Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors.

Modafinil is a well-tolerated medication for excessive sleepiness, attention-deficit disorder, cocaine dependence and as an adjunct to antidepressants with low propensity for abuse. We investigated the modafinil action on identified dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) of rat brain slices. Modafinil (20 microM) inhibited the firing of dopaminergic, but not GABAergic neurons. This inhibition was maintained in the presence of tetrodotoxin and was accompanied by hyperpolarization. Sulpiride (10 microM), a D2-receptor antagonist, but not prazosine (20 microM, an alpha1-adrenoreceptor blocker) abolished the modafinil action. Inhibition of dopamine reuptake with a low dose of nomifensine (1 microM) reduced the firing of DA neurons in a sulpiride-dependent manner and blunted the effect of modafinil. On acutely isolated neurons, modafinil evoked D2-receptor-mediated outward currents in tyrosine-hydroxylase positive cells, identified by single-cell RT-PCR, which reversed polarity near the K(+) equilibrium potential and were unchanged in the presence of nomifensine. Thus modafinil directly inhibits DA neurons through D2 receptors.

Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat.

Many neuropeptides regulate feeding and arousal; the ventral tegmental area (VTA) is likely to be one site where they act. We used whole-cell patch-clamp and single-unit extracellular recordings to examine the effects of such neuropeptides on the activity of VTA neurons. Substance P (SP; 300 nM) increased the firing rate of the majority of VTA dopaminergic and gamma-aminobutyric acid (GABA)ergic neurons, and induced oscillations in two dopaminergic cells. Corticotropin-releasing factor (CRF; 200 nM) excited the majority of VTA cells directly, whereas neuropeptide Y (NPY; 300 nM) directly inhibited a subset of dopaminergic and GABAergic cells. Consecutive application of several neuropeptides revealed that all the neurons were excited by at least one of the excitatory neuropeptides SP, CRF or/and orexins. Alpha-melanocyte-stimulating hormone had no effect on dopaminergic cells (at concentrations of 500 nM and 1 microM) and affected only a small proportion of GABAergic neurons. Ghrelin (500 nM), agouti-related peptide (1 microM); cocaine and amphetamine-related transcript (500 nM) and leptin (500 nM and 1 microM) did not modulate the firing rate and membrane potential of VTA neurons. Single-cell reverse transcription polymerase chain reaction analysis showed that all NPY receptors were present in VTA neurons, and all but one cell expressed NPY and/or at least one NPY receptor. CRF was expressed in 70% of dopaminergic VTA cells; the expression of CRF receptor 2 was more abundant than that of receptor 1. These findings suggest a link between the ability of neuropeptides to promote arousal and their action on VTA neurons.

Multiple GABAA receptor subtypes regulate hippocampal ripple oscillations.

High-frequency oscillations (140-200 Hz) were recorded in behaving rats from the CA1 area of the hippocampus. As generation of these synchronous patterns is assumed to depend on coordinated interneuronal inhibition, we studied the interference of benzodiazepines with the fine structure and occurrence of ripple oscillations. The nonselective GABAA receptor alpha-subunit agonist, diazepam, lowered the frequency of ripple oscillations and reduced their occurrence, amplitude and duration. Zolpidem, an alpha1-subunit selective benzodiazepine elevated ripple duration but acted similar to diazepam in other respects. The nonselective alpha-subunit benzodiazepine antagonist, flumazenil, reduced ripple numbers, amplitude and duration. Wavelet based analysis of the dynamics of intraripple frequency revealed a dramatic decay within a ripple. Only diazepam (1 mg/kg) accelerated this intraripple frequency accommodation. The effects were not due to increased behavioural activity and alertness as evident from vigilance state control. The results suggest a differential role of GABAA receptor subtype specific inhibitory mechanisms in the mediation and fine-tuning of the network synchronization during approximately 200 Hz hippocampal oscillations.

The effects of immunization against cholecystokinin fragment 30-33 in the behavior of white rats.

Active immunization of white rats with cholecystokinin-4 covalently linked to the antigen carrier BSA evoked long-lasting changes in the rats' behavior, which were in the opposite direction to the anxiogenic effects of cholecystokinin-4 itself, showing that immunization had anxiolytic effects. Immunoenzyme analysis demonstrated the presence of antibodies to cholecystokinin-4 in the serum of immunized rats. These data are interesting from the point of view of correcting pathological anxiety and fear states by inverse immunoregulation.

[Effect of immunization to cholecystokinin fragment (30-33) on the behavior of albino rats]. / Vliianie immunizatsii k fragmentu kholetsistokinina (30-33) na povedenie belykh krys.

Active immunisation of albino rats by the BSA-conjugated CCK-4 induced formation of antibodies to the CCK-4 and some long-term changes of the rat behaviour. These changes were contrary to anxiogenic effect of the CCK-4 and demonstrated an anxiolytic effect of the immunisation. The data obtained suggest a possibility of an immunocorrection of pathological anxiety and fear by an inverse immunoregulation.