Histamine H(3) receptors depress synaptic transmission in the corticostriatal pathway.

The effect of histamine on the main input to the striatum - the corticostriatal pathway - was studied using electrophysiological techniques in brain slices from rats and mice. Field potentials (FPs) were recorded in the striatum following stimulation at the border of the striatum and the cortex. Bath application of histamine caused a pronounced and long-lasting depression of FPs in rat slices with an IC(50) of 1.6 microM and a maximal depression of around 40%. In mouse slices histamine also depressed FPs, but to a lesser extent and more transiently. Further experiments in rat slices showed that histamine H(3) receptors were responsible for this depression since the selective H(3) receptor agonist R-alpha-methylhistamine (1 microM) mimicked the action of histamine whilst the selective H(3) receptor antagonist, thioperamide (10 microM) blocked the depression caused by histamine application. The histaminergic depression was probably not mediated indirectly through interneurons since blockade of GABA(A), GABA(B), nicotinic and muscarinic receptors or nitric oxide synthase did not prevent the histamine effect. Intracellular recordings from medium spiny neurons in the striatum revealed that histamine did not affect postsynaptic membrane properties but increased paired-pulse facilitation of excitatory synaptic responses indicating a presynaptic locus of action.

Adenosine A1 receptor-mediated depression of corticostriatal and thalamostriatal glutamatergic synaptic potentials in vitro.

Electrophysiological recordings in rat brain slices have been used to study the actions of adenosine on striatal neurons and striatal excitatory amino acid neurotransmission originating in the cortex or the thalamus. Adenosine had no effects on membrane properties of striatal neurons. Adenosine and the A1 agonist N6-Cyclopentyl adenosine reduced EPSPs of both cortical and thalamic origin by more than 50%. Depression of EPSPs was associated with an increase in paired-pulse facilitation, suggesting a presynaptic locus of action. EPSP depression was blocked by the A1 antagonist, 8-Cyclopentyl-1,3-dipropyl xanthine. The A2 agonist 5'-(N-cyclopropyl)-carboxamidoadenosine had no effect on excitatory amino acid neurotransmission. The A1 antagonist alone enhanced the synaptic component of the evoked field potential (23 +/- 12%). These results indicate that endogenous adenosine, acting via A1 receptors, limits striatal glutamatergic neurotransmission, serving a modulatory and neuroprotective role.

Linopiridine (DUP 996; AVIVA): its effects in the Morris water escape tank and on retention of an incompletely acquired bar-press response in rodents.

The present study assessed the effects of linopirdine, a putative cognition-enhancing drug, on the acquisition and retention of a bar-press response [continuous reinforcement schedule (CRF)] in young Wistar rats. It was also investigated whether this substance influenced the acquisition and retention of a standard Morris water escape tansk by young NMRI mice and by young and old Wistar rats. Linopirdine was given subcutaneously (0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg body wt.), 30 min before the first trial of a session and in one experiment immediately after the the last trial of each session. A probe trial was given after the last acquisition session. In the CRF task, linopirdine did not affect the response latency and the 24-h retention of young rats. None of the parameters investigated in the Morris maze, including the escape latency (the time the animals need to find the platform), was affected by linopirdine in the rat and mouse experiments. This was also true for performance in the probe trial: linopirdine treatment did not affect the bias of the animals for the quadrant in which the platform had been positioned during acquisition. Thus, we found no experimental evidence for the hypothesized action of linopirdine as a cognition enhancer.

General pharmacology of the putative cognition enhancer linopirdine.

The putative cognition enhancer linopirdine (3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one, CAS 105431-72-9) is supposed to act by enhancing the release of neurotransmitters, especially acetylcholine. The present study assessed the effects of a single administration of this compound on the central nervous system in eight different rat and mouse models (CNS general pharmacology). In each test performed, linopirdine was administered subcutaneously in doses of 3, 10, and 30 mg/kg. The compound did not affect traction ability and nociceptive responsiveness nor did it induce catalepsy. Linopirdine impaired motor coordination in the balance rod test. The compound showed a distinct proconvulsive action in the pentylenetetrazole threshold dose test and induced in the highest dose tested (30 mg/kg) lethal seizures in some mice. It increased the duration of hexobarbital-induced anaesthesia in mice. Rats treated with linopirdine showed ptosis, salivation, slight sedation, paw beating and slight hypothermia. These results support the hypothesis that linopirdine acts by elevating the release of different neurotransmitters such as acetylcholine and dopamine. The compound has a low potential to produce side effects at pharmacodynamic active doses.