In alcohol-treated rats, naloxone decreases extracellular dopamine and increases acetylcholine in the nucleus accumbens: evidence of opioid withdrawal

Withdrawal from ethanol is aversive. The question is why. As with the withdrawal from morphine, nicotine, diazepam and sugar, the ethanol withdrawal state may involve an increase in nucleus accumbens (NAc) acetylcholine (ACh) causing an alteration of the dopamine (DA)-ACh balance in favor of ACh. Therefore the effects of acute and chronic alcohol (1 gm/kg/day i.p.) treatment on extracellular concentrations of NAc ACh and DA were determined before and after naloxone-precipitated withdrawal. Ethanol initially increased DA to 119% of baseline as measured by microdialysis. This was still the case on the 21st day of ethanol injection when DA increased to 126%. There was no effect of ethanol on ACh. However, naloxone (3 mg/kg s.c.) injected the next day decreased extracellular DA to 83% of baseline and caused a significant rise in ACh to 119%. This state of high ACh combined with low DA may contribute to the aversive aspects of alcohol withdrawal.     

The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens

The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence.     

Preferential increase of extracellular dopamine in the rat nucleus accumbens shell as compared to that in the core during acquisition and maintenance of intravenous nicotine self-administration

Rationale It has been reported that passive administration of nicotine increases preferentially extracellular dopamine (DA) release in the shell as compared to that in the core of the nucleus accumbens (NAc). To date, no information is available if this also applies to active, response-contingent nicotine administration. Objective This study was aimed to monitor the changes of extracellular DA in the NAc shell and core during active intravenous nicotine self-administration (SA). Methods Rats were bilaterally implanted with chronic cannulae and were trained to self-administer nicotine (0.03 mg/kg, i.v.) in single daily 1-h session for 6 weeks, with an initial fixed ratio (FR) 1 schedule increased to FR 2. Dialysate DA from the NAc shell and core was monitored before and for 90 min after the start of SA. Results Significant increases of active nose-pokes over inactive ones were found starting from the 16th SA session. No differences were found in basal extracellular DA in the NAc subdivisions. Data analysis showed (1) significant increases over basal of dialysate DA in the NAc subdivisions during nicotine SA, starting from the first week in the shell and from the second week in the core, (2) preferential increase of extracellular DA during nicotine SA in the shell (24–43%) compared to that in the core (10–23%) and (3) no change in dialysate DA in NAc subdivisions during extinction. Conclusions Response-contingent nicotine SA preferentially increases the DA output in the NAc shell as compared to that in the core, independently from the duration of the nicotine exposure. Increase in NAc DA is strictly related to nicotine action since is not observed during extinction in spite of active responding.     

Behavioral and biochemical manifestations of mecamylamine-precipitated nicotine withdrawal in the rat: role of nicotinic receptors in the ventral tegmental area.

Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 micrograms/0.5 microliter/side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 micrograms mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.     

Pharmacological characterization of nicotine-induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse.

In this study, the mechanism of nicotine-induced hippocampal acetylcholine (ACh) release in awake, freely moving rats was examined using in vivo microdialysis. Systemic administration of nicotine (0.4 mg kg(-1), s.c.) increased the levels of ACh in hippocampal dialysates. The nicotine-induced hippocampal ACh release was sensitive to the pretreatment of neuronal nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine (3.0 mg kg(-1), s.c.) and dihydro-beta-erythrodine (DHbetaE; 4.0 mg kg(-1), s.c.) as well as systemic administration of the dopamine (DA) D1 receptor antagonist SCH-23390 (R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzaz epine; 0.3 mg kg(-1), s.c.). Local perfusion of mecamylamine (100 microM), DHbetaE (100 microM) or SCH-23390 (10 microM) through microdialysis probe did not increase basal hippocampal ACh release. Hippocampal ACh release elicited by systemic administration of nicotine (0.4 mg kg(-1), s.c.) was antagonized by local perfusion of SCH-23390 (10 microM), but not by MEC (100 microM) or DHbetaE (100 microM). Direct perfusion of nicotine (1 mM, but not 0.1 mM) increased hippocampal ACh levels; however, this effect was relatively insensitive to blockade by co-perfusion of either mecamylamine (100 microM) or SCH-23390 (10 microM). These results suggest that nicotine-induced hippocampal ACh release occurs by two distinct mechanisms: (1) activation of nAChRs outside the hippocampus leading to DA release and subsequent ACh release involving a permissive DA synapse, and (2) direct action of nicotine within the hippocampus leading to ACh release via non-DA-ergic mechanism.     

Accumbens dopamine-acetylcholine balance in approach and avoidance

Understanding systems for approach and avoidance is basic for behavioral neuroscience. Research on the neural organization and functions of the dorsal striatum in movement disorders, such as Huntington's and Parkinson's Disease, can inform the study of the nucleus accumbens (NAc) in motivational disorders, such as addiction and depression. We propose opposing roles for dopamine (DA) and acetylcholine (ACh) in the NAc in the control of GABA output systems for approach and avoidance. Contrary to DA, which fosters approach, ACh release is a correlate or cause of meal satiation, conditioned taste aversion and aversive brain stimulation. ACh may also counteract excessive DA-mediated approach behavior as revealed during withdrawal from drugs of abuse or sugar when the animal enters an ACh-mediated state of anxiety and behavioral depression. This review summarizes evidence that ACh is important in the inhibition of behavior when extracellular DA is high and the generation of an anxious or depressed state when DA is relatively low.     

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate-putamen

Using in vivo dialysis and voltammetry, the effect of acute administration of (−)-nicotine (0.8 mg/kg free base, s.c.) on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and ascorbic acid in the nucleus accumbens and caudate-putamen of chloral hydrateanaesthetised rats has been examined. Nicotine stimulated release of dopamine only in the nucleus accumbens, measured using dialysis. After a short time delay levels of 3,4-dihydroxyphenylacetic acid in both the nucleus accumbens and caudate-putamen also increased. In both regions, 5-hydroxyindoleacetic acid was unaffected by nicotine. Using voltammetry the effect of nicotine on extracellular levels of 3,4-dihydroxyphenylacetic acid and ascorbic acid was examined. An increase in 3,4 dihydroxyphenylacetic acid was observed in both regions after nicotine. This increase was blocked by pretreatment with the central nicotinic receptor antagonist mecamylamine (5 mg/kg). Nicotine increased the level of ascorbic acid in the nucleus accumbens and caudate-putamen; while in animals pretreated with mecamylamine, nicotine decreased levels of ascorbate.

These results show that acute administration of nicotine stimulated release of dopamine in the nucleus accumbens and increased the levels of DOPAC and ascorbic acid in the nucleus accumbens and caudate-putamen. This effect is probably mediated by nicotinic receptors as it was antagonised by mecamylamine.     

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: Comparison with caudate-putamen

Using in vivo dialysis and voltammetry, the effect of acute administration of (−)-nicotine (0.8 mg/kg free base, s.c.) on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and ascorbic acid in the nucleus accumbens and caudate-putamen of chloral hydrateanaesthetised rats has been examined. Nicotine stimulated release of dopamine only in the nucleus accumbens, measured using dialysis. After a short time delay levels of 3,4-dihydroxyphenylacetic acid in both the nucleus accumbens and caudate-putamen also increased. In both regions, 5-hydroxyindoleacetic acid was unaffected by nicotine. Using voltammetry the effect of nicotine on extracellular levels of 3,4-dihydroxyphenylacetic acid and ascorbic acid was examined. An increase in 3,4 dihydroxyphenylacetic acid was observed in both regions after nicotine. This increase was blocked by pretreatment with the central nicotinic receptor antagonist mecamylamine (5 mg/kg). Nicotine increased the level of ascorbic acid in the nucleus accumbens and caudate-putamen; while in animals pretreated with mecamylamine, nicotine decreased levels of ascorbate.These results show that acute administration of nicotine stimulated release of dopamine in the nucleus accumbens and increased the levels of DOPAC and ascorbic acid in the nucleus accumbens and caudate-putamen. This effect is probably mediated by nicotinic receptors as it was antagonised by mecamylamine.     

Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats

The aim of the present study was to investigate the relationship between physical abstinence and changes in dopamine release in the nucleus accumbens and in the medial prefrontal cortex induced by mecamylamine and naloxone in rats chronically exposed to nicotine. The rats were implanted with osmotic minipumps (Alzet) delivering nicotine tartrate at a rate of 9 mg/kg/day (3.16 mg of free base) and 8 days later with a dialysis probe in the nucleus accumbens or in the medial prefrontal cortex. Steady-state dopamine output from the nucleus accumbens of the rats implanted with nicotine minipumps was higher than that of sham implanted rats; no differences were observed in the prefrontal cortex. In nicotine but not in sham implanted rats mecamylamine (1 mg/kg s.c.) precipitated a physical abstinence syndrome and brought dopamine output back to control values in the nucleus accumbens. In contrast mecamylamine (1 mg/kg s.c.) increased dopamine output in the medial prefrontal cortex of nicotine but not sham-implanted rats. Naloxone (2 mg/kg) precipitated a physical abstinence syndrome qualitatively similar to that produced by mecamylamine but failed to modify extracellular dopamine in the nucleus accumbens or in the prefrontal cortex of nicotine-implanted and sham-implanted rats. The results indicate that the mesolimbic and mesocortical dopamine system undergo opposite changes during mecamylamine-precipitated abstinence in rats chronically exposed to nicotine and that physical abstinence signs can be dissociated from changes in dopamine transmission.     

Chronic morphine induces long-lasting changes in acetylcholine release in rat nucleus accumbens core and shell: an in vivo microdialysis study

 Previously, only in vitro studies have shown that chronic administration of morphine provokes long-lasting enhanced activity of accumbal cholinergic neurons, which may contribute to the behavioural sensitization, positive reinforcement and aversive effects associated with enhanced drug-seeking. The present study was aimed at clarifying whether these adaptive changes would also be supported by in vivo microdialysis measurements in freely moving rats, distinguishing between the accumbal substructures shell and core, and observing behavioural changes simultaneously. Acute administration of morphine dose-dependently decreased acetylcholine (ACh) release in the nucleus accumbens (NAc), with 10 mg/kg SC being most effective, 5 mg/kg ineffective. On day 5 of spontaneous abstinence from chronic morphine treatment (10–40 mg/kg morphine dose once daily for 5 days), when withdrawal symptoms were still present, even a lower morphine dose (5 mg/kg) was effective in decreasing ACh release in the NAc. During the later phase of abstinence, when no withdrawal symptoms were detectable, the opposite effect, i.e. an increase of ACh release was found. This later effect may represent a long-lasting neuroadaptive effect of morphine. These adaptive effects seemed to be more prominent in the NAc shell. Concurrent with these changes in ACh release, morphine challenges produced marked behavioural stereotypes, possibly indicating behavioural sensitization. Received: 7 April 1998 / Final version: 23 July 1998     

Effects of short-term abstinence from escalating doses of D-amphetamine on drug and sucrose-evoked dopamine efflux in the rat nucleus accumbens.

Abstinence from high doses of psychostimulant drugs, in both humans and rodents, is linked to adverse psychological effects including anhedonia, a core symptom of major depression, manifested behaviorally as decreased responding for rewarding stimuli. The present study used brain microdialysis in freely moving rats to examine the effect of D-amphetamine (D-amph) withdrawal on changes in extracellular dopamine (DA) levels in the nucleus accumbens (NAc) evoked by D-amph or behavior related to sucrose consumption. D-amph was administered intraperitoneally (i.p.) according to an escalating dose (ED) schedule (from 1 to 10 mg/kg, 3 doses/day). We first confirmed the development of tolerance by monitoring DA efflux in the NAc in response to 5 and 10 mg/kg doses of D-amph administered during the ED schedule of drug administration and again in response to the 5 mg/kg dose of D-amph 72 h following the last 10 mg/kg D-amph injection. In a separate study, DA efflux in the NAc was first shown to be increased significantly during both preparatory and consummatory phases of responding for a 4% sucrose solution. Withdrawal from the ED schedule of D-amph caused a selective attenuation of DA efflux only during the preparatory phase of the sucrose test. These results provided convincing evidence of neurochemical adaptation within the mesocorticolimbic DA pathway during and following the administration of an ED schedule of D-amph as well as suppressed neurochemical responses to a psychostimulant drug and cues associated with a natural reward after withdrawal from drug treatment. Accordingly, these findings support the hypothesis that downregulation of mesocorticolimbic DA function maintained during D-amph withdrawal may account for the selective disruption of motivated behavior reported in studies employing psychostimulant drug withdrawal as a model of depression in rodents.     

Spontaneous nicotine withdrawal potentiates the effects of stress in rats.

Anxiety is a common symptom of nicotine withdrawal in humans, and may predict an inability to abstain from cigarette smoking. It is not clear if self-reports of anxiety during abstinence reflect increased baseline anxiety and/or increased responses to exogenous stressors. We hypothesized that nicotine withdrawal selectively exacerbates reactivity to aversive stimuli in rodents. Here, we investigated the effect of withdrawal from chronic nicotine administration (3.16 mg/kg per day base, delivered via subcutaneous osmotic minipumps) in the light-enhanced startle (LES) test in Wistar rats. In this procedure, baseline startle responding in the dark is compared to startle responding when the chamber is brightly lit. Bright illumination is aversive for rats and potentiates the startle response. Hence, this procedure allows comparisons of withdrawal effects on startle reactivity between relatively neutral and stressful contexts. We found that spontaneous nicotine withdrawal (24 h post-pump removal) did not influence baseline startle responding, but produced a selective increase in LES. Precipitated nicotine withdrawal through injections of one of two nicotinic acetylcholine receptor (nAChR) antagonists, dihydro-beta-erythroidine hydrobromide (DHbetaE: 0, 1.5, 3, or 6 mg/kg) or mecamylamine (0, 1, 2, or 4 mg/kg), did not influence baseline startle responding or LES. These results suggest that spontaneous nicotine withdrawal selectively potentiates responses to anxiogenic stimuli, but does not by itself produce a strong anxiogenic effect. These findings support the hypothesis that nicotine withdrawal exacerbates stress responding, and indicate LES may be a useful model to examine withdrawal effects on anxiety.     

Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction

Rationale Enhanced reinforcing effects of nicotine during adolescence appear to contribute to the rapid development of dependence in this age group. However, the contribution of nicotine withdrawal to dependence in adolescents is unclear.Objective We compared motivational and somatic signs of nicotine withdrawal in adolescent and adult rats.Materials and methods In experiment 1, motivational signs of nicotine withdrawal were compared using intracranial self-stimulation procedures after administration of mecamylamine (1.5 mg/kg, i.p.) in adolescent and adult rats made dependent on nicotine (9 mg/kg/day). Somatic signs of withdrawal were compared in two experiments using various doses of nicotine (adolescent doses: 0, 1.6, 3.2, 4.7 mg/kg/day; adult doses: 0, 1, 2.1, 3.2 mg/kg/day, expressed as nicotine base) to produce dependence and one dose of mecamylamine (1.5 mg/kg, i.p.) to precipitate withdrawal (experiment 2) and in a subsequent experiment, using various doses of mecamylamine (0, 0.75, 1.5, 3.0 mg/kg, i.p.) to precipitate withdrawal and a dose of nicotine (adolescent dose: 4.7 mg/kg/day; adult dose: 3.2 mg/kg/day) that produced equivalent nicotine blood levels in these age groups (experiment 3).Results Adolescents did not display the decreases in brain reward function observed in adults experiencing withdrawal, and displayed fewer somatic signs of nicotine withdrawal relative to adults regardless of the dosing procedure used.Conclusion The negative effects of nicotine withdrawal are lower during adolescence relative to later periods of development. Both the enhanced rewarding effects and the diminished nicotine withdrawal likely contribute to the rapid development of nicotine use during adolescence.     

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.     

Locomotor activity as a predictor of times and dosages for studies of nicotine's neurochemical actions

Nicotine's action on the central nervous system is complex and likely involves an interaction of neurotransmitters. To determine the time after administration of nicotine and dosage for neurochemical studies, locomotor activity of CD-1 mice was determined at 5 min intervals between 0-60 min. A low nicotine dosage (0.05 mg/kg) did not alter activity 5-15 min after drug injection, but increased activity 28% at 15-25 min post-injection. A high dosage (0.8 mg/kg) reduced total distance 62% and rearing 87% at 5-15 min; at 15-25 minutes total distance declined 56% and rearing 69%; all measures returned to control values after 30 minutes; rearing then increased at 40 min after nicotine. Pretreatment (15 min before nicotine) with mecamylamine (1.0 mg/kg), but not hexamethonium (1.0 mg/kg), prevented the depressant effect of nicotine. Dopamine (DA) and its metabolites as well as acetylcholine (ACh) synthesis were measured at the point of nicotine's maximal depressant action. Striatal levels of dihydroxyphenylacetic acid (DOPAC) were increased and ACh utilization was reduced in striatum (-25%) and cortex (-24%) 10 min after nicotine (0.8 mg/kg). Mecamylamine, while preventing the depressant effect of nicotine on locomotor activity, did not alter its effects on DA metabolism. These results demonstrate that the behavioral outcome of acute nicotine treatment is time and dose-dependent. Nicotine's depressant action appears not to be due to altered DA but may be related to changes in carbohydrate and acetylcholine metabolism.     

Expression of fos-related antigens in the nucleus accumbens during opiate withdrawal and their attenuation by a D2 dopamine receptor agonist.

Previous studies from this laboratory indicated that D2 dopamine (DA) receptors within the nucleus accumbens (NAc) are important for regulating somatic signs of opiate withdrawal. The present study measured the expression of Fos-related antigens (FRAs) within the NAc during opiate withdrawal to determine whether decreases in somatic withdrawal signs produced by a D2 receptor agonist are accompanied by related changes in accumbens neuronal activity. In an initial experiment, quantitative analyses of FRA immunoreactivity revealed increases in the number of FRA-positive cells throughout the NAc of opiate dependent animals undergoing naltrexone-precipitated withdrawal relative to dependent or non-dependent animals that did not experience withdrawal. A second experiment showed that somatic signs and FRA expression within the NAc could each be attenuated when the D2 agonist propylnorapomorphine (NPA; 0.1 or 0.3 mg/kg, i.p.) was administered prior to naltrexone-precipitated withdrawal. These findings suggest that D2 regulation of neuronal activity within the NAc may be important for the expression of opiate withdrawal symptoms.     

Sensitization of cortical acetylcholine release by repeated administration of nicotine in rats

Abstract Rationale. The integrity of cortical cholinergic transmission is vital to attentional processing. A growing literature suggests that alterations in attentional processing accompany addictive drug use. This study examined the effects of acute and repeated administration of nicotine on cortical acetylcholine release. Objectives. The effects of repeated systemic nicotine administration on cortical acetylcholine (ACh) efflux in the frontal cortex were determined to test the hypothesis that repeated administration of nicotine results in a potentiated or sensitized increase in ACh efflux. Methods. Animals were injected with nicotine (0.4 mg/kg, i.p.) or vehicle twice daily for 4 days. Cortical ACh efflux was measured using repeated microdialysis sampling on four occasions: on day 1, during the first exposure to nicotine or vehicle, on day 5 during a final exposure to nicotine, on day 8 during a nicotine challenge, and again on day 10 following saline administration. Results. Acute nicotine administration on day 1 produced a 90% increase in cortical ACh efflux. Repeated exposure to nicotine resulted in a larger increase in cortical ACh efflux on day 5 (200%) and day 8 (210%) relative to ACh levels measured on day 1, and relative to animals that received vehicle during the initial treatment period. Cortical ACh efflux following acute nicotine administration was blocked by mecamylamine (1.0 mg/kg, i.p.). However, the sensitized efflux of cortical ACh on day 8 was only partially attenuated by mecamylamine (1.0 or 5.0 mg/kg, i.p.), suggesting a mecamylamine-insensitive component of the sensitized response to repeated nicotine administration. Conclusions. Repeated administration of nicotine results in a sensitized increase in cortical ACh release. Sensitized cortical ACh release may mediate, in part, the cognitive components of nicotine addiction. Electronic Publication     

Supraadditive effect of d-fenfluramine plus phentermine on extracellular acetylcholine in the nucleus accumbens: possible mechanism for inhibition of excessive feeding and drug abuse

The combination of d-fenfluramine plus phentermine (d-FEN/PHEN) provides a tool for exploring neural mechanisms that control food intake and drug abuse. Prior research suggests that dopamine (DA) in the nucleus accumbens can reinforce appetitive behavior and acetylcholine (ACh) inhibits it. When rats were given d-fenfluramine (5 mg/kg, IP) DA increased to 169% (p < 0.01), and ACh decreased slightly. Phentermine (5 mg/kg, IP) increased extracellular DA to 469% of baseline and ACh increased slightly to 124% (both p < 0.01). The d-FEN/PHEN combination, however, increased both DA and ACh with a supraadditive effect on ACh to 172%. One interpretation is that dFEN/PHEN increases DA like a meal or drug of abuse, while also increasing ACh to stop further approach behavior. This leaves the animal "satiated," as defined by reduced intake of food or drugs.     

Iptkalim inhibits cocaine challenge—induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up—regulating Kir6.1 and Kir6.2 mRNA expression

目的:研究钾通道开放剂埃他卡林对急慢性可卡因应用引起的伏隔核、纹状体和额叶皮层的多巴胺和谷氨酸水平变化的影响及其机制。方法:采用高效液相色谱与电化学检测、荧光检测联用的方法测定各脑区谷氨酸和多巴胺的含量;采用半定量逆转录聚合酶链反应(RT-PCR)研究ATP敏感性钾通道亚单位Kir6.1、Kir6.2、SUR1和SUR2 mRNA表达的变化。结果:埃他卡林不影响急性可卡因应用引起纹状体和伏隔核中多巴胺和谷氨酸水平的增高(P>0.05),能够逆转激发剂量可卡因诱导的慢性成瘾大鼠纹状体和伏隔核的多巴胺含量增高(P<0.05),对激发后皮层和伏隔核谷氨酸水平增高有降低趋势但差异无显著性(P>0.05)。激发剂量可卡因能提高可卡因预处理组和埃他卡林预处理组纹状体和伏隔核的Kir6.1和Kir6.2 mRNA表达以及皮层的Kir6.2 mRNA表达,而且IPT预处理组的升高幅度显著高显著高于可卡因慢性处 理组。结论:埃他卡林通过上调Kir6.1和Kir6.2 mRNA表达抑制可卡因激发引起的纹状体和伏隔核的多巴胺水平的增高。     

Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats

Rationale Adolescent onset of smoking is associated with a rapid progression to dependence. Although adolescents may exhibit a greater susceptibility to nicotine addiction, relatively little is known about the influence of the aversive effects of nicotine withdrawal in maintaining smoking behavior. Objectives The present study investigated age differences in the motivational effects of mecamylamine-precipitated and spontaneous nicotine withdrawal in adolescent and adult rats using the conditioned place aversion procedure (CPA). Materials and methods In experiment 1, adolescent (postnatal day (PD) 28) and adult (PD60) male Wistar rats chronically treated with nicotine (3 or 6 mg/kg/day, s.c.) received mecamylamine (1 mg/kg, s.c.), a nicotinic receptor antagonist, or vehicle prior to place conditioning; physical withdrawal signs were also measured. Experiment 2 was conducted to increase nicotine levels in which adolescents were treated with 4.5 or 9 mg/kg/day nicotine. In experiment 3, age differences in spontaneous nicotine withdrawal were evaluated. Results Nicotine-treated adults developed a CPA to the mecamylamine-associated compartment and expressed significant physical withdrawal signs, whereas similarly treated adolescents did not. Increasing nicotine exposure levels did not modify the adolescent response to mecamylamine-precipitated withdrawal. Spontaneous nicotine withdrawal produced similar physical withdrawal signs in adolescents and adults, but did not elicit CPA. Conclusions The current study indicates that adolescent rats are less responsive to the aversive effects of mecamylamine-precipitated, but not spontaneous, nicotine withdrawal compared to adult rats. These findings suggest that adolescents and adults may exhibit similar sensitivity to the affective and physical effects of withdrawal following smoking cessation.