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BACKGROUND Wound healing is among the frequent illnesses that affects the skin, and therefore, the screening of natural preparation to treat skin burn is important. In Morocco, Cynara humilis is a Moroccan medicinal plant widely used for the treatment of skin burn. OBJECTIVES The aim of this study was to investigate the safety of C. humilis and its wound healing potential against skin burn. METHODS In this work, C. humilis was selected based on an ethnopharmacological survey. As revealed by traditional medicine, C. humilis powder extract (CHPE) was used to test wound healing effects. Furthermore, to assure the safety of this powder, acute and subchronic dermal toxicities were investigated on animal models. RESULTS The oral acute toxicity test of CHPE did not show mortality in treated rats (LD50 >2000 mg/kg). Moreover, in the acute dermal toxicity, CHPE at 5 g/kg did not induce clinical signs observed during the observation period of 48 h. In the subchronic toxicity test, CHPE did not cause significant abnormalities in the physiological parameters and pathological changes in the major organs of the rats. Body weight evolution and macroscopic analysis of skin burn showed CHPE exhibited important wound healing effects in a time-dependent manner. CHPE reduced significantly wound surface (6.93 ± 0.25 cm2 ) compared with the SDA group (8.30 ± 0.37 cm2 ) and the no-treated group (10.05 ± 0.28 cm2 ). Moreover, the retention rate was increased importantly after the treatment with CHPE (61.66 ± 1.42%) compared with the SDA-treated group (53.57% ± 2.83%) and the no-treated group control animals (43.34% ± 1.27%). CONCLUSION These results were confirmed by a histological evaluation, which showed that CHPE increased the neovascularization, the collagen deposition, and the re-epithelialization. The findings of this work suggest that CHPE could be a promising source for developing drugs against skin burn.

Alcohol abuse is a widespread cause of aggressive and impulsive behaviors that impact the users as well as their entourage. However, only a few medications are effective. Recently, cannabidiol has been reported to improve mood disorders and recovery from substance abuse, yet the psychopharmacologic effects of cannabidiol in ethanol-induced drug reward and aggressivity remain unexplored. In the present study, we investigated the effects of cannabidiol on ethanol-induced place preference and aggressivity in individually and group-housed male rats using the conditioned place preference test, and intruder evoc aggression test, respectively. The obtained results showed that ethanol significantly increased locomotor activity, induced conditioned place preference in all animals, and, specifically, increased aggressivity in individually housed rats. These behavioural impairments induced by ethanol were associated with decreased glucocorticoid and mineralocorticoid receptors transcription in the prefrontal cortex. Notwithstanding, cannabidiol at a dose of 10 mg/kg significantly inhibited Et-OH-induced place preference in group-housed, but not in individually housed rats, and markedly inhibited the aggressive behaviour. These findings suggest that ethanol-induced behavioural impairments are dependent on the housing condition that may affect corticosterone receptors expression and subsequently the animal responsivity to cannabidiol treatment.

Chronic cannabinoid exposure during adolescence in male rats induces chronic cognitive and emotional impairments. However, the impact of this form of exposure on offspring vulnerability to stress is unknown. The aim of this study was to evaluate the behavioural and epigenetic effects of stress in the offspring of male rats whose fathers were exposed to cannabinoids during adolescence. Male adolescent offspring of Win55,212-2 (1.2 mg/kg) treated rats were exposed during one week to variable stressors and subjected to behavioural tests of anxiety and episodic-like memory, followed by an assessment of global DNA methylation and expression of DNA methyltransferases enzymes DNMT1 and DNMT3a mRNA in the prefrontal cortex. Stress exposure induced a significant anxiogenic-like effect but did not affect the episodic-like memory in the offspring of Win55,212-2 exposed fathers in comparison to the offspring of non-exposed fathers. These behavioural changes were subsequent to a significant increase in global DNA methylation and DNMT1 and DNMTa3 transcription in the prefrontal cortex. These data suggest that the deleterious effect of chronic exposure to cannabinoids during adolescence are not limited to the exposed individuals but may increase the vulnerability to stress-induced anxiety in the offspring and alter their epigenetic programming.

Cannabis sativa preparations are some of the most widely used illicit recreational drugs. In addition to their direct addictive potential, cannabinoids may influence the sensitivity to other drugs. The aim of the present study was to determine if a cross-sensitization between Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and other drugs (amphetamine and heroin) could be demonstrated. We examined the effects of a chronic treatment with Delta(9)-THC (0.6, 3 and 15mg/kg, ip) on the locomotor response to amphetamine (1mg/kg, ip) and heroin (1mg/kg, ip). Chronic treatment with Delta(9)-THC resulted in tolerance to the initial hypothermic and anorexic effects. Pre-treatment with Delta(9)-THC increased the locomotor responses to amphetamine and heroin. This cross-sensitization was time-dependent as it was observed three days after the last injection of Delta(9)-THC for amphetamine, and a relatively long time after the end of chronic treatment (41 days) for heroin. Moreover, the enhanced response to amphetamine or heroin was noted in some individuals only: the high-responder rats (HR). These animals have previously been shown to be vulnerable to drug taking behaviors. It is hypothesised that repeated use of Cannabis derivates may facilitate progression to the consumption of other illicit drugs in vulnerable individuals.

Background: In common with other animal models of psychopathology, the forced-swimming test (FST) suffers from the fact that it involves normal animals. Moreover, powerful antidepressant drugs such as the selective serotonin reuptake inhibitors have been found to give false negatives in this behavioral test. Methods: To circumvent these theoretical and practical difficulties, we studied the interindividual variability of the behavioral reactivity of rats in the FST. The effects of fluoxetine treatment or of a stressful experience (repeated testing in the FST) were analyzed on various behavioral responses. Results: The following observations were made in replicated experiments: 1) a dimensional behavioral response from passivity to high reactivity in the FST; 2) an antidepressant-like effect of fluoxetine only in a subgroup of animals categorized as low responders on the dimension of passivity–reactivity; and 3) a switch toward passive responses following a past experience of stress, which was corrected by fluoxetine treatment. Conclusions: It is concluded that a dimensional approach could improve the screening of antidepressant drugs and could aid the development of new ones by identifying the biobehavioral characteristics of responder and nonresponder subjects.

Introduction: The frequency of spontaneous alternation in a Y-maze (visiting each arm in turn at p>50%) depends on the influence of the attention given to intra- and extra-maze cues. We examined the observing responses shown by rats (collateral rearing and head-turning behaviour), the habituation to the novelty and alternation responses over 15 minutes/day, four days in a row - in a Y-maze under enhanced and reduced dopamine (DA) activity (amphetamine- and haloperidol treatment). Methods: Prior to placement in a Y-maze for 15 minutes observation on 4 successive days animals were treated with either amphetamine (0.5 or 2.5 mg/kg) or pre-treated with a low dose of haloperidol (0.08 mg/kg, ip). Results: 1/ Amphetamine treated animals chose the arms at random on day 1, but after the higher dose on day 2-4 they perseverated their choice. The controls maintained their alternation over this period. 2/ The amphetamine-induced effects on alternation were prevented by prior treatment with the neuroleptic haloperidol. 3/ Amphetamine treatment increased the frequency of rearing in the middle at the choice point of the Y-maze. Haloperidol pre-treatment blocked this increase at the midpoint on day 1, and blocked the rearing behavior at the end of an arm on day 2. 4/ Amphetamine also increased the frequency of head turning and "looking", - an effect that was also prevented by haloperidol. (day 2 onwards). 5/ Haloperidol increased the duration of" looking" and of rearing at the end of an arm later in testing. Conclusions: Two effects are postulated to have occurred. a) a conflict on day 1 between the novelty-controlled sensory or attentional effects, that leads to an alternation of arm-choice, and amphetamine-induced DA activity that facilitates an alternation of behavioural responses: -- the result was random choice and increased rearing at the choice point. b) On days 2-4 the drug-induced effects on switching motor responses came to control behaviour (cf. Oades, 1985 review on the role of DA activity in switching between alternative sources of information).

The effects of early undernutrition on behavior and brain biochemistry were examined in rats. At weaning, rats were provided either an ad lib diet (control group) or maintained at 80% of the weight of their control littermates (undernourished group). Three weeks into the diet they were tested in an open field. After 6 weeks of diet, HPLC analyses were conducted on sample brains from each group to assess levels of dopamine and metabolites, respectively dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum. At seven weeks of diet, remaining rats were trained in an 8-arm radial maze, and a retention test conducted 72 h after attaining the learning criterion. At fourteen weeks of diet, sensory reactivity was measured by tail-immersion in a water bath maintained at constant temperature 50 +/- 1 degrees C. Undernourished rats exhibited hyperactivity and increased exploratory behavior in the open field, as well as increased sensory reactivity in the tail flick test. In the radial maze, however, undernourished rats did not differ from controls in either learning or retention. Haloperidol (i. p. injection) impaired retention by control but not undernourished animals. HPLC analyses showed an increase in dopamine turnover in the striatum of undernourished rats. Our results suggest that, unlike its effects when induced immediately at birth or in adulthood, undernutrition at weaning does not appear to influence learning and retention but induced an hyperactivity and alterations in striatal DA turnover which was associated with a decrease in responsiveness to i. p. haloperidol injection.

Male Sprague-Dawley rats received bilateral ibotenic acid lesions of the central amygdaloid nucleus (CeA) and were compared to sham-lesioned rats in their response to different concentrations of saccharin and quinine solutions. In two-bottle choice test situation, the lesioned rats exhibited a lower saccharin preference at concentrations of 2.5; 7.5 and 25 mM, while their aversion towards quinine and the highest concentration of saccharin (50 mM) was increased. In a one-bottle test, the lesioned rats showed consistent decreases in their consumption of 2.5 and 7.5 mM saccharin solutions whereas their intake of 0.9 mM solution of saccharin was equal to that of the sham-lesioned rats. The lesion of the CeA had no significant effects on the acquisition of conditioned taste aversion. There was less postoperative weight gain in lesioned rats as compared to sham-lesioned animals but the lesion had no significant effect on daily water intake. These findings suggest that the CeA plays an important role in the normal response to exteroceptive food stimuli via modulation of the aversive value of taste stimuli. The results are discussed in the context of an interaction between the CeA and the lateral hypothalamus (LH) in the modulation of palatability and feeding behavior.

The present study aimed to describe the localization, organization and density of lateral hypothalamic neurones projecting to the central amygdaloid nucleus (CeA) using WGA-apoHRP-Au as a retrograde tracer. In the lateral hypothalamus (LH) a cluster of labelled neurones was located in the middle and posterior parts of this region. This retrograde labelling is organized into perifornical and juxtacapsular subpopulations. These results provide a neuroanatomical basis for the concept that these lateral hypothalamic neurones modulate projections from CeA to pons and brainstem autonomic and gustatory centres which integrate responses related to fundamental and adaptive behaviours, and could be related to self-stimulation behaviour elicited from the CeA.

Spontaneous alternation which is disrupted by lesion of septal dopaminergic (DA) afferents was chosen as a behavioral marker for the study of functional interactions between DA and noradrenergic (NA) innervation of the lateral septum. Three groups of rats were studied: a solvent group which received only vehicle injection, and two lesioned groups, one with DA lesion and the second with simultaneous DA + NA lesion of the septal innervation. DA lesion was produced by infusing 6-hydroxydopamine (6-OHDA) into the lateral septum after pretreatment with desmethylimipramine (DMI) injected intraperitoneally. The DA + NA lesion was produced by infusing 6-OHDA without DMI pretreatment. The lesion of DA innervation alone led to a disturbance of alternation behavior in a Y-maze, but performance was not affected by the combined DA + NA lesion. The group with septal DA lesion was then injected with 6-OHDA into the pedunculus cerebellaris superior (PCS) in order to destroy NA efferents from the locus coeruleus. The two other groups were sham-operated. After post-operative recovery, the rats were retested for spontaneous alternation. The rats with the PCS NA lesion subsequent to the DA septal lesion displayed normal alternation behavior. Their performance was not different from that of animals with both NA and DA lesions in the septum. Thus the NA lesion appears to prevent the alternation deficits induced by the DA septal lesion, and also abolishes the deficits induced by the prior DA lesions. These results may have therapeutic implications.

Bovine serum albumin haloperidol (BSA-Hal) is a macromolecular complex with 14 molecules of haloperidol immobilized on the BSA protein backbone. This compound produces a selective, long lasting and reversible blockade of dopamine receptor activity. Its action was demonstrated by the ability to trigger a high rate of ipsilateral amphetamine-induced rotation up to 6 days after a single unilateral injection of the conjugate into the striatum. In the present study, the effect of the blockade of dopamine transmission in the nucleus accumbens (n.Acc) on spontaneous and learned behaviors was tested. The results indicate that the specific and long lasting blockade of dopamine receptors by bilateral injection of BSA-Hal in the n.Acc (1.6 micrograms/2 microliters) induced deficits in spontaneous alternation in a Y-maze on the 2nd and 5th days after the injection but not on the 11th day of the experiment, impaired acquisition but not retention in a radial 8-arm maze, increased latency to escape during learning in the place navigation task. These findings confirm the involvement of the n.Acc system in processes that have been generally attributed to the limbic system.

The effects of dopaminergic depletion of the nucleus accumbens was tested in various behavioral tasks such as alternation, spatial discrimination, and reversal learning, and in an extinction paradigm in a T maze. Animals with lesions showed impairment of spontaneous alternation behavior, disturbances in the acquisition of spatial discrimination, and great difficulty in reversing previously learned habits. In the extinction phase, experimental animals are unable to adjust their behavior, and continue to choose the previously reinforced arm of the T maze. It is suggested that the nucleus accumbens plays an important role in the transition of motivation into action, and that dopamine has a facilitatory influence on the mediation of these processes.

In a previous study using differential pulse voltammetry we demonstrated an interaction between dopaminergic activity in the amygdala and the nucleus accumbens. In the present study, by post-mortem biochemical measurements, we showed that bilateral 6-OHDA lesions of DA innervation of the amygdala leads to an increase in DA activity in the nucleus accumbens (DOPAC/DA ratio +24%) and a reduction (DOPAC/DA ratio-40%) in the prefrontal cortex. In addition, after these lesions in the amygdala, there was an increased behavioral sensitivity to d -amphetamine, demonstrated by enhanced locomotor activity. Increased understanding of the interregulations between dopaminergic activity in forebrain structures may help explain forebrain functions and/or dysfunction.

The study and the method: The locomotor activity of adult male Sprague-Dawley was automatically recorded in a circular corridor - circadian changes are described as well as the response to the novel situation and its habituation over three hours. Four groups of animals were compared, - those with sham/vehicle operations and those with 6-OHDA dopamine (DA) depleting lesions in - the frontal cortex, the limbic septum, and the ventral tegmental area (VTA - A10). Results: 1/ Lesions of the VTA resulted in increased dark-phase activity, - and a large response to an apomorphine challenge in comparison to other lesion and control groups: 2/ Septal 6-OHDA lesions did not alter locomotion: 3/ After frontal DA depletion there was a small increase of locomotion after the apomorphine challenge, that might reflect increased receptor sensitivity in cortical or sub-cortical areas: (Table 1: HPLC measures of NA, DA and DOPAC for each group in the prefrontal cortex, septum and N. accumbens) Figure 1 illustrates the cumulative photocell counts per hour over 24 hours for the 4 groups:. Figure 2 illustrates the cumulative photocell counts every 10 minutes over 90 minutes post-apomorphine treatment - maximal at 20-30 minutes and habituating over 60 minutes (90 minutes for the VTA group): overall activity VTA >> Frontal > Septal > Controls. Conclusions: Along with correlations found for motor activity with cortical levels of DA and NA, these results are interpreted to support a role for DA, NA and the region of the frontal cortex in modulating locomotion that is primarily mediated by mesolimbic VTA - accumbens - DA activity.

The effects of 6-hydroxydopamine (6-OHDA) injected into the lateral septum in rats were investigated for spontaneous alternation behavior in a Y maze and for spatially oriented behavior in an 8-arm radial maze. The performance of the animals in these tests was assessed under two physiological states, food-satiated and food-deprived. The selective depletion of septal dopaminergic concentrations leads to behavioral disturbances in both the Y and the radial mazes. These deficits disappeared when the animals with 6-OHDA lesions were food-deprived. These results confirm other studies from our laboratory and support two conclusions. First, lesions of dopaminergic neurons lead to behavioral impairments which resemble those found after the total lesion of the structure they innervate. Second, these behavioral impairments are responsive to therapeutic treatments, manipulations of the internal or external environment, or the level of arousal, since under certain conditions a recovery of function can occur in the absence of dopaminergic neurons. These two points provide additional support for a nonspecific role for the dopaminergic neurons originating in the ventral tegmental area. These neurons could have a permissive role in the functioning of the forebrain structures they innervate.

The behavioural and physiological consequences of social status and reciprocal fighting in resident-intruder dyads of Long Evans male rats were evaluated. Before a chronic cohabitation of 10 days, residents and intruders were individually housed for one month to increase their aggressiveness. Control animals included isolates, i.e., animals kept individually housed throughout the experiment and pair-housed rats, i.e., pairs of rats housed together from their rats in the laboratory. In 19 out of 20 dyads, a clear dominance relationship developed with an advantage to the resident in 68% of the cases. Dominants showed more exploratory activity than subordinates in a open-field test at the end of the cohabitation period; subordinates groomed longer than animals from other experimental groups. Dominants had lower pain thresholds than individually and pair-housed animals. Both dominants and subordinates had higher tyrosine hydroxylase enzymatic activities in the left adrenal than isolated and pair-housed rats. Subordinates lost body weight and had higher plasma corticosteroid concentrations than animals from the other experimental groups. In addition, they had smaller thymus glands and reduced spleen lymphocyte responses to mitogenic stimulation in vitro, in comparison to dominant animals. These results show that subordination in the dyadic resident-intruder paradigm leads to a complex syndrome of behavioural and physiological changes, some of which may be modulated by the intensity of aggressive interactions.

The behavioral effects of 6-hydroxydopamine, injected bilaterally into the lateral septum, were investigated in two tests of spatial memory (radial 8-arm and T-maze). Three different experiments were conducted in the radial maze. In experiment I, rats were permitted to learn the task with food reinforcement in all arms of the maze. In experiment II, retention of the spatial information (working memory) learned in experiment I was tested by interposing various time intervals between choice 4 and 5 of each trial. In experiment III, reference and working memory were simultaneously assessed by only reinforcing 4 choices in the radial maze. Performances were compared in spaced versus massed trials. In the T-maze, the rats were first tested for learning a spatial discrimination between the two arms of the maze, and subsequently for reversal of the previously learned response. The results showed that the rats with lesions were impaired in all experiments. This impairment was particularly marked in some aspects of the procedures used: (1) in the search for the last 4 pellets in experiment I, (2) in the first presentations of various intervals interposed between choices 4 and 5, (3) in the search for food in the baited arms when the trials were massed in experiment III and (4) in the reversal of previously learned spatial discrimination in the T-maze. These behavioral deficits in the rats with septal dopaminergic lesions were interpreted as an increased susceptibility to interference. The lesions were shown to have selectively depleted dopamine concentrations in the septum without damaging noradrenergic terminals or cholinergic cell bodies. It was concluded that dopaminergic neurons could have a modulatory influence on memory processes.

As shown in the rat brain, the development of the classical "denervation supersensitivity" of receptors does not always occur despite the complete destruction of the corresponding afferent fibers. This is due to the concomitant destruction of heterologous fibers which directly or indirectly contribute to the regulation of the denervated receptors. In this review, on the basis of data obtained in rats with lesions of ascending DA neurons, three examples of hetero-regulation of receptors will be provided. In the prefrontal cortex, the concomitant destruction of afferent noradrenergic fibers (NA) prevents the development of the denervation supersensitivity of DA receptors of the D1 type. In the nucleus accumbens, the development of the denervation supersensitivity of D1 receptors seems to be dependent on the state of activity of the cortico-nucleus accumbens glutamatergic projection. Finally, in cortico-limbic structures, the prolonged interruption of DA transmission leads to an increased density of 125I-neurotensin binding sites. These hetero-regulations reflect the existence of possible functional relationships between the two types of neuronal populations under investigation. As an example, it will be shown that some dysfunctions seen following the degeneration of the mesocortico-prefrontal and mesolimbic DA neurons disappear following the combined destruction of ascending NA neurons.

The present study was undertaken in order to develop a long-lasting antagonist of dopamine receptors with a technique applicable to other molecules. Haloperidol was immobilized on a macromolecular backbone (bovine serum albumin) with a coupling ratio of 14 molecules haloperidol per molecule of bovine serum albumin. The long-lasting blockade of dopamine receptor activity was evaluated with the d-amphetamine-induced rotation model in rats. Unilateral intracerebral infusion of the conjugate into the caudate nucleus induced a blockade of dopamine receptors which lasted more than six days. The conjugate was able to trigger a greater amphetamine-induced rotation rate then haloperidol alone. This ipsilateral rotation appeared after doses of conjugate lower than those needed for unilateral haloperidol intracaudate infusion. This compound will enable the reversible blockade of dopaminergic transmission in a restricted area of the brain (diffusion of the conjugate was studied in detail) over a period of time needed for a behavioural study without the drawbacks of chemical or mechanical lesions.

The effect of local injections of 6-hydroxydopamine (6-OHDA) into the lateral septum was tested in a paradigm known to lead to an energizing behavior, through a possible frustrative effect, induced by partial or total omission of reward in hungry rats. Biochemical assays in the septum showed that 6-OHDA reduced endogenous dopamine and, to a lesser extent, noradrenaline concentrations and left intact noncatecholaminergic neurons such as serotoninergic terminals. The first behavioral experiment was conducted in a double straight alley. The animals were submitted to three phases of testing with differing degrees of reinforcement: (a) an acquisition phase, in which the reinforcement was continuously delivered in the goal box of the two alleys, (b) a partial reinforced phase, in which animals received 50% partial reinforcement in the first alley and continuous reinforcement in the second alley, and (c) an extinction phase performed in one alley without any reinforcement. Animals with lesions ran faster for food than controls in the partial reinforcement or extinction situation, although there was no difference between the two groups in the acquisition phase of the continuous schedule of reinforcement or in the 50% reinforced trials of the partial reinforcement phase. The two groups also behaved similarly after the first six trials of the extinction phase. In a second experiment, the animals were tested in a lever-press conditioning task. Animals with lesions and control animals learned this task equally well, both with respect to the number of lever presses and the time to obtain a fixed number of food pellets.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationships between dopaminergic afferents and GABAergic neurones were studied at the electron microscopic level in the rat lateral septum and nucleus accumbens by coupling 6-hydroxydopamine degeneration and gamma-aminobutyric acid (GABA) immunocytochemistry. Degenerating fibres were observed in the two regions making synaptic contact with GABA-immunoreactive and non-labelled cell bodies and dendrites. It is concluded that dopaminergic afferents to the septum and the nucleus accumbens contact, among others, a population of GABAergic cells. A similar route of regulation of the basalo-cortical and septo-hippocampal cholinergic pathways by dopaminergic afferents is proposed.

The bilateral electrolytic lesion of the ventral mesencephalic tegmentum (VMT) induces, in the rat, behavioural deficits such as locomotor hyperactivity and disappearance of spontaneous alternation (‘VMT syndrome’). When a specific 6-hydroxy dopamine (6-OHDA) destruction of the dorsal noradrenergic (NA) ascending pathway was superimposed to an electrolytic lesion of the VMT, animals recovered a normal locomotor activity and the possibility to alternate. Since many studies indicate that the development of the ‘VMT syndrome’ is linked to the disruption of the dopaminergic (DA) meso-cortico-limbic transmission, it is proposed that the recovery observed is due to an interaction between NA and DA ascending systems in cortical and/or subcortical structures; noradrenergic innervation would have a permissive role on the expression of the ‘VMT syndrome’, possibly via a mechanism of heteroregulation of DA receptors by NA fibers.

Introduction: The performance of rats on the conditioned blocking test (CB) of learned inattention was measured in a two-way shuttle avoidance task after sham and dopamine (DA) - depleting lesions of the frontal cortex, the limbic septum, and the ventral tegmental area (VTA - A10). Methods: Animals were trained on two sessions with tone and / or light as conditioned stimuli. One group was trained with both stimuli on both sessions. A second group was trained on the first session with one stimulus and on the second with both stimuli. The blocking of conditioning to the added stimulus (b) was tested by presenting the stimuli (a and b) separately and measuring the blocking ration (avoidance to b/a + b) and response latencies. Results: 1/ No deficits were recorded on tests of sensory and motor ability; 2/ The VTA group alone showed a hyperlocomotor response to apomorphine treatment, - and did not acquire the avoidance response (i.e. did not learn the active avoidance task); 3/ The appearance of blocking in the septally lesioned group was delayed until the end of the 20-trial test session - then it was exaggerated; 4/ Blocking was mildly attenuated in the frontally lesioned group. 5/ Dopamine (DA) levels were depleted by about 80% and noradrenaline (NA) levels by, respectively, 20% and 50% in the frontal and septal regions. Figure 2 illustrates a) the CB impairment in the frontal group relative to sham controls, and b) the late development of "supr-blocking" in septally-damage animals. Figure 3 illustrates the results of the HPLC analysis for NA, DA and DOPAC in frontal cortex, septum, N. accumbens and striatum after 6-OHDA lesions (& vehicle treatment) in the frontal, septal, and VTA areas. Conclusions: The results show that the levels of DA activity, or rather the balance between the activity of DA and NA in frontal and limbic regions can contribute to efficient associative conditioning and / or the normal ability of rats not to attend to a redundant stimulus.

Embryonic dopaminergic neurons were implanted in the form of a cellular suspension in the nucleus accumbens previously deprived of its dopaminergic innervation by a local injection of 6-hydroxydopamine. The graft provided a dopaminergic reinnervation to the nucleus accumbens, the anteromedial striatum, the anteromedial frontal cortex and also, in some cases, of the septum. The pattern of reinnervation was specific for each structure and similar to the innervation provided by mesocorticolimbic dopaminergic neurons to these same structures in the normal animal. The graft restored the locomotor stimulatory action of amphetamine which was abolished in the lesioned controls. Hoarding behavior, which was disrupted following the lesion, was not reinstated by the graft alone. However, if the grafted neurons were stimulated by a small dose (0.2 mg/kg, i.p.) of (+)-amphetamine, hoarding reappeared in the grafted animals, while the same dose of amphetamine had no effect in the lesioned controls.

Anatomically, the nucleus accumbens (n.Acc.) has been considered as an interface between limbic and striatal sensorimotor structures. In the light of this hypothesis we have investigated the behavioral effects of destruction of the dopaminergic innervation of the n.Acc. after local injection of 6-hydroxydopamine. The following behavioral deficits were observed: (1) hypoexploration in a 4-hole box and 2-compartment field, (2) failure to inhibit response strategies either with positive reinforcement in a straight alley test or negative reinforcement in a passive avoidance test. These disturbances comprise a syndrome of perseveration, reduced distraction by irrelevant information, decreased behavioral switching and flexibility, and a paradoxical locomotor disinhibition in an emotional context. Very similar behavioral changes are found following lesions of limbic structures. In addition, these lesioned animals exhibit an enhanced latency to initiate motor responses. This deficit of behavioral initiation is classically observed in motor striatal disease. It is suggested that the n.Acc. is a key structure for the integration of limbic and striatal sensorimoto functions.

Using in vivo voltammetry, dopaminergic (DAergic) activity in the nucleus accumbens (ACC) was assessed following microinjection of DAergic agonists and antagonists in the amygdala (AMY). It was found that DAergic activity in the ACC was under the inhibitory influence of DAergic transmission in the AMY. Therefore, it can be suggested that there is a functional interdependence between the activity of these two DAergic pathways originating from the ventral mesencephalic region.

The effects of 6-OHDA lesions of dopamine terminals within the amygdala were investigated on i) (+) amphetamine-induced locomotor hyperactivity and ii) the acquisition of intravenous self-administration of (+) amphetamine. The lesioned rats exhibited increased locomotor activity in response to (+) amphetamine (0.75 and 1.5 mg/kg), but not at the higher dose (3 mg/kg). Self-administration of (+) amphetamine was also significantly greater than in controls. Biochemical analysis of the 6-OHDA-induced lesions of the amygdala indicated increased turnover of dopamine (DOPAC/DA) in the nucleus accumbens. We hypothesize that the behavioural effects were mediated by amygdala-accumbens interactions.