Time course of frontal somatosensory evoked potentials. Relation to L-dopa plasma levels and motor performance in PD.

OBJECTIVE: To verify whether the change in L-dopa plasma levels after a single dose of carbidopa/L-dopa 50/200 (controlled-release) transiently modifies frontal components of somatosensory evoked potentials (SEPs) in patients with PD in parallel with improvement of motor performance. BACKGROUND: Apomorphine, a potent dopamine-agonist drug, transiently increases frontal SEP components, which may be depressed in PD; however, relationships between clinical status, frontal SEPs, and therapy are still unclear. METHODS: Nineteen PD patients (mean age 65.9 years, range 52 to 77, responders to L-dopa therapy, were studied in the same day at times T0 (baseline predose level), T1 (presumed L-dopa peak time), and T2 (end of dose-induced motor response). The following were monitored: L-dopa plasma concentration, tapping test, reaction times, peak latency (with central conduction times), and amplitude of cervical, subcortical, as well as cortical parietal and frontal SEP components elicited by median nerve stimulation of the more clinically affected arm. RESULTS: The average amplitude of frontal components of PD patients was significantly reduced at T0 with respect to control subjects. A significant and transient amplitude increase of frontal SEPs was found at T1, in parallel with the L-dopa peak concentration and improvement in motor performance (tapping and reaction times), without significant changes in amplitude of parietal SEP waves. No latency shifts were observed in brain and spinal waves. CONCLUSIONS: L-Dopa may influence the responsiveness of the parkinsonian brain as assessed by frontal somatosensory evoked potentials. The time course of these modifications coincides with that of the clinical response in the motor performance.

Efficacy of an Hypericum perforatum (St. John's wort) extract in preventing and reverting a condition of escape deficit in rats.

The treatment of unselected depressed patients with an hydro-alcoholic extract of Hypericum perforatum has been reported to have an efficacy similar to that of classical antidepressants. In the present report, the effects of H. perforatum were studied on three animal models of depression: (i) an acute form of escape deficit (ED) induced by an unavoidable stress; (ii) a chronic model of ED, which can be maintained by the administration of mild stressors on alternate days; (iii) a model of anhedonia based on the finding that repeated stressors prevent the development of an appetitive behavior induced by vanilla sugar in satiated rats fed ad libitum. H. perforatum acutely protected animals from the sequelae of unavoidable stress; such an effect was partially prevented by the administration of SCH 23390 or (-)-pindolol. Moreover, H. perforatum reverted the ED maintained by repeated stressors and preserved the animal's capacity to learn to operate for earning a positive reinforcer. It was concluded that H. perforatum contains some active principle(s) endowed with antidepressant activity.

The effects of long-term administration of rubidium or lithium on reactivity to stress and on dopamine output in the nucleus accumbens in rats.

Rubidium and lithium are alkali metals belonging to the same periodic series as sodium, potassium and cesium. In the present report the effects of lithium and rubidium on animal reactivity to stressful stimuli and on dopamine output in the nucleus accumbens were studied. A dose-response curve with rubidium, administered acutely before exposure to unavoidable stress, showed a maximal protective activity on escape deficit development at the dose of 0. 41 mEq/kg. Rubidium injected at doses of 0.008-0.08 mEq/kg 72 h before the unavoidable stress had the same efficacy as the acute 0. 41 mEq/kg dose. Tolerance to the effect of rubidium developed after 9 days of treatment and, on day 15, rats presented a spontaneous escape deficit. The acute effect of lithium, administered for 3.5 days at the dose of 0.8 mEq/kg, i.p. twice a day before the exposure to unavoidable stress, was analogous to that of rubidium, but after repeated treatment a spontaneous escape deficit developed. Rats showing an escape deficit secondary to chronic stress also presented decreased extraneuronal dopamine concentrations in the nucleus accumbens. Accordingly, microdialysis studies showed significantly lower extracellular dopamine levels in rats chronically treated with lithium or rubidium compared to control animals. Cocaine (5 mg/kg i. p.) administered acutely increased extracellular dopamine concentrations in control rats, as well as in rats chronically stressed or chronically treated with lithium or rubidium. However, the dopamine increase was significantly higher in controls compared to the other groups. In conclusion, long-term treatment with lithium or rubidium, or the exposure to chronic stress, produced a condition of behavioral hypo-reactivity accompanied by a decreased dopamine output in the nucleus accumbens.

A chronic stress that impairs reactivity in rats also decreases dopaminergic transmission in the nucleus accumbens: a microdialysis study.

Chronic stress induces in rats a decreased reactivity toward noxious stimuli (escape deficit), which can be reverted by antidepressant treatments. The present study reports that this condition of behavioral deficit is accompanied by a decreased level of extracellular dopamine in the nucleus accumbens shell. To assess whether this finding was the result of a decreased release or of an enhanced removal of dopamine, we acutely administered cocaine, and 2 h later d-amphetamine, to stressed and control rats. The increases in dopamine output observed in stressed animals after cocaine administration were significantly lower than those observed in control rats; whereas the total amount of dopamine released after d-amphetamine administration was similar in both groups of rats. These data suggest a reduced activity of dopaminergic neurons as the possible mechanism underlying dopamine basal level reduction in stressed animals. It is interesting that the stress group showed a locomotor response to cocaine not different from control rats, thus suggesting a condition of sensitization to dopamine receptor stimulation. Imipramine administered daily concomitantly with stress exposure completely reverted the escape deficit condition of chronically stressed rats. Moreover, stressed rats treated with imipramine showed basal and cocaine stimulated levels of extraneuronal dopamine similar to those observed in control animals.

Under continuous dizocilpine infusion an N-methyl-D-aspartate receptor independent form of cocaine sensitization develops in rats.

N-methyl-D-aspartate (NMDA) receptor blockade is thought to prevent the development of cocaine-induced sensitization. Moreover, when cocaine is administered daily along with dizocilpine infusion to previously sensitized rats, the extinction of sensitization occurs. We report here two sets of experiments: (1) Rats were infused with dizocilpine through a subcutaneous mini-pump (0.1 mg/kg/day) during the induction of cocaine sensitization and, after 2 or 7 days of wash-out, were challenged with: cocaine, dizocilpine plus cocaine or 3-((+/-)2-carboxypiperazin-4-yl)-propyl-L-phosphonic acid (CPP) plus cocaine. Cocaine induced stereotypy scores significantly lower than that produced by the two drug combinations. Animals infused with dizocilpine alone did not present stereotypies when challenged either with dizocilpine or with dizocilpine plus cocaine. (2) Rats previously sensitized to cocaine received dizocilpine by infusion and daily cocaine treatments for a week. During the first days of infusion, sensitization appeared to be significantly decreased, but it resumed the initial intensity on days 6-7. After 2 and 9 days of wash-out, the expression of sensitization could be retrieved only by dizocilpine plus cocaine. Two distinct forms of sensitization to cocaine thus seem to exist: one dependent on and the second independent of NMDA receptor activity.

Palatable food induces an appetitive behaviour in satiated rats which can be inhibited by chronic stress.

An experimental model for the study of antidepressant treatments was devised by exploiting the response maintained by vanilla pellets in rats freely fed on a standard diet. The apparatus used was a Y-maze and the rats were trained, during 10-12 consecutive sessions, to earn a vanilla pellet placed at the end of the one of the two divergent arms. Animals exposed to repeated unavoidable stressors during the training phase did not develop the appetitive behaviour. Rats previously trained on the Y-maze, however, did not modify their performance under the effect of repeated stressors. Long-term treatment with imipramine and fluoxetine, given for 2 weeks before training and during the whole of the training phase, was able to antagonize the disrupting effect of chronic stress on the acquisition of the Y-maze. Finally, vanilla pellet consumption in trained animals induced a consistent increase in extraneuronal dopamine in the nucleus accumbens, as measured by microdialysis.

Desensitization of the D1 dopamine receptors in rats reproduces a model of escape deficit reverted by imipramine, fluoxetine and clomipramine.

1. The present study investigated the effect of long-term D1 dopamine receptor stimulation on an animal model of depression derived from the learned helplessness paradigm. 2. The model used is based on the escape deficit produced by a series of unavoidable shocks administered to rats 24 h before the test session. SKF 38393 administered acutely, completely prevented the development of animal hyporeactivity, while given repeatedly produced tolerance to its own protective effect. Moreover it also reduced the spontaneous escape reactivity of rats not exposed to the inescapable shocks. Animals chronically receiving SKF 38393 and showing a clearcut escape deficit, were treated daily with either imipramine, fluoxetine, or clomipramine. After 21 days of combined treatment the 3 antidepressants appeared equally effective in reverting the behavioral deficit. Moreover, long term administration of both imipramine or SKF 38393 down regulated D1 dopamine receptor number in the prefrontal cortex, while the association of the two drugs resulted in a receptor density similar to that of control rats. 3. The present results further support the crucial role played by D1 dopamine receptors in the control of animal reactivity to stressful stimuli and in the mechanism of action of imipramine. Moreover they show that the D1 dopamine receptor related escape deficit is sensitive also to compounds selectively acting through the serotonergic neuronal system.

Reversal of stable behavioural modifications through NMDA receptor inhibition in rats.

In order to study the effect of long-term dizocilpine infusion on memory, two different paradigms of stably modified behaviour were used in rats. The first was the escape deficits (ED) induced and maintained either by repeated daily administrations of SKF 38393, a rather selective D1 dopamine receptor agonist, or by repeated stress; the second was sensitisation to the effect of cocaine on motility. Fluoxetine (FLX), imipramine (IMI) and clomipramine (CMI) were equally effective in reversing the reduced reactivity of animals in both ED models. Dizocilpine showed a similar efficacy to that of classic antidepressants on the pharmacologically-induced ED, but failed to affect the stress-induced ED. In rats previously sensitised to cocaine and then infused with dizocilpine for 7 days after suspension of cocaine administration, the state of sensitisation, remained intact; however, in animals receiving dizocilpine plus a concomitant daily injection of cocaine, dizocilpine significantly reduced cocaine sensitisation. These results potentially suggest a new approach to the treatment of drug addiction and other psychiatric disorders. Finally, it was concluded that NMDA receptor blockade not only prevents, but also reverses many, if not all, learned behaviours, and that this phenomenon differs from the effect of antidepressants.

Crucial role of D1 dopamine receptors in mediating the antidepressant effect of imipramine.

Although the neurochemical effects of chronic imipramine (IMI) treatment have been related to an increased adrenergic as well as dopaminergic transmission, no clear-cut evidence exists on whether one of these two neuronal systems mediates the behavioral effects of the tricyclic compound. Because a large body of evidence favors the role of dopamine, the interference of a selective inhibition of D1 or D2/D3 dopamine receptors on IMI effect upon the learned helplessness behavior (LH) in rats was studied. A 2-week treatment with SCH 23390, followed by a 24-h washout, showed almost the same efficacy as chronic IMI in preventing LH induction. Moreover, SCH 23390 given acutely before the pretest completely antagonized the effect of chronic IMI. Furthermore, SKF 38393 administered to drug-naive animals prior to the unavoidable shocks completely neutralized its behavioral sequelae. Finally, the inhibition of D2/D3 dopamine receptors by acute sulpiride did not modify IMI efficacy. These results strongly suggest that D1 dopamine receptor function controls the reactivity of animals exposed to a prolonged unavoidable stress, and mediates IMI antidepressant effect.

Imipramine and fluoxetine prevent the stress-induced escape deficits in rats through a distinct mechanism of action.

A large body of evidence indicates that brain monoamines are involved in the pathogenesis of mental depression, as well as in the mechanism of action of most antidepressant treatments. The present report shows that long-term exposure to imipramine (IMI) or fluoxetine (FLX) was equally potent in preventing the escape deficits produced in rats by repeated unavoidable shocks. The acute administration of SCH 23390, a selective D1 dopamine receptor blocker, shortly before the inescapable shock session, entirely prevented IMI effect on escape performance, but only partially prevented that of FLX. Moreover, pindolol (an antagonist of beta-adrenoceptors and of serotonin 5-HT(1A) and 5-HT(1B) receptors) completely antagonized the efficacy of FLX in preventing escape deficits, whereas it did not effect the activity of IMI. The acute administration of propranolol failed to alter the effect of either antidepressant. It was concluded that in rats, the efficacy of IMI in counteracting the stress-induced behavioral sequelae is mainly mediated by the activation of D1 dopamine receptors, whereas that of FLX is largely dependent upon the stimulation of post-synaptic 5-HT(1A) receptors. Finally, the effects of the two drugs appear to be totally unrelated to activation of beta-adrenoceptors.