Interaction between endogenous opioids and dopamine within the nucleus accumbens.
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Animals↗
Biomedical subjects
L Stinus
Publications and source records attributed to L Stinus.
Behavioral sensitization induced by psychostimulants or stress: search for a molecular basis and evidence for a CRF-dependent phenomenon.
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Amphetamine↗
Neural substrates of opiate withdrawal.
Drug withdrawal is an integral part of most types of dependence and, to a large extent, opiate withdrawal has been considered the prototypic, classic measure of opiate dependence. The opiate withdrawal syndrome is characterized by multiple behavioral and physiological signs such as behavioral activation, ptosis, diarrhea, 'wet dog' shakes and motivational dysfunction, which may be represented in the CNS at multiple sites. It seems that the activating effects associated with the opiate withdrawal syndrome may be mediated by the nucleus locus coeruleus. Other signs such as wet dog shakes may involve sites in the hypothalamus important for temperature regulation. Certain other signs such as diarrhea and lacrimation may be dependent on peripheral opiate receptors. The motivational aspects of opiate withdrawal as demonstrated by the aversive stimulus effects or negative reinforcing effects (e.g. disrupted lever-pressing for food and place aversions) may involve those elements of the nucleus accumbens that are known to be important for the acute reinforcing effects of opiates in nondependent rats. Evidence exists at the cellular and molecular level for both 'within-system' and 'between-system' adaptations to dependence. Elucidation of the neural networks, cellular mechanisms and molecular elements involved in opiate withdrawal may provide not only a model for our understanding of the adaptive processes associated with drug dependence but also of those associated with other chronic insults to CNS function.
Animals↗
Role of different brain structures in the expression of the physical morphine withdrawal syndrome.
The aim of this study was to investigate the neuroanatomical regions implicated in the expression of the physical signs of morphine withdrawal by using local intracerebral injections of methylnaloxonium in dependent rats. Guide cannulas were implanted and aimed at the lateral ventricle, nucleus accumbens, central amygdala, anterior hypothalamus, medial thalamus, periaqueductal gray matter, locus coeruleus and nucleus raphe magnus. After surgery, rats were made physically dependent by s.c. implantation of two 75-mg morphine pellets. Methylnaloxonium, a quaternary derivative of naloxone (31-1000 ng), was administered 72 hr after pellet implantation. Methylnaloxonium administered i.c.v. induced a withdrawal syndrome similar to systemic naloxone, although several signs such as diarrhea, salivation, lacrimation and rhinorrhea did not appear, suggesting possible peripheral mediation. The most sensitive site for methylnaloxonium-precipitated withdrawal was the locus coeruleus. Signs such as jumping, rearing and locomotor activity were particularly frequent after methylnaloxonium injections into the locus coeruleus. Rearing and locomotor activity were also strongly increased after methylnaloxonium administration into the periaqueductal gray matter. Wet dog shakes were mainly observed after methylnaloxonium administration into the anterior preoptic hypothalamus and nucleus raphe magnus. Injections of methylnaloxonium into the amygdala produced a weak withdrawal syndrome, and the nucleus accumbens and medial thalamus were the least sensitive structures. These results suggest that the locus coeruleus, and secondarily the periaqueductal gray matter, play an important role in the precipitation of the physical signs of opiate withdrawal, mainly in the expression of its motor component. The expression of other signs of withdrawal appear to be multisite determined.
Animals↗
Transcutaneous electrical stimulation with Limoge current potentiates morphine analgesia and attenuates opiate abstinence syndrome.
Transcutaneous electrostimulation is a somewhat controversial technique used in the management of the opiate withdrawal syndrome. We report an animal study of a particular transcutaneous electrostimulation called transcutaneous cranial electrostimulation, based on a technique used for many years on heroin addicts for the rapid severance of their addiction, which has been validated in a clinical setting by a double-blind trial. This technique involves the application of an intermittent high-frequency current (Limoge's current). Our experimental data show that this transcutaneous cranial electrostimulation increases morphine analgesia by threefold on the tail flick latency measure and produces a 48% attenuation of the abstinence syndrome observed after abrupt cessation of morphine administration. These results were obtained using a double-blind paradigm.
Animals↗
Intra-accumbens implants of embryonic dopaminergic neurons reverse the behavioral supersensitivity to opiates evoked by lesion of the mesolimbic dopaminergic pathway.
The ascending mesotelencephalic dopaminergic systems of rat pups of 3 days of age were bilaterally lesioned using 6-hydroxydopamine injected at the level of the lateral hypothalamus. A sub-group of lesioned pups received, 5 days after the lesion, a dopamine neuron-rich cell suspension graft implanted bilaterally into the striatum and nucleus accumbens. Behavioral tests were conducted 6 months later. The lesion induced an increase in the locomotor activation induced by D-Ala2-Met5-enkephalinamide injected into the nucleus accumbens (2.5 micrograms/side) as compared to the activation observed in control animals. Locomotor activation by systemic apomorphine (0.1 mg/kg s.c.) was also increased while that induced by amphetamine (1.5 mg/kg i.p.) was abolished. The presence of DA neuron implants reversed each of these post-lesion modifications.
Amphetamine↗
Central administration of a CRF antagonist blocks the development of stress-induced behavioral sensitization.
This experiment examined the effects of intracerebroventricular (i.c.v.) administration of a corticotropin-releasing factor (CRF) antagonist on the development of stress-induced sensitization of the behavioral response to amphetamine. Restraint stress was found to enhance both the locomotor response to a s.c. injection of saline and the intensity of stereotypy induced by a s.c. injection of 3.0 mg/kg D-amphetamine. Both of these effects of restraint stress were severely attenuated in rats that had been injected with the CRF antagonist prior to restraint stress. This result is compatible with the hypothesis that CRF is critically involved in initiating behavioral and physiological responses to aversive stimuli.
Amphetamines↗
Critical role of the hypothalamic pituitary adrenal axis in amphetamine-induced sensitization of behavior.
Behavioral sensitization can be observed with repeated administration of amphetamine where the intensity of motor stimulation increases over time. The process of sensitization has been well characterized, however, the neurochemical mechanisms that are critical for the development of sensitization are not known. In the present study, the role of the hypothalamic pituitary adrenal axis (HPA) in the development of behavioral sensitization to amphetamine was explored by pretreating rats with an intravenous administration of an antiserum to corticotropin-releasing factor in a volume that has been shown to block significantly stress- and cocaine-induced activation of the HPA. Four groups of eight rats were pretreated intravenously with either heparinized saline or CRF antiserum and subcutaneously with saline or d-amphetamine in a balanced design. The rats were then returned to their home cages and left undisturbed for seven days after which they were given three consecutive behavioral tests with saline SC, 0.75 mg/kg d-amphetamine SC, and 3.0 mg/kg d-amphetamine SC. The rats pretreated with intravenous CRF antiserum showed a significant attenuation of the development of d-amphetamine-induced sensitization but the antiserum did not alter the magnitude of the behavioral response to the initial, sensitizing dose of d-amphetamine. These results suggest that activation of the hypothalamic pituitary adrenal axis may be of critical importance to the development of behavioral sensitization to amphetamine.
Animals↗
Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal.
Specific brain sites for the opiate abstinence syndrome syndrome have been elusive to delineate, and the classic overt signs of withdrawal such as wet dog shakes, ptosis and teeth chattering appear to be widely represented in the brain. Using a more general motivational test involving a disruption of operant behavior in dependent rats, the brain site most sensitive to the response disruptive effects of intracerebral administration of the opiate antagonist, methylnaloxonium, was the region of the nucleus accumbens, a site also implicated in the acute reinforcing properties of opiates. This disruption of operant responding was hypothesized to reflect the aversive properties of opiate withdrawal. The present study directly tested that hypothesis by exploring whether intercerebral administration of methylnaloxonium produced aversive stimulus effects as measured by the formation of place aversions. Rats implanted intracerebroventricularly or with bilateral cannulae aimed at the medial dorsal thalamus, periaqueductal gray, ventral tegmental area, amygdala or nucleus accumbens were made dependent on morphine by subcutaneous implantation of two 75-mg morphine pellets. The animals were then subjected to place aversion training by pairing of a distinct environment (one of three arms of a three-armed box with distinct texture, markings and smell) with a single injection of methylnaloxonium intracerebroventricularly or intracerebrally. Results showed that at high doses of methylnaloxonium (1000-2000 ng) all sites produced a place aversion. However, lower doses (250-500 ng) produced a significant brain site selectivity with the region of the nucleus accumbens the most sensitive. Observational measurements taken during the postinjection period with the high dose of methylnaloxonium showed that agitation was particularly observed following methylnaloxonium administration into the nucleus accumbens and periaqueductal gray.(ABSTRACT TRUNCATED AT 250 WORDS)
Amygdala↗
Behavioral sensitization to amphetamine is dependent on corticosteroid receptor activation.
Thirty rats received 3 amphetamine injections (1.5 mg/kg, s.c.) 6 days apart and the locomotor response was measured. One day before the second injection they were adrenalectomized or sham operated. Corticosteroid replacement treatments (500 micrograms/kg, s.c.) were given every evening. Sham adrenalectomized animals exhibited behavioral sensitization to successive injections of amphetamine, which was prevented by adrenalectomy. Treatment with corticosterone or deoxycorticosterone did not reverse the effect of adrenalectomy, whereas dexamethasone completely restored and even potentiated sensitization to amphetamine. These results demonstrate that corticosteroids are necessary for sensitization of the dopaminergic system to occur and that they most probably act through the type II (or glucocorticoid) receptor subtype.
Adrenal Glands↗
Substance P, neurotensin and enkephalin injections into the ventral tegmental area: comparative study on dopamine turnover in several forebrain structures.
A comparison of dopaminergic (DAergic) turnover changes in several forebrain structures was investigated after local injection of substance P (SP), neurotensin and D-Ala-Met-enkephalin (DALA) into the ventral tegmental area (VTA). A dose-dependent increase in the DOPAC/DA ratio was elicited by all 3 peptides in the nucleus accumbens and the septum. DAergic turnover was enhanced in the anteromedial prefrontal cortex only after SP injection and in the amygdala only after neurotensin injection. In the anteromedial striatum as well as in the posterolateral striatum, a significant increased DOPAC/DA ratio was observed following SP and DALA injection into the VTA. No significant changes were noticed in the olfactory tubercles after injection of the 3 peptides in the VTA. From these results, it appears that each peptide induced a different profile of DAergic activation. Taking into account the facilitatory role of the DA neurons at the level of the forebrain integrative structures, the differential activation may explain the difference in behavioral response obtained after injection of the 3 peptides in the VTA.
Animals↗
Differential mechanisms in the acquisition and expression of heroin-induced place preference.
These experiments examined the neurochemical mechanisms involved in the development and expression of place conditioning produced by heroin. Conditioned place preferences (CPP) lasting up to 8 weeks were obtained with doses of 50-1000 micrograms/kg heroin, using a regimen shown not to produce physical dependence. Naloxone pretreatment (50 micrograms/kg) during conditioning prevented the acquisition of heroin-induced CPP, but when given only on the test day, naloxone (50 or 1000 micrograms/kg) did not prevent the expression of heroin CPP. Clonidine disrupted the establishment of heroin CPP at 20 micrograms/kg, but disrupted its expression only at debilitating doses (100 and 200 micrograms/kg). Pimozide attenuated the acquisition (100 micrograms/kg) and expression (250 micrograms/kg) of heroin CPP. Together, these results support a role for opioid and catecholamine systems in the acquisition of heroin reinforcement, but they suggest that once heroin CPP is established, its expression in opiate-free subjects is not opiate receptor mediated and is relatively refractory to pharmacological treatments which disrupt acquisition. The data challenge the notion that the conditioned effects of opiates in drug-free animals are related to the release of endogenous opioids, and they also may help to explain why naloxone and clonidine are ineffective in the treatment of opiate addiction.
Animals↗
Neurotensin, substance P, neurokinin-alpha, and enkephalin: injection into ventral tegmental area in the rat produces differential effects on operant responding.
The neuropeptides neurotensin, substance P, neurokinin-alpha (substance K), and met-enkephalin are present endogenously in the ventral tegmental area (VTA), site of the A10 dopaminergic (DA) cell bodies. In the present study these four peptides were injected bilaterally into the VTA in the rat, and the effects on operant behavior were assessed. Cannulae aimed at the VTA were implanted in four groups of animals, which had been trained to bar-press for food reward on a fixed-interval, 40-s schedule. A fifth group, in which the effects of systemically administered amphetamine were assessed, was also tested. Response rate across the interval was measured, and the index of quarter-life was taken as an indication of the temporal pattern of responding. In addition, a rate-dependency analysis was carried out for all data. Neurotensin (NT, 0.0175, 0.175, 0.5 micrograms in 1 microliter) dose-dependently decreased response rates without affecting quarter-life, and reduced the number of reinforcements obtained. Substance P (SP, 0.1, 1.0, 3.0 micrograms) did not affect responding, and neurokinin-alpha (NKA, 0.1, 1.0, 3.0 micrograms) induced a small increase in responding. Quarter-life was not affected by SP or NKA, but responding on the non-reinforced lever was significantly increased by both peptides. d-Ala-met-enkephalin (DALA, 0.01, 0.1, 1.0 micrograms) induced a dose-dependent increase in responding which was also rate-dependent, and reduced quarter-life. DALA effects were similar to the classic pattern of responding observed after systemic amphetamine. These results suggest that although all these peptides elicit behavioral activation and may affect DA neuronal activity, the behavioral responses can be differentiated with respect to operant behavior.
Animals↗
Chronic flupentixol treatment potentiates the reinforcing properties of systemic heroin administration.
The behavioral effects of systemic heroin administration were examined in rats subjected to flupentixol impregnation prior to and during behavioral testing. In the first experiment, the dose of heroin required to produce a place preference was determined in two groups of rats, one of which had received chronic flupentixol decanoate (12 mg/kg, sc, every 10 days for 6 weeks) and the other which had received the palm oil vehicle during the same time period. It was found that whereas 60 micrograms/kg of heroin was required to produce a place preference in control rats, only 7.5 micrograms/kg was sufficient to do so in chronic neuroleptic-treated rats. In a second experiment, the locomotor activating effect of heroin was evaluated in two groups of rats that had been subjected to the same chronic regimen as in Experiment 1. Locomotor activity was enhanced in both groups following 120 micrograms/kg heroin, whereas 30 micrograms/kg was ineffective in either group. Finally, it was found that neuroleptic-treated, but not control, rats rapidly learned to self-administer intravenous infusions of an unusually low dose of heroin (4 micrograms) and to discriminate these infusions from vehicle infusions. Together, these data show that chronic dopamine (DA) receptor blockade produces a marked increase in the sensitivity to the reinforcing and discriminative stimulus properties of systemic heroin administration and that this increase is not attributable to heroin-induced locomotor activation. The results are discussed in terms of the role of DA systems in opiate reinforcement processes.
Animals↗
Aversive properties of opiate receptor blockade: evidence for exclusively central mediation in naive and morphine-dependent rats.
The motivational effects of exclusively peripheral or central opiate receptor blockade were studied using place conditioning. Place aversions were observed with intraventricular (i.c.v.) methylnaloxone (MN) in both naive (200-1000 ng) and morphine-dependent rats (50-500 ng). Subcutaneous MN (0.03-10 mg/kg) was ineffective in naive rats; in dependent rats a small aversion was seen at the highest dose. Place aversions were not necessarily associated with behavioral signs of withdrawal. The data suggest that the aversive properties of opioid receptor antagonism are centrally mediated in both naive and dependent rats, and that their enhancement in morphine-dependent subjects results from a sensitized central mechanism rather than from the recruitment of a peripheral component.
Animals↗
Effects of two alpha 2 agonists, rilmenidine and clonidine, on the morphine withdrawal syndrome and their potential addictive properties in rats.
The interaction between adrenergic systems and opiate receptors or neuronal systems linked to these receptors has been previously demonstrated. For this reason, clonidine can be used to reduce withdrawal syndrome to opiates. Rilmenidine (S 3341) is a new agonist of alpha 2 adrenoceptors. The purpose of these experiments was to compare the effects of rilmenidine and clonidine on morphine withdrawal syndrome and their potential addictive properties in the rat. Rats were made morphine-dependent by repeated intraperitoneal (i.p.) administration of increasing doses of morphine. Withdrawal was precipitated by injecting naloxone subcutaneously. Withdrawal scores were evaluated for 10 minutes. Clonidine (0.05, 0.1 and 0.2 mg/kg, i.p.) and rilmenidine (5 and 10 mg/kg, i.p.) significantly reduced overall withdrawal scores. Addictive potential was evaluated in the rat by a place preference test after the following treatments (mg/kg, i.p.): rilmenidine 0.1 to 5, clonidine 0.01 to 0.5, heroin 0.12, and d-amphetamine 1.5. Rilmenidine did not modify the time spent in the conditioned side at doses of 0.1 to 1 and 5 mg/kg, but increased it at 2.5 mg/kg (+25%). In contrast, a reinforcing effect was induced by clonidine (+21%, +43%, +34% at 0.1, 0.25, 0.5 mg/kg), heroin (+39%) and amphetamine (+52%). In conclusion, rilmenidine as well as clonidine reduced the morphine withdrawal syndrome. However, rilmenidine was 100 times less active than clonidine. Clonidine, heroin and d-amphetamine have clear reinforcing properties. Rilmenidine did not exhibit dose-dependent reinforcing properties and the isolated effect noted after 2.5 mg/kg is difficult to interpret because it is minor and is not observed with a higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Agonists↗
d-Ala-met-enkephalin injection into the ventral tegmental area: effect on investigatory and spontaneous motor behaviour in the rat.
The mesolimbic dopamine (DA) system, originating in the ventral tegmental area and projecting to limbic forebrain regions, plays a crucial role in mediating several important aspects of behaviour. Proximal to these DA neurons are enkephalin-containing nerve fibers. In an attempt to characterize the behavioural role of enkephalinergic transmission in the VTA, the present experiment examined in detail the investigatory and motor responses to microinfusion of d-ala-met-enkephalin (DALA), a long lasting analogue of enkephalin, into the ventral tegmental area (VTA). Injections into the substantia nigra (SN) and the hippocampus (HPC) were also performed as controls for site specificity. The behavioural apparatus consisted of an eight-hole box monitored by a video camera. Four doses of DALA were injected in the VTA (0.05, 0.1, 1 and 2.5 micrograms/microliters bilaterally in 1 microliter volume) and one dose in the SN and HPC (0.1 microgram/microliter bilaterally in 1 microliter volume). The effect of DALA injections in the VTA was characterized by an inverted U-shape dose-effect curve. The low doses (0.05 and 0.1) induced an increase in the frequency of hole visits accompanied by a decrease in the mean duration of visits, whereas the highest doses induced a decrease in hole visit frequency. Low doses of DALA had no effect on strategy or organization of exploration, whereas the high doses produced decreased switching between holes. After low doses of DALA, locomotor activity at the periphery of the testing box was not significantly affected but locomotor activity in the centre was increased. After high doses of DALA, locomotor activity in the center and at the periphery of the box were decreased. Frequency of rearing was either not affected or decreased by DALA treatment. DALA injected in the SN resulted in a small increase in frequency of hole visits and did not affect rearing and locomotor activity. DALA injection in the HPC had no effect on investigatory and spontaneous motor behaviour. The results are discussed in terms of a modulatory role of endogenous enkephalin on mesolimbic dopamine neurons.
Animals↗
Amphetamine, apomorphine and investigatory behavior in the rat: analysis of the structure and pattern of responses.
In the present experiments, the effects of a wide range of doses of d-amphetamine and apomorphine were studied on investigatory behavior in an automated eight-hole box. Amphetamine (0.125, 0.25, 0.5, 1.0, 3.0, 5.0 mg/kg) increased frequency and total duration of responses, and decreased mean duration in a dose-dependent manner. The strategy and organization of responses, as measured by the order of hole-visits and hole-switching, were unchanged at lower doses of amphetamine but were altered at higher doses. Perseverative hole-poking was observed at the highest dose (5.0) as indicated by increased number of hole-pokes per hole-visit. Apomorphine (0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 mg/kg) decreased mean duration of responses, but in contrast to amphetamine markedly diminished frequency. Locomotor activity was also measured at all doses of both drugs. Our observations indicate that these two stimulant drugs both of which increase motor activity, have markedly different effects on investigatory responses. It is likely that amphetamine increases prepotent response tendencies (i.e., hole-poking), although this does not necessarily reflect enhanced exploration. Further, the results obtained with amphetamine support predictions made by the Lyon-Robbins behavioral theory of amphetamine effects.
Amphetamine↗