Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats.

In order to study a possible modulatory effect of glutamatergic afferents to the nucleus accumbens (NAC) on psychostimulant-induced locomotion, L-glutamic acid diethyl ester (GDEE), a glutamate antagonist, was injected in the NAC of rats acutely treated with cocaine, amphetamine or caffeine. GDEE at the doses of 5, 10, and 20 micrograms/side significantly reduced locomotion induced by cocaine (20 mg/kg, i.p.). Amphetamine-induced hyperactivity was also reduced by GDEE, whereas caffeine-induced hyperactivity was not significantly decreased by GDEE. This suggests that glutamatergic afferents to the NAC modulate the effects of psychostimulants and also dopamine function in the mesolimbic system.

A controlled trial of methylphenidate in black adolescents. Attentional, behavioral, and physiological effects.

The short-term effects of methylphenidate were examined on behavioral, laboratory, academic, and physiological measures in 11 black male adolescents diagnosed as having attention deficit disorder (ADD). In a double-blind, crossover design with randomized order, the subjects received placebo and each of three methylphenidate doses (0.15 mg/kg, 0.30 mg/kg, and 0.50 mg/kg) for a period of 2 weeks per medication dosage. Significant drug effects were found for the majority of measures. In general, the higher doses resulted in the most beneficial response in behavioral, academic, and laboratory measures of attention and impulsivity. However, a significant linear increase occurred in diastolic blood pressure. The results suggest that methylphenidate is an effective adjunct to the treatment of ADD in adolescents.

Behavioural consequences of the infusion of dopamine into the nucleus accumbens of the common marmoset (Callithrix jacchus).

Marmosets, shown to have comparable levels of spontaneous locomotor activity, assessed in cages equipped with infra-red photocell units, could be separated into "high", "moderate" and "low activity" responders on the basis of their locomotor hyperactivity response to peripherally administered (-)N-n-propylnorapomorphine [(-)NPA]. Animals selected as "low" and "high activity" responders to (-)NPA were subjected to chronic infusion of dopamine, or its solvent, bilaterally into the nucleus accumbens for 13 days through Alzet osmotic minipumps. Both "low" and "high activity" responders exhibited an increased locomotor activity which peaked on days 6-7 of the infusion. This hyperactivity, caused by infusion of dopamine was antagonised by small doses of sulpiride and fluphenazine. After the infusion, the level of spontaneous locomotor activity of the marmosets was unchanged from pre-infusion values. However, 2-3 weeks after discontinuing the infusion, the animals initially classified as "low activity" responders showed markedly enhanced activity when challenged with (-)NPA, and conversely, animals initially classified as "high activity" responders showed a reduced responsiveness to (-)NPA. It is concluded that the consequences of a persistent increase in the activity of dopamine in the nucleus accumbens of the brain of the marmoset are to (a) enhance locomotor activity during infusion and (b) after discontinuing infusion, to modify the locomotor responsiveness to challenge with a dopamine agonist, with the direction of the change dependent on the initial basal locomotor responsiveness to (-)NPA.

Classical conditioning, decay and extinction of cocaine-induced hyperactivity and stereotypy.

Following 10 daily pairings of multiple conditioned stimuli with injection of cocaine (15 mg/kg), the presentation of the stimuli alone elicited behaviors in rats similar to those induced by cocaine. The behaviors included increased duration or frequency of rearing, sniffing, head bobbing, and horizontal locomotor activity (crossing). The level of the conditioned response for several of these behaviors approximated that induced by the drug itself. The conditioned drug effect showed decay over 15 days but little extinction during 4 daily trials. Brain concentrations of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid, were similar in the conditioned and pseudoconditioned control groups in both the caudate and mesolimbic areas. The behavioral results demonstrate that, in a classical conditioning paradigm, previously neutral stimuli can elicit behaviors similar to those induced by cocaine and that certain conditioned responses show time related decline. This agrees with the reported conditioning of amphetamine's behavioral effects but differs in terms of the action on brain dopamine turnover.

Studies on the mechanisms by which clenbuterol, a beta-adrenoceptor agonist, enhances 5-HT-mediated behaviour and increases metabolism of 5-HT in the brain of the rat.

The head twitch response in mice produced by injection of 5-hydroxytryptophan (100 mg/kg i.p.) and carbidopa (25 mg/kg i.p.) was enhanced by administration of clenbuterol (0.5 mg/kg i.p.), a beta-adrenoceptor agonist. Clenbuterol also enhanced the hyperactivity syndrome in rats produced by quipazine (25 mg/kg i.p.), a 5-hydroxytryptamine (5-HT) agonist. This enhancement was not prevented by depletion of 5-HT in brain with p-chlorophenylalanine or after pretreatment with prazosin. The behavioural responses of the rats to administration of the alpha 2-adrenoceptor agonist, clonidine, was unaltered by acute or longer-term administration of clenbuterol. Following chronic administration of clenbuterol (5 mg/kg daily for 14 days), a procedure resulting in down-regulation of central beta-adrenoceptors, a larger dose of clenbuterol was necessary to enhance the quipazine-induced hyperactivity, suggesting that the mechanism of enhancement involved central post-synaptic beta-adrenoceptors. Further evidence for this conclusion was that a lesion of central noradrenaline pathways produced by 6-hydroxydopamine did not abolish the clenbuterol-induced enhancement of the quipazine-mediated behaviour. The binding characteristics of 5-HT2-receptors were unchanged by acute or chronic administration of clenbuterol. Clenbuterol (5 mg/kg) increased the percentage of plasma free (non-albumin bound) tryptophan, plasma free fatty acid concentration and the concentration of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in the brain. The increase in 5-HT turnover in brain was prevented by pretreatment with the beta 1-adrenoceptor antagonist atenolol, which enters the brain poorly. It is therefore suggested that the clenbuterol-induced increase in 5-HT metabolism results from the increase in the concentration of plasma free fatty acid which increases plasma free tryptophan and thus increases the concentration of tryptophan in brain and 5-HT synthesis in brain. The clenbuterol-induced enhancement of 5-HT-mediated behaviour is therefore not associated with its effect on 5-HT metabolism. The data are discussed in relation to that obtained after administration of antidepressant drugs.

A survey study of the use of electropupillogram in predicting response to psychostimulants.

To confirm the conclusions from a previous study supporting the usefullness of electropupillogram (E.P.G.) in predicting clinical response, data from three separate studies with hyperkinetic and learning disabled (L.D.) children treated with stimulants were surveyed. Change in extent of pupillary contraction (E.C.) after a test dose of stimulant as measured by E.P.G. did not correlate significantly with actual clinical rating change (with one exception out of 14 correlations calculated). These negative results are reported with a reservation regarding their validity because of technical difficulties in data collection.

Biochemical aspects of Huntington's chorea.

Fifteen patients affected by Huntington's chorea were divided into two groups, 'slow' and 'fast', according to IQ scores on the Wechsler-Bellevue scale, and scores on some motor performance tests. A possible correlation was looked for between some biochemical data (cerebrospinal fluid (CSF), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5HIAA) levels, plasma dopamine-beta-hydroxylase (DBH), dopamine (DA) uptake by platelets), and clinical data (duration of illness, severity of symptoms, age of patients, IQ scores, 'slow' and 'fast' groups). The CSF, HVA, and 5HIAA levels were found to be significantly lowered in comparison with normal controls. DBH activity and DA uptake by platelets did not differ significantly from normal subjects. Treatment with haloperidol in all patients and with dipropylacetic acid in three patients did not appear to modify the CSF, HVA, and 5HIAA concentrations, the plasma DBH activity, or the DA uptake. There were no significant differences in the CSF, HVA, and 5HIAA contents between the two groups of patients, and there was no correlation between biochemical data and clinical features.