CB1 receptor antagonist precipitates withdrawal in mice exposed to Delta9-tetrahydrocannabinol

Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with Delta9-tetrahydrocannabinol (Delta9-THC) twice a day for 1 wk. SR141716A administration after the last Delta9-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a decrease in normal behavior such as grooming and scratching. Of the three Delta9-THC regimens tested, daily Delta9-THC injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in Delta9-THC-treated mice as compared with vehicle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids.     

Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR141716A

We evaluated delta-9 tetrahydrocannabinol (Delta9-THC), delta-8 tetrahydrocannabinol (Delta8-THC), CP55,940 (CP55), 1-deoxy-11-hydroxy-Delta8-THC-dimethylheptyl (deoxy-HU210, a CB2-selective cannabinoid that also binds the CB1 receptor) and the endogenous cannabinoid anandamide (ANA) via i.c.v. and/or intrathecal (i.t.) routes of administration, alone and in combination with SR141716A (SR), a CB1 antagonist, using the tail-flick test. Our studies were performed in order better to characterize potential diversity in interactions of the cannabinoids with the cannabinoid (CB1) receptor. When SR was administered i.c.v. or i.p. before Delta9-THC, Delta8-THC or CP55 (i.c.v. or i.t.), SR was a potent antagonist and the blockade was complete (AD50 相似文献   

Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids

The intravenous administration of the psychoactive constituent of marijuana, delta9-tetrahydrocannabinol (delta9-THC) (62.5-1000 microg/kg), and the synthetic cannabinoid agonist WIN 55212,2 (WIN) (62.5-500 microg/kg), produced a dose-related increase in the firing rate and burst firing in the majority of antidromically identified meso-prefrontal dopaminergic neurons. In a restricted number of neurons (n=4), WIN administration did not increase firing rate but produced an increment of bursting activity. These effects of the cannabinoids were reversed by the intravenous administration of SR 141716 A, a selective cannabinoid antagonist (1 mg/kg), per se ineffective to modify the electrical activity of dopaminergic neurons. The results indicate that stimulation of cannabinoid CB1 receptors produces an activation of meso-prefrontal dopaminergic transmission. Considering that supranormal stimulation of D1 dopamine receptors in the prefrontal cortex has been shown to impair working memory, the present results suggest that the negative effects of cannabinoids on cognitive processes might be related to the activation of dopaminergic transmission in the prefrontal cortex.     

Discriminative Stimulus Effects of the Cannabinoid Antagonist, SR 141716A, in Δ?-Tetrahydrocannabinol-Treated Rhesus Monkeys.

This study examined whether the cannabinoid antagonist, SR 141716A, could be established as a discriminative stimulus in rhesus monkeys treated with Δ?-tetrahydrocannabinol (Δ?-THC). Stimulus control was established with SR 141716A (1.0 mg/kg) in 3 Δ?-THC-treated monkeys (1.12 mg/kg/day) in 113-124 sessions. The SR 141716A discriminative stimulus was dose related, attenuated by an acute injection of Δ?-THC, and not mimicked by cocaine or ketamine. SR 141716A-appropriate responding occasioned by temporary discontinuation of Δ?-THC treatment was attenuated by Δ?-THC and not ketamine. The SR 141716A discriminative stimulus in Δ?-THC-treated monkeys appears to be mediated by cannabinoid receptors and could be related to Δ?-THC withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Time course of the effects of different cannabimimetics on prolactin and gonadotrophin secretion: evidence for the presence of CB1 receptors in hypothalamic structures and their involvement in the effects of cannabimimetics

Several reports have demonstrated that (-)-delta9-tetrahydrocannabinol (delta9-THC) and arachidonylethanolamide [anandamide (AEA)] were able to inhibit prolactin (PRL) secretion from the anterior pituitary gland in male rodents, whereas ovarian phase-dependent effects were seen in females. However, in most of these studies, the analysis of PRL levels was performed at times longer than 30 min after cannabinoid administration. In the present study, we examined the time course of the effects of three different cannabimimetics, delta9-THC, AEA, and AM356 (R-methanandamide), a more stable analog of AEA, on PRL and gonadotrophin secretion in male Wistar rats. In addition, we characterized the presence of cannabinoid receptors in hypothalamic structures related to neuroendocrine control and studied their potential involvement in the effects of cannabimimetics. We found that the three compounds decreased plasma luteinizing hormone (LH) levels, although only the effects of delta9-THC were statistically significant. The inhibitory effect was already apparent at 40 min after administration, but only in the case of delta9-THC did it persist up to 180 min after administration. No significant changes were seen in plasma follicle-stimulating hormone (FSH) levels after the administration of any of the three different cannabimimetics at any of the four times analyzed. Both AEA and AM356 produced a significant decrease in plasma PRL levels, which appeared at 20 min after administration and persisted up to 60 min, waning after this time. Interestingly, the time course of the effect of delta9-THC resembled that of AEA and AM356 only during the later part of the response, because delta9-THC produced a marked increase in plasma PRL levels at 20 min, no changes at 40 min and a decrease from 60 min up to 180 min. In additional experiments, we tried to elucidate which of these two phases observed after delta9-THC administration was mediated by the activation of cannabinoid receptors. These receptors are present in hypothalamic structures related to neuroendocrine control, with the highest densities in the arcuate nucleus (dorsal area) and the medial preoptic area, and the lowest in the lateral hypothalamic area, although none of these regions exhibited high densities for this receptor as compared with classical regions containing cannabinoid receptors, such as the basal ganglia. The activation of these receptors by delta9-THC seems to be involved in the inhibitory phase of the effect of this cannabinoid on PRL release, but not in the early stimulation; when these receptors were blocked with a specific antagonist, SR141716, the stimulation by delta9-THC was still observed, but the late inhibition was abolished. In summary, AEA and AM356 markedly decreased PRL release and slightly decreased LH secretion, with no changes on FSH release. delta9-THC also produced a marked inhibition of LH secretion, but its effects on PRL were biphasic with an early stimulation not mediated by the activation of cannabinoid receptors, followed by a late and cannabinoid receptor-mediated inhibition. Their site of action may well be the hypothalamic structures related to neuroendocrine control, which contain a small, but probably very active, population of cannabinoid receptors.     

The competence-related abilities of women criminal defendants

Delta9-tetrahydrocannabinol (delta9-THC) elicits antinociception in rodents through the central CB1 cannabinoid receptor subtype. In addition. Delta9-THC stimulates the release of dynorphin-related peptides leading to kappa-opioid spinal antinociception. In this work we describe the effect of a mixture of thiorphan (a neutral endopeptidase EC3.4.24.11 inhibitor) and bestatin (an aminopeptidase inhibitor), administered i.c.v., on the antinociceptive effect of peripherally administered delta9-THC in mice. As in the case of morphine or DAMGO ([D-Ala2.N-Me-Phe4,Gly-ol]enkephalin), a mu-selective opioid receptor agonist, the mixture of enkephalin-degrading enzyme inhibitors also enhanced the antinociceptive effect of delta9-THC. This effect was blocked by the CB1 cannabinoid receptor antagonist, SR-141,716-A, as well as by naloxone. The kappa-opioid receptor antagonist nor-binaltorphimine, administered i.t., also antagonized the effect of this combination. Similar results were obtained with the mu-opioid receptor antagonist beta-funaltrexamine after i.c.v. administration. These results demonstrate the involvement of both mu-opioid supraspinal and kappa-opioid spinal receptors in the interaction of both opioid and cannabinoid systems regulating nociception in mice.     

Assessment of anandamide interaction with the cannabinoid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain

Anandamide is the newly discovered endogenous cannabinoid ligand that binds to brain cannabinoid receptors and shares most, but not all, of the pharmacological properties of delta 9-THC. Therefore, this study was undertaken to determine whether its interaction with the CB1 receptor in brain was identical to that of delta 9-THC. Anandamide depressed spontaneous activity and produced hypothermia, antinociception and immobility in mice after i.v. administration. However, none of these effects was blocked by pretreatment with the selective CB1 antagonist, SR 141716A. However, the metabolically stable analog 2-methyl-2'-fluoroethylanandamide produced reductions in motor activity and antinociception in mice, effects that were blocked by the antagonist. To determine whether anandamide's receptor binding mimicked that of other cannabinoids, an autoradiographic comparison of anandamide, SR 141716A and CP 55,940 competition for [3H]CP55,940 binding was conducted throughout rat brain. The receptor affinities for all three compounds did not change according to brain area. As expected, Bmax values differed dramatically among differ brain areas. However, the Bmax values for each brain area were similar regardless of the compound used for displacement. These data suggest that anandamide, SR 141716A and CP 55,940 compete for the same cannabinoid receptor throughout brain despite SR 141716A's failure to block anandamide's pharmacological effects. Although there is no question that anandamide binds to the cannabinoid receptor, failure of SR 141716A to block its pharmacological effects in mice poses a dilemma. The results presented herein raise the possibility that anandamide may not be producing all of its effects by a direct interaction with the CB1 receptor.     

Regulation of delta opioid receptors by delta9-tetrahydrocannabinol in NG108-15 hybrid cells

In this study we employed the neuroblastoma x glioma NG 108-15 cell line as a model for investigating the effects of long-term activation of cannabinoid receptors on delta opioid receptor desensitization, down-regulation and gene expression. Exposure of NG 108-15 cells to (-)-delta9-tetrahydrocannabinol (delta9-THC) reduced opioid receptor binding, evaluated in intact cells, by approximately 40-45% in cells exposed for 24 h to 50 and 100 nM delta9-THC and by approximately 25% in cells exposed to 10 nM delta9-THC. Lower doses of delta9-THC (0.1 and 1 nM) or a shorter exposure time to the cannabinoid (6 h) were not effective. Down-regulation of 6 opioid receptors was not observed in cells exposed for 24 h to pertussis toxin (PTX) and then treated for 24 h with 100 nM delta9-THC. In cells that were exposed for 24 h to the cannabinoid, the ability of delta9-THC and of the delta opioid receptor agonist [D-Ser2, Leu5, Thr6]enkephalin to inhibit forskolin-stimulated cAMP accumulation was significantly attenuated. Prolonged exposure of NG 108-15 cells to 100 nM delta9-THC produced a significant elevation of steady-state levels of delta opioid receptor mRNA. This effect was not observed in cells pretreated with PTX. The selective cannabinoid receptor antagonist SR 141716A blocked the effects elicited by delta9-THC on delta opioid receptor desensitization, down-regulation and gene expression; thus indicating that these are mediated via activation of cannabinoid receptors. These data demonstrate the existence, in NG 108-15 cells, of a complex cross-talk between the cannabinoid and opioid receptors on prolonged exposure to delta9-THC triggered by changes in signaling through Gi and/or G0-coupled receptors.     

Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors

Delta9-tetrahydrocannabinol (delta9-THC), cannabinol and cannabidiol are three important natural cannabinoids from the Marijuana plant (Cannabis sativa). Using [35S]GTP-gamma-S binding on rat cerebellar homogenate as an index of cannabinoid receptor activation we show that: delta9-THC does not induce the maximal effect obtained by classical cannabinoid receptor agonists such as CP55940. Moreover at high concentration delta9-THC exhibits antagonist properties. Cannabinol is a weak agonist on rat cerebellar cannabinoid receptors and cannabidiol behaves as an antagonist acting in the micromolar range.     

Perinatal delta(9)-tetrahydrocannabinol exposure alters the responsiveness of hypothalamic dopaminergic neurons to dopamine-acting drugs in adult rats

We have recently reported that perinatal cannabinoid exposure altered the normal development of dopaminergic neurons in the medial basal hypothalamus at early postnatal and peripubertal ages. Most of these effects tended to disappear in adulthood, although we suspect the existence of a persistent, but possibly silent, alteration in the adult activity of these neurons. To further explore this possibility, we evaluated the responsiveness of these neurons to pharmacological challenges with a variety of dopaminergic drugs administered to adult male and female rats that had been exposed to delta(9)-tetrahydrocannabinol (delta(9)-THC) or vehicle during the perinatal period. In the first experiment, we evaluated the sensitivity of hypothalamic dopaminergic neurons to amphetamine (AMPH), which causes enhancement of dopaminergic activity by a variety of mechanisms. The most interesting observation was that both adult males and females, when perinatally exposed to delta(9)-THC, showed a more marked AMPH-induced decrease in the production of L-3,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metabolite of dopamine (DA), although this did not affect the prolactin (PRL) release. In the second experiment, we evaluated the in vivo synthesis of DA by analyzing the magnitude of L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation caused by the blockade of L-DOPA decarboxylase with NSD 1015. As expected, NSD 1015 increased L-DOPA accumulation and decreased DOPAC production, with a parallel increase in PRL release, all of similar magnitude in both delta(9)-THC- and oil-exposed adult animals. In the last experiment, we tested the magnitude of the increase in PRL release produced by the administration of either SKF 38393, a specific D1 agonist, or sulpiride, a specific D2 antagonist. Both compounds increased plasma PRL levels in adult animals of both sexes, the effects in females being significantly more marked. The perinatal exposure to delta(9)-THC also modified the degree of increase in plasma PRL levels induced by both compounds, with opposite responses as a function of sex. Thus, delta(9)-THC-exposed females responded more intensely to SKF 38393 and, particularly, to sulpiride than oil-exposed females, whereas delta(9)-THC-exposed males responded to SKF 38393 lesser than oil-exposed males, although both responded equally to sulpiride. In summary, our results are consistent with the possible existence of subtle changes in the activity of hypothalamic dopaminergic neurons in adulthood caused by the exposure to delta(9)-THC during perinatal development. These silent changes could be revealed after the administration of drugs such as: (i) AMPH, whose effect producing a decreased DOPAC accumulation was more marked in delta(9)-THC-exposed males and females; and (ii) SKF 38393 and sulpiride, whose stimulatory effects on PRL secretion were of different magnitude in delta(9)-THC-exposed animals, with an evident sexual dimorphism in the response. The neurochemical basis for these differences remains to be determined.     

Glutamate dehydrogenase, the marker protein of Plasmodium falciparum--cloning, expression and characterization of the malarial enzyme

To characterize the time course of the behavioral and biochemical aspects of the cannabinoid withdrawal syndrome, we injected the cannabinoid antagonist SR141716A (5 mg/kg i.p.) in rats made tolerant to CP-55,940 (0.4 mg/kg i.p., twice daily for 6.5 days), 1, 24 and 96 h after the last CP-55,940 injection. Because the CB1 receptor and G protein alpha subunit are involved in cannabinoid tolerance, we observed their changes throughout the brain during the withdrawal syndrome by use of in situ hybridization. In vehicle-pretreated rats SR141716A per se induced abnormal behavior significantly different from the vehicle group: wet dog shakes, forepaw fluttering and scratching. These signs remained significantly elevated even after the second and third antagonist doses. SR141716A significantly modified the mRNA levels of G alpha s and G alpha i subunits in some brain areas without affecting CB1 receptor and G alpha o expression. These findings led us to conclude that SR141716A may have intrinsic activity. Concerning cannabinoid withdrawal, the first SR141716A injection in tolerant rats resulted in behavioral signs different from those observed with the antagonist alone; this moderate withdrawal syndrome was characterized by turning, chewing and digging. Additional SR141716A doses 24 and 96 h later did not induce a significant abstinence syndrome. In situ hybridization after the first SR141716A injection showed that CB1 receptor and G protein alpha subunits, whose levels were low in tolerance, recovered their basal level of expression. Thus, the general desensitization of the cannabinoid receptor and of the transduction system in tolerance are recovered in abstinent rats and might be part of the molecular mechanisms underlying cannabinoid dependence.     

An analgesia circuit activated by cannabinoids

Although many anecdotal reports indicate that marijuana and its active constituent, delta-9-tetrahydrocannabinol (delta-9-THC), may reduce pain sensation, studies of humans have produced inconsistent results. In animal studies, the apparent pain-suppressing effects of delta-9-THC and other cannabinoid drugs are confounded by motor deficits. Here we show that a brainstem circuit that contributes to the pain-suppressing effects of morphine is also required for the analgesic effects of cannabinoids. Inactivation of the rostral ventromedial medulla (RVM) prevents the analgesia but not the motor deficits produced by systemically administered cannabinoids. Furthermore, cannabinoids produce analgesia by modulating RVM neuronal activity in a manner similar to, but pharmacologically dissociable from, that of morphine. We also show that endogenous cannabinoids tonically regulate pain thresholds in part through the modulation of RVM neuronal activity. These results show that analgesia produced by cannabinoids and opioids involves similar brainstem circuitry and that cannabinoids are indeed centrally acting analgesics with a new mechanism of action.     

A Comparison of the Discriminative Stimulus Effects of Δ?-Tetrahydrocannabinol and O-1812, a Potent and Metabolically Stable Anandamide Analog, in Rats.

Efforts to determine whether Δ?-tetrahydrocannabinol (Δ?-THC) and anandamide elicit similar discriminative stimulus effects have yielded conflicting results. The difficulty in establishing a discriminative cue to anandamide may be due to its metabolic instability. Rats were trained to discriminate either Δ?-THC or O-1812, a metabolically stable anandamide analog, from vehicle to avoid this issue. O-1812 and Δ?-THC substituted for each other; however, both drugs were more potent in the O-1812-trained rats. Further, O-1812 only substituted for Δ?-THC at response rate decreasing doses. The CB? antagonist, SR141716A, blocked the discriminative stimulus effects of both drugs but augmented their rate effects. O-1839, a VR? agonist, failed to substitute for either cannabinoid. These results suggest that the discriminative stimulus effects of Δ?-THC and O-1812 are similar, but subtle differences also exist. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of cannabinoids on prolactin and gonadotrophin secretion: involvement of changes in hypothalamic gamma-aminobutyric acid (GABA) inputs

CB1 cannabinoid receptors are located in hypothalamic nuclei and their activation alters several hypothalamic neurotransmitters resulting in, among other things, decreased prolactin (PRL) and luteinizing hormone (LH) secretion from the anterior pituitary gland. In the present study, we addressed two related objectives to further explore this complex regulation. First, we examined whether changes in gamma-aminobutyric acid (GABA) and/or dopamine (DA) inputs in the medial basal hypothalamus might occur in parallel to the effects resulting from the activation of CB1 receptors on PRL and gonadotrophin secretion in male rats. Thus, the acute administration of (-)-delta9-tetrahydrocannnabinol (delta9-THC) produced, as expected, a marked decrease in plasma PRL and LH levels, with no changes in follicle-stimulating hormone (FSH) levels. This was paralleled by an increase in the contents of GABA, but not of DA, in the medial basal hypothalamus and, to a lesser extent, in the anterior pituitary gland. The co-administration of delta9-THC and SR141716, a specific antagonist for CB1 receptors, attenuated both PRL and LH decrease and GABA increase, thus asserting the involvement of the activation of CB1 receptors in these effects. As a second objective, we tested whether the prolonged activation of these receptors might induce tolerance with regard to the decrease in PRL and LH release, and whether this potential tolerance might be related to changes in CB1-receptor binding and/or mRNA expression. The chronic administration of R-methanandamide (AM356), a more stable analog of anandamide, the putative endogenous cannabinoid ligand, produced a marked decrease in plasma PRL and LH levels, with no changes in FSH. The decreases were of similar magnitude to those caused by a single injection of this cannabimimetic ligand, thus suggesting the absence of tolerance. In parallel, the analysis of CB1-receptor binding and mRNA expression in several hypothalamic structures proved that the acute or chronic administration of AM356 did not affect either the binding or the synthesis of these receptors. In summary, the activation of CB1 receptors in hypothalamic nuclei produced the expected decrease in PRL and LH secretion, an effect which might be related to an increase in GABAergic activity in the hypothalamus-anterior pituitary axis. The prolonged activation of these receptors for five days did not elicit tolerance in terms of an attenuation in the magnitude of the decrease in PRL and LH, and, accordingly, did not alter CB1-receptor binding and mRNA levels in the hypothalamic nuclei examined.     

Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors

Previous studies indicate that the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR141716A), inhibits the anandamide- and delta9-tetrahydrocannabinol- (THC) induced hypotension and bradycardia in anesthetized rats with a potency similar to that observed for SR141716A antagonism of THC-induced neurobehavioral effects. To further test the role of CB1 receptors in the cardiovascular effects of cannabinoids, we examined two additional criteria for receptor-specific interactions: the rank order of potency of agonists and stereoselectivity. A series of cannabinoid analogs including the enantiomeric pair (-)-11-OH-delta9-THC dimethylheptyl (+)-11-OH-delta9-THC dimethylheptyl were evaluated for their effects on arterial blood pressure and heart rate in urethane anesthetized rats. Six analogs elicited pronounced and long lasting hypotension and bradycardia that were blocked by 3 mg/kg of SR141716A. The rank order of potency was (-)-11-OH-delta9-THC dimethylheptyl > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > THC > anandamide > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol, which correlated well with CB1 receptor affinity or analgesic potency (r = 0.96-0.99). There was no hypotension or bradycardia after palmitoylethanolamine or (+)-11-OH-delta9-THC dimethylheptyl. An initial pressor response was also observed with THC and anandamide, which was not antagonized by SR141716A. We conclude that the similar rank orders of potency, stereoselectivity and sensitivity to blockade by SR141716A indicate the involvement of CB1-like receptors in the hypotensive and bradycardic actions of cannabinoids, whereas the mechanism of the pressor effect of THC and anandamide remains unclear.     

Constitutive and regulated prolactin secretion: effects of estradiol

Dysfunction of dopamine neural systems is hypothesized to underlie neuropsychiatric disorders and psychostimulant drug abuse. At least three dopamine systems have been characterized in the brain-nigrostriatal, mesolimbic, and mesocortical. Abnormalities of nigrostriatal dopamine neurons cause motor impairment leading to Parkinson's disease, whereas dysfunction of mesolimbic and mesocortical dopamine neurons are most implicated in psychotic disorders such as schizophrenia and in drug addition. One of the primary neural sites of action of potent antipsychotic agents and psychostimulant drugs of abuse are dopamine receptors and dopamine transporters which, respectively, mediate the induction and termination of dopamine's actions. Very limited information is, however, available about which particular set of dopaminergic cells in the human brain actually express the genes for these dopamine-specific proteins. In this study, we observed that the dopamine transporter and D2 receptor messenger RNAs are differentially expressed within the human mesencephalon: highest expression in ventral subpopulations of the substantia nigra pars compacta neurons with lowest expression in the mesolimbic/mesocortical ventral tegmental area and retrorubral cell groups. These findings suggest that motor- and limbic-related mesencephalic neurons in the human brain differ in the degree of dopamine transporter and D2 receptor gene expression.     

Dual dopamine/serotonin releasers: Potential treatment agents for stimulant addiction.

"Agonist therapy" for cocaine and methamphetamine addiction involves administration of stimulant-like medications (e.g., monoamine releasers) to reduce withdrawal symptoms and prevent relapse. A significant problem with this strategy is that many candidate medications possess abuse liability because of activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs is to add in serotonin (5-HT) releasing properties, since substantial evidence shows that 5-HT neurons provide an inhibitory influence over mesolimbic DA neurons. This article addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, the authors briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, the authors discuss data demonstrating that 5HT release can dampen DA-mediated stimulant effects, and the "antistimulant" role of 5-HT2C receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, the authors discuss recently published data with PAL-287, a novel nonamphetamine DA/5-HT releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers could be useful therapeutic adjuncts for the treatment of cocaine and alcohol addictions, as well as for obesity, attention-deficit disorder, and depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons

The mesolimbic dopamine system, which arises in the ventral tegmental area (VTA), is an important neural substrate for opiate reinforcement and addiction. Chronic exposure to opiates is known to produce biochemical adaptations in this brain region. We now show that these adaptations are associated with structural changes in VTA dopamine neurons. Individual VTA neurons in paraformaldehyde-fixed brain sections from control or morphine-treated rats were injected with the fluorescent dye Lucifer yellow. The identity of the injected cells as dopaminergic or nondopaminergic was determined by immunohistochemical labeling of the sections for tyrosine hydroxylase. Chronic morphine treatment resulted in a mean approximately 25% reduction in the area and perimeter of VTA dopamine neurons. This reduction in cell size was prevented by concomitant treatment of rats with naltrexone, an opioid receptor antagonist, as well as by intra-VTA infusion of brain-derived neurotrophic factor. In contrast, chronic morphine treatment did not alter the size of nondopaminergic neurons in the VTA, nor did it affect the total number of dopaminergic neurons in this brain region. The results of these studies provide direct evidence for structural alterations in VTA dopamine neurons as a consequence of chronic opiate exposure, which could contribute to changes in mesolimbic dopamine function associated with addiction.