugs on D1 and D2 receptor subfamilies are also analyzed.