Tomas Ljungberg

A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis

An intracerebral microdialysis method was used in awake rats to directly compare the effect of amphetamine on dopamine (DA) release in the striatum and nucleus (n.) accumbens with alterations in behaviour. Amphetamine (0.5-5.0 mg/kg, s.c.) caused a dose-dependent release of DA in both brain regions; however the n. accumbens appeared for the most part more sensitive to amphetamine than the striatum. At each individual dose of the drug, 0.5, 2.0 and 5.0 mg/kg s.c., DA release was closely followed over the time course by the overall behavioural syndrome. Certain components of behaviour showed a regional-specific association with DA release. The intensity of stereotyped head and forepaw movements was closely correlated over the dose range with the amount of DA released in striatum but not n. accumbens. Over the time course, however, the occurrence of this behaviour was delayed compared to increased striatal DA release. In contrast, increased locomotor activity was correlated with the time course change in, and amount of, DA released in n. accumbens by low doses of amphetamine, but not at any dose with DA released in striatum. Repetitive sniffing was better correlated with DA released in n. accumbens than striatum. These in vivo measurements of DA release add further support to the hypothesis that amphetamine-induced stereotypy and locomotion are mediated via DA released in striatum and n. accumbens, respectively. Our data suggest that the occurrence of intense stereotypy rather than locomotor activity at high doses of amphetamine is not due to a selection action in striatum but probably competition between the two behaviours.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological and cytological studies of brain homografts in the anterior chamber of the eye: Maturation of cerebellar cortex in oculo

The intraocular transplantation technique was used to study maturation of cerebellar homografts with electrophysiological and cytological methods. Taking of the transplants was optimal using donors with a gestational age of 15–17 days, whereafter it declined markedly. The time-table for the cytological maturation mimicked the in situ maturation surprisingly well, being retarded at the most by 5 days. External granule cells appeared 5 days postoperatively, and had completely disappeared about 5 weeks later. Internal granule cells appeared from about day 12. Purkinje cells were identified in clusters from day 8. They slowly fanned out to form a monolayer after about 3 weeks in oculo, situated between an internal granule cell layer and a molecular layer. The molecular layer was clearly recognized from the third week and often contained apical dendrites from the Purkinje cells. The overall cytological organization of the mature transplants was very similar to the normal cerebellum, also including some foliation and always including typical trialaminar areas. The intraocular transplantation technique is thus very suitable for producing cytologically homotypical cerebellar transplants. The electrophysiological maturation of the transplants was also followed using extracellular recordings. A spontaneous discharge pattern strongly suggesting the presence of Purkinje cells mimicked the well known in situ activity both regarding time course and way of firing. Thus, few single spikes were recorded 12 days postoperatively having very few high frequency bursts. The interspike intervals and the inter- and intraburst intervals then gradually decreased to reach values very close to those of normal adult cerebellum about 4 weeks postoperatively. Interspike and interburst interval histograms are presented to show these similarities. Also, potentials evoked by stimulating the base or the surface of the transplants showed action potential responses similar to those of normal cerebellum. Thus, (1) stimulating the base of the transplant, a short latency all-or-none single spike was elicited. (2) When stimulating the surface of the transplant often 1–3 driven spikes over a 5–10 msec period could be elicited. This response was invariably graded. (3) Stimulation of the surface often produced a short latency inhibition of spontaneous discharge lasting 40–120 msec. This response was also graded. The inhibition was shown to be independent of adrenergic fiber influence as shown by superior cervical ganglionectomy or parenteral reserpine administration. The inhibition was antagonized by the GABA-blocker bicuculline when administered parenterally. These 3 responses closely resemble the antidromic spike response, the parallel fiber excitation response and the basket-stellate cell inhibition response respectively, as seen in the normal adult cerebellum in situ. It is concluded that the intraocular cerebellar homografts develop and mature in a very homotypical way as shown by means of electrophysiology and histology in spite of the complete lack of normal connections with the rest of the brain and underlines the importance of intrinsic regulatory mechanisms in CNS ontogeny.

Responses of monkey midbrain dopamine neurons during delayed alternation performance

Cognitive deficits are important components of the parkinsonian syndrome. In order to investigate the role of dopamine (DA) neurons in cognitive functions, we recorded the electrical activity of midbrain DA neurons in a monkey performing in a spatial delayed alternation task. Triggered by a light, the animal reached toward one of two levers to receive a drop of liquid reward. The lever associated with reward was alternated after each correct movement. Of 88 DA neurons, 65% and 52% showed phasic responses to the trigger light and reward, respectively. By contrast, sustained delay-related activity described for striatum and frontal cortex was not observed, suggesting that the activity of DA neurons does not reflect mnemonic or preparatory representational task components. Rather, DA neurons respond to the salient attentional and motivating stimuli guiding task performance.

A rapid and simple behavioural screening method for simultaneous assessment of limbic and striatal blocking effects of neuroleptic drugs

A simple and rapid screening method, where the ability of neuroleptic drugs to antagonise the abnormal pattern of exploration induced by a low dose of d-amphetamine in a 10 min test, was evaluated. The d-amphetamine 2 mg/kg pretreatment induced both an increased locomotion, thought to reflect an increased dopamine transmission in the nucleus accumbens, and weak stereotypies, thought to reflect an increased dopamine transmission in the neostriatum. Haloperidol, chlorpromazine and thioridazine blocked all ongoing behaviours while clozapine and sulpiride, regarded as causing less extrapyramidal side effects in the clinic, only antagonised the d-amphetamine induced locomotion. The findings support the notion that the common site of action for anti-psychotic drugs is blockade of dopamine receptors outside the neostriatum while the blockade of dopamine receptors within the striatum probably are related to the propensity of these drugs to induce the extrapyramidal side effects. It seems possible with this method to screen neuroleptic drugs for their relative potency in blocking limbic and striatal dopamine receptors simultaneously in one short experiment. The method might be used when new anti-psychotic drugs with low incidences of extrapyramidal side effects are sought for.

A method for simultaneous recording of eight behavioral parameters related to monoamine neurotransmission

In response to the increasing demand for refined techniques to record drug induced changes in motor activity we have designed and evaluated against observations an automatic test box that quantifies eight defined components of behaviour in rats. Activity, corresponding to the recordings from the commonly used photocell activity boxes. Total, and forward locomotion, expressing the actual distance the rat walks. Corner count, and corner time, reflecting the position of the animal in the box. Hole count, and hole time, expressing the reaction of the rat to an environmental stimulus i.e. holes in the bottom of the test box. Gnawing, which is a direct counting of the number of gnaws made by the animal. The recording parameters relate to our interest in behaviour influenced by monoamine neurotransmission and the result shows that the selected parameters are recorded with high reliability.

Differential attenuation of water intake and water-rewarded operant responding by repeated administration of haloperidol and SCH 23390 in the rat

It has previously been described that water intake in thirsty rats require higher doses of dopamine (DA) D-1 and D-2 antagonists to be attenuated than operant lever-pressing with water as reward. In the present study, effects of repeated administration of the DA D-1 antagonist SCH 23390 and the DA D-2 antagonist haloperidol were investigated in the same experimental paradigm. In agreement with previous reports, attenuation of operant responding increased progressively by haloperidol (0.05 mg/kg) given for four consecutive days. However, this attenuation was not accompanied by decreased water intake, tested for in parallel experiments. After haloperidol (0.2 mg/kg), in contrast, a progressively decreasing attenuation of water intake was found. After SCH 23390, both the initial attenuation of lever-pressing (0.02 mg/kg) and consummatory water intake (0.1 mg/kg) became less pronounced over time. The results thus show that: 1) the previously reported progressively increasing attenuation of operant responding caused by repeated administration of D-2 antagonists is not mimicked by the D-1 antagonist SCH 23390, and 2) attenuation of water intake caused by higher doses of neuroleptics is, in direct opposition, less pronounced after repeated administrations. The results also show that attenuation of operant responding by neuroleptics cannot solely be dependent upon a blunting of the impact of the reward.

Reliability of two activity boxes commonly used to assess drug induced behavioural changes.

Rats were given different drug treatments known to affect central catecholamine neurotransmission and to induce different types of behavioural changes which were recorded simultaneously by two different types of conventional activity boxes: an Animex activity meter and a photocell cage. All animals were also visually observed simultaneously with the automatic recordings. It was found that the two activity boxes reflected the behavioural changes differently and that the results from the two boxes were not correlated. When comparing the observations with the automatic recordings it was found that some clearly observable changes in behaviour were not reflected as changes in the automatic recordings and conversely that increases or decreases in the recorded motor activity were not always related to any particular changes in behaviour. The results show that motor activity can not be regarded as a simple or homogeneous behaviour that is reliably measured in conventional activity boxes. It is an undescriptive measure consisting of an artificial summation of those components of behaviour that affect the movement-detecting device in the particular box which is used. Practical and theoretical implications of this are discussed.

Scopolamine reverses haloperidol-attenuated lever-pressing for water but not haloperidol-attenuated water intake in the rat

The operant lever-pressing response has previously (Ljungberg, Pharmacol Biochem Behav 27: 341-350, 1987) been found to be inhibited by lower doses of haloperidol than the corresponding consummatory act, i.e., water intake. In the present study it was found that the attenuation of the lever-pressing response caused by the neuroleptic, but not the attenuation of the water intake, could be counteracted by scopolamine. The results support the notion that blockade of operant responding by low doses of neuroleptics are probably related to the extra-pyramidal side-effects of neuroleptics seen in the clinic, as both phenomena can be counteracted by anticholinergics. These results therefore conflict with the anhedonia hypothesis put forward as an explanation of the attenuating effects of neuroleptics in operant settings. The findings also have a clear bearing on the role of dopamine in feeding and drinking behavior, as the results implies that different aspects of the control of water intake (i.e., the operant vs. the consummatory phase) are governed by different mechanisms in the CNS.

Effect of sulpiride on amphetamine-induced behaviour in relation to changes in striatal dopamine release in vivo.

Intracerebral dialysis was used to simultaneously monitor extracellular dopamine (DA) in striatum and behaviour in rats following administration of amphetamine and sulpiride. Amphetamine (2 mg/kg s.c.) caused a marked release of DA into striatal perfusates, an effect which was potentiated in rats pretreated with sulpiride (50 mg/kg s.c.). Amphetamine-induced stereotyped head and forepaw movements were potentiated by sulpiride at a time point corresponding with the enhanced release of DA. In comparison, amphetamine-induced locomotor activity was completely inhibited by sulpiride.

Interaction before conflict and conflict resolution in pre‐school boys with language impairment

BACKGROUND Children with language impairment (LI) experience social difficulties, including conflict management. The factors involved in peer-conflict progression in pre-school children with LI, and which of these processes may differ from pre-school children with typical language development (TL), is therefore examined. AIMS To describe the relationship between opponents interacting before conflict, aberrant conflict causes, the conflict-resolution strategy reconciliation (i.e. friendly contact between former opponents shortly following conflict termination), and conflict outcome in the form of social interaction after a conflict has run its course. It is hypothesized that without social interaction before conflict, children with LI will experience increased difficulties attaining reconciliation. METHODS AND PROCEDURES Unstructured play of 11 boys with LI (4-7 years old), at a specialized language pre-school, and 20 boys with TL (4-6 years old), at mainstream pre-schools, were video filmed. Conflicts were identified and recorded according to a validated coding system. Recorded conflict details include social interaction between conflict in the pre-conflict period, behavioural sequences constituting conflict cause (conflict period), reconciliatory behaviours in the post-conflict period, and social interaction between former opponents in the succeeding non-conflict period. The groups mean proportion of individual childrens conflicts in which specific behavioural sequences occurred were calculated and compared between and within the groups. OUTCOMES AND RESULTS When conflicts with and without pre-conflict social interaction were analysed separately, aberrant caused conflicts occurred more often in LI group conflicts than in TL group conflicts. However, in conflicts without social interaction in the pre-conflict period, boys with LI exhibit reconciliatory behaviours in, and reconcile a comparatively smaller proportion of, conflicts. Social interaction in the succeeding non-conflict period was proportionately less for boys with LI. This appears to stem from lower reconciliation rates in LI conflicts that do not begin with social interaction in the pre-conflict period. It was also confounded by the larger number of aberrant caused LI conflicts that were rarely reconciled. In turn, non-reconciliation and aberrant caused conflicts were independently associated with comparatively less social interaction in the succeeding non-conflict period. CONCLUSIONS The results suggest that in addition to traditional psycholinguistic training, children with LI may gain from interventions that support concluding behavioural turns, as in aberrant caused conflicts; and in initiating contact in conflict situations, even when a frame of reference is not immediately available, as was the case when opponents have not established social interaction in the pre-conflict period.