M. Gewiss

Balance of glutamate and dopamine in the nucleus accumbens modulates self-stimulation behavior after injection of cholecystokinin and neurotensin in the rat brain

Subpopulations of dopamine (DA) neurons in the ventral mesencephalon have been reported to contain cholecystokinin (CCK) and neurotensin (NT), giving rise to DA, DA/NT, NT/CCK and DA/CCK/NT projections. More precisely, colocalized DA/CCK neurons project mainly to the caudal part of the medial nucleus accumbens, whereas its rostral portion receives CCK and DA nerve terminal networks that are structurally independent. We investigated the respective effects of both CCK and NT on the intracranial self-stimulation behavior (ICSS) from the posterolateral hypothalamus after their direct administration into the lateral ventricle (ICV), into both portions of the nucleus accumbens, into the ventral tegmental area (VTA), and into the subiculum of the hippocampal formation (SUB). The ICV injection of 150 pmol CCK8 induced a decrease in the rate of ICSS. By contrast, the direct administration of 150 pmol CCK8 into the mediocaudal part of the nucleus accumbens induced an enhanced rate of ICSS while a similar injection into its rostral portion gave rise to a slight transient decrease of ICSS. When injected into the SUB, both CCK8 and glutamate produced decreased rates of ICSS at femtomolar doses one thousand-fold under the picomolar concentrations used for ICV injections. Neurotensin induced similar behavioral profiles to that observed after the ICV injection of CCK8 or into both portions of the nucleus accumbens. Neurotensin and CCK8 displayed opposite effects on ICSS when administered into the SUB or into the VTA, suggesting they may regulate ICSS most probably through different synaptic mechanisms and through different anatomical pathways.

Neuroleptic-like properties of cholecystokinin analogs: distinctive mechanisms underlying similar behavioral profiles depending on the route of administration

Rats were trained to discriminate vehicle injections from intraperitoneal injections of 3 micrograms/kg caerulein, a cholecystokinin (CCK) neuropeptide analog. The reward that reinforced correct choices was an electrical brain stimulation self-administered by bar pressing. Dose-response quantitative generalization was obtained by using 1 and 2 micrograms/kg caerulein. Qualitative generalization to the vehicle occurred after injecting 10, 20 and 200 micrograms/kg unsulfated CCK-8, 10, 20 and 200 micrograms/kg CCK-4, 5 micrograms/kg CCK-8 and 1 microgram/kg caerulein, neurotensin or bombesin and 200 micrograms/kg apomorphine or 320 micrograms/kg amphetamine. Total generalization to the caerulein cue was obtained with 20 micrograms/kg sulfated CCK-8 or gastrin 2-17, 25 micrograms/kg somatostatin, 50 micrograms/kg haloperidol and 2 mg/kg chlorpromazine. The previous 5 mg/kg injection of an antiemetic drug such as chlorhydrate of trimethobenzamide did not eliminate the discriminative properties of a subsequent injection of caerulein. Our data thus tend to show that IP injection of caerulein produces effects similar to those of IP neuroleptics.

Inhibition of enkephalin metabolism and activation of mu- or delta-opioid receptors elicit opposite effects on reward and motility in the ventral mesencephalon

The coexistence of endogenous opioid systems and dopaminergic neurones in the midbrain tegmental area suggests functional interactions between dopamine and enkephalins. Nevertheless, the identification of the specific opioid receptors associated with modulation of tegmental dopamine activity and its behavioural concomitants on motility and reward is far from clear, considering the mixed nature of the ligands usually employed. In this way, kelatorphan, a potent inhibitor of enkephalinases and selective agonists for mu- and delta-opioid receptor subtypes (DAGO and DSTBULET, respectively) were infused directly into the ventral tegmental area of the rat to study the role of endogenous enkephalins and opioid receptors in regulating spontaneous motor activity and intracranial self-stimulation behaviour. A greater increase in the rate of intracranial self-stimulation behaviour was found after activation of mu-opioid receptors in the ventral tegmental area, as compared to activation of delta-opioid receptors, whereas enhancement of endogenous enkephalins by inhibiting their metabolism through kelatorphan, reduced the rate of intracranial self-stimulation behaviour. On the contrary, spontaneous motor activity was reduced by the delta-opioid receptor agonist, whereas kelatorphan increased the movements of the animal. Taken together, these results show that inhibition of the metabolism of enkephalins in the ventral tegmental area decreased positive reinforcement from the lateral hypothalamic medial forebrain bundle and increased spontaneous movements. On the contrary, activation of both mu- or delta-opioid receptors in the ventral tegmental area significantly increased self-stimulation and decreased spontaneous motor activity, supporting the view that different mechanisms underlie the behavioural effects, resulting from enhancement of endogenous enkephalins and from activation of specific opioid receptors in the ventral mesencephalon.

Similar effect of caerulein on intracranial self-stimulation in vagotomized and non-vagotomized rats.

Electrical stimulation eliciting self-stimulation behavior from postero-lateral hypothalamic implanted electrode was controlled by factors that control normal feeding. In this idea, lateral hypothalamic stimulation possessed an appetite whetting property and this is experienced as rewarding. The octapeptide cholecystokinin, a gut hormone, has been experimented upon to produce the complete behavioral sequence of satiety in rats. We observed that an i.p. injection of caerulein (an analog of cholecystokinin) did decrease, in a dose-related manner, the rate for brain self-stimulation. However, a similar effect on the rate of ICSS was measured after a bilateral cut of the vagus nerve at a subdiaphragmatic level. This result suggests that the decreasing effect on ICSS after an i.p. injection of caerulein is not strictly related to feeding. We interpret the decrease of reinforcement induced by caerulein as the action of a general satiety for any object presenting a rewarding value for behavior.

Regional amines levels in the rat brain following intra-accumbens cholecystokinin and intraperitoneal amphetamine pre-treatment

Cholecystokinin octapeptide (CCK8) coexists with dopamine (DA) in a subpopulation of mesolimbic DA neurons including the projections to the nucleus accumbens. In this structure, CCK8 has been reported to exert agonist-like or antagonist-like effects on DA-mediated behaviours and on amphetamines locomotor-activating effects in rodents. These findings raise the possibility that CCK8 plays a role in modulating the neurochemical mechanisms underlying the effects of DA and amphetamine in the mesolimbic DA system. The purpose of this study was to determine regional tissue monoamine levels in the rat brain and their modulation following injection of CCK8 in the nucleus accumbens. The same paradigm was used to determine the effects of this octapeptide on changes in amine levels induced by amphetamine administered intraperitoneally. DA, norepinephrine (NE), serotonin (5-HT) and their primary metabolites, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured using a reversed-phase ion pair high-pressure liquid chromatography system with electrochemical detection (HPLC-ED). Frontal cortex displayed the highest DOPAC/DA ratio and the lowest DOPAC/HVA ratio in contrast to the olfactory tubercle. The intraperitoneal injection of amphetamine (1 mg/Kg) followed by the intra-accumbens administration of 0.15M saline decreased the levels of DOPAC and increased DA, 5-HT and 5-HIAA both in nucleus caudatus and nucleus accumbens. The DA agonist induced a decrease in the level of NE in olfactory tubercle and frontal cortex. The direct administration of CCK8 (300 pmol) into the nucleus accumbens decreased the level of DA, DOPAC and 5-HT mainly in olfactory tubercle and nucleus accumbens itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Preference and aversion for brain stimulations estimated by the conditioned place preference.

Rats implanted with chronic electrode into the medial forebrain bundle at the level of the hypothalamus (which elicited self-stimulation behaviour) display conditioned place preference after repeated stimulations of this area; conversely rats implanted into the mesencephalic dorso-medial tegmentum (which elicited switch-off behaviour) present conditioned place aversion after such repeated stimulations. Furthermore rats implanted in these two area without exhibiting self-stimulation or switch-off behaviours also display preference or aversion for the location paired with the brain stimulations. It was thus hypothesized that the conditioned place preference procedure seemed to present a higher sensitivity than the bar pressing procedures to detect preference or aversion for brain stimulation. Moreover the activation of the medial forebrain bundle which was associated with positive affect is more effective for a long term retention of the preferred location than midbrain periventricular reticular activation which induces a negative affect.

Differential effects of caerulein and bombesin on the ethanol intake in the rat.

Male Wistar rats were allowed to drink either water or water mixed with ethyl alcohol (4%, 8% and 12%) as part of a water-deprived procedure. The decapeptide caerulein (1, 3 and 6 micrograms/kg i.p.), a cholecystokinin analog, decreased the intake of ethanol while the consumption of tap water remained unchanged in a choice paradigm. The addition of quinine (a bitter substance) in drinking bottles did not significantly modify the fluid consumption while the i.p. injection of caerulein produced a significant decrease in the consumption of the saccharin containing bottle. The i.p. administration of bombesin (10 and 20 micrograms/kg) failed to modify the intake of water or ethanol solution in water-deprived animals. Interpretations are given in terms of the action of the cholecystokinin analog on differences in the taste intensity induced by the beverage or in terms of a direct consequence of the caerulein-induced decreased gastric emptying effect leading to an accumulation of ethanol in the gut.

Cortical Microvascular Changes in Chronological Aging, Cortical Insults and Chronic Alcohol-intoxication in Rats - Effects of Antihypoxic Drug On These Phenomena

Chronic alcohol pulmonary exposure in rats produced a cortical hypervascularization from one to four weeks after the onset of the alcoholization procedure. This alcohol-induced cortical hypervascularization, resembling closely the enhanced cortical vascular network observed in chronologically aged rats as well as around a lesion-induced cavity performed on the cortex, was significantly reduced by a concomitant treatment with Sabeluzole, a chemically benzothiazol derivative with antihypoxic and antiischaemic properties. The blood alcohol level of rats treated with the antihypoxic agent remained stable and constant at a mean level of 1 g/l during a whole 2-week-alcoholization duration in contrast to that of untreated rats which was directly related to the increased alcohol concentration of the atmosphere insufflated in the alcoholization chamber. Finally, a free-choice paradigm achieved after the chronic intoxication also revealed that Sabeluzole-treated rats chose to drink less alcohol as compared to untreated rats suggesting Sabeluzole well modulated the alcohol-induced behavioral preference.

Effects of Variations of Reinforcement Magnitude On Alcohol Discrimination Using Intracranial Stimulation As the Reinforcer

Male Wistar rats were trained to discriminate intraperitoneal injections of 2 g/kg of alcohol from 0.5 g/kg alcohol injections. Intracranial stimulation in the posterolateral area of the hypothalamus served as the reinforcer according to a FR 10 schedule of bar pressing. After discrimination between the two alcohol doses had been established, the response-reinforcement contingency was modified by progressively increasing the intensity of the intracranial stimulation. The results indicate that the generalization gradient varies with the number of reinforcements. The more the lever associated with a training dose was reinforced, the more the ED50 had the tendency to approach this dose. Our paradigm, by using electrical brain reinforcer, allowed to deliver in an equal manner the reinforcement schedule in order to obtain equal performances and equal number of reward received.

Prefrontal cortex aspiration in pups and juvenile rats: behavioural changes and recovery of function.

Male Wistar rats sustaining prefrontal cortex aspiration or sham operation at 6 days or 30 days of age were submitted to the following behavioural tests: open-field, acquisition and retention of two-way active as well as passive avoidance tasks. In the open-field the locomotor activity proved enhanced in all the aspirated animals and this enhancement lasted for 30 days. In the two-day active avoidance task, an acquisition deficit was observed in both aspirated groups; but when retrained one month later, they were able to acquire the avoidance task like sham-operated rats and no difference appeared between the groups aspirated at 6 or at 30 days of age. Concerning the passive avoidance task, no difference could be detected between aspirated and sham-operated animals of both groups except that the rats aspirated at an early age (6 days) seemed to display a better avoidance ability in the retention test. These behavioural alterations (hyperactivity and impairment of the acquisition of the 2-way active avoidance) resulted from the prefrontal cortex aspiration, at whatever age this aspiration was performed (6 days or 30 days). They disappeared after a postoperative recovery period of about one month, as evidenced by this longitudinal study.