Multispecialty screening, brief intervention, and referral to treatment (SBIRT) training in an academic medical center: Resident training experience across specialties.

BACKGROUND: The Substance Abuse and Mental Health Services Administration (SAMHSA) has recently begun to fund programs that train medical residents on how to utilize an evidence-based validated system known as screening, brief intervention, and referral to treatment (SBIRT) for providing early detection and brief treatment of unhealthy substance use. This paper investigates training outcomes of multispecialty SBIRT training at one such program at Albany Medical Center (AMC), one of the initial SAMHSA grantees. METHODS: Training outcomes were measured across 3 domains of learning: trainee satisfaction, acquired knowledge, and perceived usefulness. The authors explored differences in learning experience by postgraduate year and by specialty. RESULTS: Overall, residents were highly satisfied with the training, and learning outcomes met objectives. Residents' ratings of usefulness did not vary by program year. However, the results indicate that relative to residents in other programs, residents in psychiatry and pediatrics found the training components significantly more useful, whereas emergency medicine residents found training components to have less utility. Residents who found the training relevant to their daily work were more satisfied and more receptive to SBIRT training overall, which may help explain difference scores by program. CONCLUSIONS: Residents were highly satisfied with SBIRT skills training, although ratings of usefulness varied by residency program. Specialization by program and on-site modeling by senior faculty may enhance trainee satisfaction and perceived usefulness.

Residents' experience of screening, brief intervention, and referral to treatment (SBIRT) as a clinical tool following practical application: A mixed-methods study.

BACKGROUND: Screening, brief intervention, and referral to treatment (SBIRT), an evidence-based validated system for providing early detection and brief treatment of substance use disorders, has been widely used in the training of medical residents across specialties at a number of sites. This article investigates the effectiveness of SBIRT training during short-term follow-up at Albany Medical Center, one of the initial Substance Abuse and Mental Health Services Administration (SAMHSA) grantees. METHODS: Training outcomes were measured by training satisfaction following opportunities to apply SBIRT skills in clinical work, the rate at which these techniques were applied in clinical work, and the degree to which residents felt that the SBIRT training provided skills that were applicable to their practice. We examined differences in learning experience by postgraduate year and by program, and conducted a qualitative analysis in a convergent parallel mixed-methods design to elucidate barriers encountered by residents upon using SBIRT techniques in clinical practice. RESULTS: Residents remained highly satisfied with the training at 4-month follow-up, with 80.1% reporting that they had used SBIRT skills in their clinical work. Use of SBIRT techniques was high at 6-month follow-up as well, with 85.9% of residents reporting that they regularly screened their patients for substance use, 74.4% reporting that they had applied brief intervention techniques, and 78.2% indicating that SBIRT training had made them overall more effective in helping patients with substance use issues. Differences in application rates and satisfaction were found by specialty. Qualitative analyses indicated that residents encountered patient readiness and specific contextual factors, such as time constraints, externally imposed values, and clinical norms, as barriers to implementation. CONCLUSIONS: Despite encountering obstacles such as time constraints and patient readiness, residents utilized many of the skills they had learned during SBIRT training in clinical practice and reported finding these skills useful in their management of patients with substance use issues.

18-methoxycoronaridine: a potential new treatment for obesity in rats?

RATIONALE: Excessive eating often leads to obesity. Although a variety of neurotransmitters and brain regions are involved in modulating food intake, a role of accumbal dopamine is thought to be critical for several aspects of this behavior. Since 18-methoxycoronaridine (18-MC), a selective antagonist of alpha3beta4 nicotinic receptors, was previously shown to alter dopamine release in the nucleus accumbens in response to chronic injections of cocaine and morphine, this drug could be a promising therapy for abnormal eating behavior. OBJECTIVES: Assess the effect of 18-MC on the consumption of sucrose (15%) vs. water in a self-administration paradigm and on the intake of freely available palatable fluids (i.e., 5% sucrose, 0.1% saccharin, and 0.6% saline solutions) as well as on water intake. Determine whether repeated administration of 18-MC (20 mg/kg i.p.) affects weight gain, food intake, and fat deposition in rats drinking 30% sucrose solution. RESULTS: Acute administration of 18-MC (10-40 mg/kg i.p.) reduced operant responding for sucrose and decreased ad libitum ingestion of sucrose, saccharin, and saline. The highest dose of 18-MC also reduced consumption of water when palatable fluids were not available. In rats having unlimited access to sucrose (30%), chronic treatment with 18-MC (20 mg/kg i.p.) prevented sucrose-induced increases in body weight, decreased fat deposition, and reduced consumption of sucrose while not altering food intake. CONCLUSIONS: These data suggest that antagonism of alpha3beta4 nicotinic receptors may be involved in the regulation of intake of palatable substances regardless of its caloric value and may participate in maintaining obesity.

Brain regions mediating alpha3beta4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration.

The novel iboga alkaloid congener 18-methoxycoronaridine (18-MC) is a putative anti-addictive agent that has been shown, in rats, to decrease the self-administration of several drugs of abuse. Previous work has established that 18-MC is a potent antagonist at alpha3beta4 nicotinic receptors. Because high densities of alpha3beta4 nicotinic receptors occur in the medial habenula and the interpeduncular nucleus and moderate densities occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, the present study was conducted to determine if 18-MC could act in these brain areas to modulate methamphetamine self-administration in rats. Local administration of 18-MC into either the medial habenula, the interpeduncular area or the basolateral amygdala decreased methamphetamine self-administration. Similar results were produced by local administration into the same brain areas of two other alpha3beta4 nicotinic antagonists, mecamylamine and alpha-conotoxin AuIB. Local administration of 18-MC, or the other antagonists, into the dorsolateral tegmentum or the ventral tegmental area had no effect on methamphetamine self-administration. In contrast, local administration of 18-MC and the other antagonists decreased sucrose self-administration when administered into the dorsolateral tegmentum or basolateral amygdala but had no effect when infused into the medial habenula, interpeduncular nucleus, or ventral tegmental area. These data are consistent with the hypothesis that 18-MC decreases methamphetamine self-administration by indirectly modulating the dopaminergic mesolimbic pathway via blockade of alpha3beta4 nicotinic receptors in the habenulo-interpeduncular pathway and the basolateral amygdala. The data also suggest that the basolateral amygdala along with a different pathway involving alpha3beta4 receptors in the dorsolateral tegmentum mediate the effect of 18-MC on sucrose self-administration.

Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats.

Owing to multiple anatomical connections and functional interactions between the habenulo-interpeduncular and the mesolimbic pathways, it has been proposed that these systems could together mediate the reinforcing properties of addictive drugs. 18-Methoxycoronaridine, an agent that reduces morphine self-administration and attenuates dopamine sensitization in the nucleus accumbens in response to repeated morphine, has been shown to produce these effects by acting in the medial habenula and interpeduncular nucleus. Acetylcholine, one of the predominant neurotransmitters in the interpeduncular nucleus, may be a major determinant of these interactions. To determine if and how morphine acts in the interpeduncular nucleus, the effects of acute and repeated administration of morphine on extracellular acetylcholine levels in this brain area were assessed. In addition, the motor behavior of rats receiving repeated morphine administration was monitored during microdialysis sessions. Acutely, morphine produced a biphasic effect on extracellular acetylcholine levels in the interpeduncular nucleus such that low and high doses of morphine (i.e., 5 and 20mg/kg i.p.) significantly increased and decreased acetylcholine levels, respectively. Repeated administration of the same doses of morphine resulted in tolerance to the inhibitory but not to the stimulatory effects; tolerance was accompanied by sensitization to morphine-induced changes in locomotor activity and stereotypic behavior. The latter results suggest that tolerance to morphine's effect on the cholinergic habenulo-interpeduncular pathway is related to its sensitizing effects on the mesostriatal dopaminergic pathways.

18-Methoxycoronaridine acts in the medial habenula and/or interpeduncular nucleus to decrease morphine self-administration in rats.

The novel iboga alkaloid congener 18-methoxycoronaridine (18-MC) is a putative anti-addictive agent that has been shown, in rats, to decrease the self-administration of morphine and other drugs of abuse. Previous work has established that 18-MC is a potent antagonist at alpha3beta4 nicotinic receptors. Because alpha3beta4 nicotinic receptors in the brain are preferentially located in the medial habenula and the interpeduncular nucleus, the present study was conducted to determine if 18-MC could act in these brain areas to modulate morphine self-administration in rats. Local administration of 18-MC into either the medial habenula or the interpeduncular area decreased morphine self-administration while having no effect on responding for a non-drug reinforcer (sucrose). Similar results were produced by local administration into the same brain areas of two other alpha3beta4 nicotinic antagonists, mecamylamine and alpha-conotoxin AuIB. Local administration of 18-MC into the ventral tegmental area had no effect on morphine self-administration. These and other data are consistent with the hypothesis that 18-MC decreases morphine self-administration by blocking alpha3beta4 nicotinic receptors in the habenulo-interpeduncular pathway.

Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine.

18-Methoxyroconaridine (18-MC), a synthetic derivative of ibogaine, reduces morphine self-administration and alleviates several signs of acute opioid withdrawal in rats. Although there is already well documented evidence of the mechanism mediating 18-MC's action to reduce the rewarding effects of morphine, nothing is known about the mechanism responsible for 18-MC's attenuation of opioid withdrawal. In vitro studies have demonstrated that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors (IC50=0.75 microM), which are predominantly located in the medial habenula and interpeduncular nuclei. Previous work indicating that alpha3beta4 nicotinic receptors mediate 18-MC's effects on drug self-administration prompted us to assess whether brain areas having high or moderate densities of alpha3beta4 receptors might be involved in 18-MC's modulation of opioid withdrawal. To test this possibility, 18-MC was locally administered into the medial habenula, interpeduncular nucleus and locus coeruleus of morphine-dependent rats; this treatment was followed by naltrexone to precipitate a withdrawal syndrome. Pretreatment with various doses of 18-MC into the locus coeruleus significantly reduced wet-dog shakes, teeth chattering, burying and diarrhea, while pretreatment into the medial habenula attenuated teeth chattering, burying, and weight loss. Some doses of 18-MC administered into the interpeduncular nucleus significantly ameliorated rearing, teeth chattering, and burying, while other doses exacerbated diarrhea and teeth chattering. The present findings suggest that 18-MC may act in all three nuclei to suppress various signs of opioid withdrawal.

Is antagonism of alpha3beta4 nicotinic receptors a strategy to reduce morphine dependence?

18-Methoxycoronaridine, a synthetic iboga alkaloid congener, has been previously shown to attenuate several signs of morphine withdrawal in rats. The recently discovered action of 18-methoxycoronaridine to block alpha3beta4 nicotinic receptors may be responsible for this effect. To test this hypothesis the effects of non-selective alpha3beta4 receptor antagonists, dextromethorphan, mecamylamine, bupropion, and their combinations, were assessed on of acute naltrexone-precipitated (1 mg/kg i.p.) morphine withdrawal in rats. Dextromethorphan (5-40 mg/kg, s.c.), mecamylamine (0.25-4 mg/kg, i.p.) and bupropion (10-30 mg/kg, i.p.) alone produced variable effects on signs of withdrawal. However, two low-dose combinations, i.e., dextromethorphan (5 mg/kg, s.c.) and mecamylamine (0.25 mg/kg, i.p.), mecamylamine (0.25 mg/kg, i.p.) and bupropion (10 mg/kg, i.p.) as well as the three-drug combination significantly attenuated diarrhea and weight loss; none of the agents administered alone had these effects. The results of the present study provide evidence that alpha3beta4 nicotinic receptors are involved in the expression of at least two signs of opioid withdrawal.

Differences between d-methamphetamine and d-amphetamine in rats: working memory, tolerance, and extinction.

RATIONALE: Previously, we have shown that d-amphetamine (AMPH) was more potent than d-methamphetamine (METH) at increasing extracellular levels of dopamine (DA) in the prefrontal cortex (PFC) at doses that had similar effects in the nucleus accumbens. Since working memory depends on PFC DA, it was postulated that AMPH would also be more potent than METH at affecting working memory. OBJECTIVE: To determine if AMPH is more potent than METH at affecting working memory. METHODS: Working memory was measured in adult female Sprague-Dawley rats using a delayed-alternation T-maze task with multiple delays (1, 10, 60 s) and food rewards. The percentage of food rewards consumed was also recorded. Animals were tested with METH and AMPH before and after a chronic protocol, with measurements of locomotor activity used to test for pharmacological tolerance or sensitization. The effects of METH and AMPH on extinction were also examined by omitting the food rewards from the T-maze. RESULTS. Both METH and AMPH produced dose-related bimodal effects on working memory at the intermediate delay (10 s); however, AMPH was more potent than METH. Both METH and AMPH initially also decreased the percentage of food rewards consumed in the T-maze. After chronic testing, animals displayed tolerance to both the working memory impairments and the reduction in food reward intake produced by AMPH. Animals did not display significant tolerance to the effects of METH on food reward consumption and performed worse in the T-maze after chronic testing. METH, but not AMPH, interfered with extinction. CONCLUSIONS: These results indicate that METH and AMPH differ in altering working memory and the expression of tolerance, perhaps due to differences in behavioral inhibition.

Neurochemical and behavioral differences between d-methamphetamine and d-amphetamine in rats.

RATIONALE: Methamphetamine (METH) and amphetamine (AMPH) are both abused psychostimulants. Although METH is generally accepted to be more addictive and potent than its analogue AMPH, there are no known neurobiological differences in action between the two drugs that may account for such differences. OBJECTIVE: METH and AMPH were compared to determine potential mechanisms for such differences between the two drugs in order to provide new targets for the treatment of METH addiction. METHODS: Using in vivo microdialysis on rats, dopamine (DA), DA metabolites, and glutamate (GLU) release in the nucleus accumbens (NAC) and prefrontal cortex (PFC) were measured after administration of 2 mg/kg, IP, of METH or AMPH. Based on the neurochemical differences between METH and AMPH, a locomotor activity study was designed to assess differences in locomotor activation for a range of doses (1-4 mg/kg, IP) of METH and AMPH and after pretreatment with intra-accumbens GLU antagonists. RESULTS: METH and AMPH raised NAC DA levels to a similar degree. In the PFC, both METH and AMPH raised DA levels, but METH was less effective than AMPH. In the NAC, AMPH raised GLU levels but METH did not. In the PFC, METH raised GLU levels but AMPH did not. The locomotor activity dose response curve for METH had a lower peak than that of AMPH. This difference was blocked by pretreatment with either the GLU NMDA antagonist AP5 or the GLU AMPA antagonist DNQX locally in the NAC. CONCLUSIONS: This study reveals several previously unknown neurochemical and behavioral differences between METH and AMPH. Based on these results, it is suggested that new pharmacotherapeutic agents that produce augmentations of NAC GLU or PFC DA activity, or perhaps inhibition of PFC GLU activity, may someday be useful for the treatment of METH addiction.

Modulation of nicotine self-administration in rats by combination therapy with agents blocking alpha 3 beta 4 nicotinic receptors.

18-Methoxycoronaridine, a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In previous work, 18-methoxycoronaridine was found to be a somewhat selective antagonist at alpha3beta4 nicotinic receptors; and low dose combinations of 18-methoxycoronaridine with other drugs known to have the same action (e.g., mecamylamine, dextromethorphan) decreased both morphine and methamphetamine self-administration in rats at doses that were ineffective if administered alone. In the present study, similar drug combinations (but including bupropion as well) were found to decrease nicotine self-administration in rats. The data further support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating polydrug abuse.

Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration.

The iboga alkaloid ibogaine and the novel iboga alkaloid congener 18-methoxycoronaridine are putative anti-addictive agents. Using patch-clamp methodology, the actions of ibogaine and 18-methoxycoronaridine at various neurotransmitter receptor ion-channel subtypes were determined. Both ibogaine and 18-methoxycoronaridine were antagonists at alpha 3 beta 4 nicotinic receptors and both agents were more potent at this site than at alpha 4 beta 2 nicotinic receptors or at NMDA or 5-HT(3) receptors; 18-methoxycoronaridine was more selective in this regard than ibogaine. In studies of morphine and methamphetamine self-administration, the effects of low dose combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan and of mecamylamine with dextromethorphan were assessed. Mecamylamine and dextromethorphan have also been shown to be antagonists at alpha 3 beta 4 nicotinic receptors. All three drug combinations decreased both morphine and methamphetamine self-administration at doses that were ineffective if administered alone. The data are consistent with the hypothesis that antagonism at alpha 3 beta 4 receptors is a potential mechanism to modulate drug seeking behavior. 18-Methoxycoronaridine apparently has greater selectivity for this site than other agents and may be the first of a new class of synthetic agents acting via this novel mechanism to produce a broad spectrum of anti-addictive activity.

Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration.

18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self-administration in animal models of addiction. Previously, we proposed that these effects are mediated by the ability of 18-methoxycoronaridine to inhibit nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more potent 18-methoxycoronaridine analogs, we have tested a series of 18-methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293 cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. The congeners exhibited a range of inhibitory potencies at alpha3beta4 receptors. Five congeners had IC(50) values similar to 18-methoxycoronaridine, and all of these were ineffective at NMDA receptors. The congeners also retained their ability to reduce morphine and methamphetamine self-administration. These data are consistent with the importance of nicotinic alpha3beta4 receptors as a therapeutic target to modulate drug seeking. These compounds may constitute a new class of synthetic agents that act via the nicotinic alpha3beta4 mechanism to combat addiction.

Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment.

18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.

Effects of dextromethorphan on dopamine release in the nucleus accumbens: Interactions with morphine.

Dextromethorphan has been reported to decrease the self-administration of several drugs of abuse, including morphine, methamphetamine, cocaine, and nicotine. Most drugs of abuse increase extracellular levels of dopamine (DA) in the shell of the nucleus accumbens. The effects of dextromethorphan on DA release in the nucleus accumbens of nai;ve rats and of rats treated acutely and chronically with morphine were studied using in vivo microdialysis. DA dialysate levels were evaluated by high-performance liquid chromatography with electrochemical detection. Acute morphine (5 mg/kg i.p.) treatment increased the levels of DA in the nucleus accumbens to approximately 175% of basal levels. Chronic morphine (20 mg/kg i.p. daily for 5 days) increased DA release in the nucleus accumbens to 250% of basal levels. Acute treatment with dextromethorphan (20 or 30 mg/kg s.c.) alone did not alter nucleus accumbens DA levels. Pretreatment with dextromethorphan (20 mg/kg s.c., 20 min prior) potentiated the effects of acute morphine, while attenuating the effects of chronic morphine on nucleus accumbens DA levels. These results with dextromethorphan suggest that the mechanism mediating the effects of dextromethorphan on drug self-administration involves modulation of the dopaminergic mesolimbic pathway.

Resistance of male Sprague-Dawley rats to sucrose-induced obesity: effects of 18-methoxycoronaridine.

Evidence suggests that the development of obesity in males and females might be mediated by distinct mechanisms, warranting different treatment approaches. In previous studies from this laboratory, a high sucrose diet induced excessive weight gain in female Sprague-Dawley rats and administration of a selective antagonist of α3ß4 nicotinic receptors, 18-methoxycoronaridine (18-MC), prevented this form of obesity. In the present study similar parameters were studied in male rats by using an identical experimental protocol. The effects of repeated administration of 18-MC on body weight gain, deposition of fat, consummatory behavior and biochemical markers of obesity in male rats were also assessed. In contrast to females, males consuming ad libitum quantities of sucrose solution (30%) in combination with normal chow did not become obese; they did not gain excessive weight nor show excessive fat deposition. Repeated administration of 18-MC (20mg/kg, i.p.) attenuated weight gain in both sucrose-consuming and control animals without altering food or fluid intake. The present results indicate that males and females are differentially responsive to high carbohydrate-diet obesity. Such gender disparities could be secondary to sex-specific alterations in cholinergic mechanisms of feeding and body weight regulation.

Sex differences in high fat-induced obesity in rats: Effects of 18-methoxycoronaridine.

Evidence suggests that the development of diet-induced obesity in males and females might be mediated by distinct mechanisms, warranting different treatment approaches. In previous studies from this laboratory, a high sucrose diet induced excessive weight gain in female but not in male Sprague-Dawley rats, while weight gain in both sexes was similarly attenuated by the administration of a selective antagonist of α3ß4 nicotinic receptors, 18-methoxycoronaridine (18-MC). In the present study, assessment of high-fat induced weight gain, consummatory behavior and biochemical markers of obesity was conducted in male and female Sprague-Dawley rats and the effects of 18-MC treatment were compared in the two sexes. Male rats consuming a high-fat (HF) diet developed excessive weight gain and fat deposition compared to same same-sex controls fed with a low-fat (LF) diet. The development of obesity in these rats was attenuated by repeated administration of 18-MC (20mg/kg, i.p.), which significantly reduced their food intake without altering water intake. In contrast, female rats consuming a HF diet did not become obese and did not respond to 18-MC treatment. These results show that males and females are differentially responsive to HF-induced obesity; the 18-MC data suggest that α3ß4 nicotinic receptors may participate in maintaining obesity, possibly becoming a new and important target for anti-obesity agents.

Brain regions mediating α3ß4 nicotinic antagonist effects of 18-MC on nicotine self-administration.

18-Methoxycoronaridine (18-MC), a putative anti-addictive agent, has been shown to decrease the self-administration of several drugs of abuse in rats. 18-MC is a potent antagonist at α3ß4 nicotinic receptors. Consistent with high densities of α3ß4 nicotinic receptors being located in the medial habenula and the interpeduncular nucleus, 18-MC has been shown to act in these regions to decrease both morphine and methamphetamine self-administration. The present study was conducted to determine if 18-MC's effect on nicotine self-administration is mediated by acting in these same brain regions. Because moderate densities of α3ß4 receptors occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, these brain areas were also examined as potential sites of action of 18-MC. Local administration of 18-MC into either the medial habenula, the basolateral amygdala or the dorsolateral tegmentum decreased nicotine self-administration. Surprisingly, local administration of 18-MC into the interpeduncular nucleus increased nicotine self-administration while local administration of 18-MC into the ventral tegmental area had no effect on nicotine self-administration. Similar effects were produced by local administration of either mecamylamine or conotoxin AuIB. These data are consistent with the hypothesis that 18-MC decreases nicotine self-administration by indirectly modulating the dopaminergic mesolimbic pathway via blockade of α3ß4 nicotinic receptors in the medial habenula, basolateral amygdala, and dorsolateral tegmentum. The data also suggest that an action of 18-MC in the interpeduncular nucleus may attenuate aversive and/or depressive effects of nicotine.

18-Methoxycoronaridine, a potential anti-obesity agent, does not produce a conditioned taste aversion in rats.

18-Methoxycoronaridine (18-MC), a selective antagonist of alpha3beta4 nicotinic receptors, has been shown to reduce the self-administration of several drugs of abuse. Recently, this agent has also been shown to attenuate sucrose reward, decrease sucrose intake and prevent the development of sucrose-induced obesity in rats. The present experiments were designed to determine whether the latter effect was due to an 18-MC-induced conditioned taste aversion to sucrose. Both 18-MC (20mg/ kg, i.p.) and control agent, lithium chloride (100mg/kg, i.p.), reduced sucrose intake 24h after association with sucrose; however, only lithium chloride reduced sucrose intake 72h later. Consistent with previous data, 18-MC appears to have proactive effect for 24h and it does not induce a conditioned taste aversion.

18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens.

18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, is a potential treatment for drug addiction. 18-MC has been shown to decrease self-administration of drugs (e.g., morphine, methamphetamine, nicotine) and attenuate opioid withdrawal in rats. In previous studies, systemic pretreatment with 18-MC abolished the sensitized increase in accumbens dopamine levels induced by chronic morphine administration. In vitro studies have shown that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors, and alpha3beta4 antagonism is believed to be the primary mechanism responsible for 18-MC's effects on drug self-administration and possibly on morphine-induced changes in mesolimbic dopamine. While there are very low densities of alpha3beta4 nicotinic receptors in the mesolimbic pathway, these receptors are prominently localized in the medial habenula (MHb) and in the interpeduncular nucleus (IPN). These nuclei and the habenulo-interpeduncular pathway connecting them are believed to function as part of an alternate reward pathway modulating the dopaminergic mesolimbic pathway known to be involved in drug addiction. In the present study, to determine if 18-MC acts in the MHb or in the IPN, the effects of local infusion of 18-MC into these brain areas were assessed on mesolimbic dopamine responses to acute and repeated morphine treatment. Administration of 18-MC (10 mug) into either the IPN or MHb blocked the sensitized dopamine response to repeated morphine in the nucleus accumbens; 18-MC had no effect on the dopamine response to acute morphine. The results suggest that 18-MC acts in the habenulo-interpeduncular pathway to modulate the effects of repeated morphine in the dopaminergic mesolimbic system.