Prior Morphine Exposure Enhances Ibogaine Antagonism of Morphine-induced Dopamine Release in Rats

The present study examines the effect of prior morphine exposure on ibogaine antagonism of morphine-induced dopamine release. Female Sprague-Dawley rats were pretreated once a day for 2 days with morphine (20 mg/kg, i.p.) or saline and given a low dose of ibogaine (10 mg/kg, i.p.) or saline 5 hr after the last morphine or saline injection. Nineteen hours later, rats (awake and freely moving) were challenged with morphine (5 mg/kg, i.p.), and dopamine and its metabolites were monitored in the striatum and nucleus accumbens using in vivo microdialysis. Neither saline pretreatment, morphine pretreatment, nor ibogaine alone altered morphine-induced increases in extracellular dopamine and dopamine metabolites in either structure. However, when morphine pretreatment was combined with ibogaine, the morphine-induced elevation of dopamine, but not of metabolites, was completely blocked. These data suggest that prior morphine exposure enhances an opioid antagonist action of ibogaine on dopaminergic systems and that prior drug exposure may be a clinically significant determinant of ibogaine efficacy and/or potency in the treatment of opioid addiction. © Elsevier Science Ltd. All rights reserved.     

Adrenalectomy attenuates nicotine-induced dopamine release and locomotor activity in rats

Adrenalectomy (ADX) in mice can potentiate several physiological and behavioural responses to nicotine. The present experiments sought to examine this issue in the rat by characterising the influence of ADX upon the locomotor depressant, activating and dopamine-releasing properties of nicotine. Nicotine (0.8–1.2 mg/kg SC) dose-dependently depressed locomotor activity, an effect that was potentiated by ADX, while the locomotor activating effects of a smaller dose (0.4 mg/kg) were attenuated by ADX. In both SHAM and ADX rats chronically treated with nicotine for 5 days (daily injections of 0.4 mg/kg SC), the locomotor depressant effects of nicotine did not differ from saline-treated controls. Nicotine (0.4 mg/kg SC) increased extracellular levels of dopamine in the nucleus accumbens. This response was unaffected in rats pretreated with nicotine for 5 days (daily injections of 0.4 mg/kg SC). However, both ADX groups of rats showed smaller increases in dopamine following administration of nicotine. The results suggest that depletion of circulating corticosteroids can modulate sensitivity to nicotine in rats. The suppressant effects of ADX on nicotine-induced locomotor activity may be due to its effects on dopamine release in the nucleus accumbens. Received: 13 July 1995/Final version: 28 July 1996     

Ibogaine and the dopaminergic response to nicotine

There is increasing evidence that the rewarding effect of nicotine is mediated by the mesolimbic dopamine system. The first objective of this study was to examine the dopamine response to repeated IV infusions of nicotine. Using in vivo microdialysis in awake and freely moving male Sprague-Dawley rats, we demonstrated that IV nicotine infusions (0.16 mg/kg or 0.32 mg/kg per infusion) produced increases in extracellular dopamine levels that were dose- and infusion order-dependent. Acute tolerance was evidenced by the smaller dopamine response produced by a second infusion of nicotine, administered 1 h after the first one. Tolerance was reversible, since the dopamine response to a second infusion of nicotine was unchanged when the interval between the infusions was increased to 3 h. Ibogaine, an alkaloid found in Tabernanthe iboga, is claimed to decrease smoking and to have an anti-nicotinic action. The second objective of this study was to establish whether this claim has any neurochemical basis. Pretreatment with ibogaine (40 mg/kg, IP) 19 h prior to the first nicotine infusion (0.32 mg/kg per infusion) significantly attenuated the increase in extracellular dopamine levels induced by the nicotine infusions, suggesting that ibogaine may decrease the rewarding effect of nicotine. Received: 16 May 1996 / Final version: 18 September 1996     

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.     

Tranylcypromine enhancement of nicotine self-administration

Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 microg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 microg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 microg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.     

Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine.

1. The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg-1 day-1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg-1 day-1 for 5 days) of the drug. 2. The extracellular dopamine concentration in the NAc was significantly increased (P < 0.05) following a challenge dose of nicotine (0.4 mg kg-1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine. 3. The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P < 0.01) by the prior administration of mecamylamine (2.0 mg kg-1, s.c.) but not by hexamethonium (2.0 mg kg-1, s.c.). 4. The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg-1 day-1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine-pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg-1 day-1 was also significantly (P < 0.05) higher than that observed in the rats treated acutely with nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)     

α3β4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo

Habenulo-interpeduncular nicotinic receptors, particularly those containing α3, β4 and α5 subunits, have recently been implicated in the reinforcing effects of nicotine. Our laboratory has shown that injection of α3β4 nicotinic receptor antagonists into the medial habenula (MHb) decreases self-administration of multiple abused drugs, including nicotine (Glick et al., 2006, 2008; 2011). However, it is unclear whether blockade of MHb nicotinic receptors has a direct effect on mesolimbic dopamine. Here, we performed in vivo microdialysis in female rats. Microdialysis probes were implanted into the nucleus accumbens (NAcc) and α3β4 nicotinic receptor antagonists (18-methoxycoronaridine; 18-MC or α-conotoxin AuIB; AuIB), were injected into the ipsilateral MHb, just prior to systemic nicotine (0.4 mg/kg, s.c.). Dialysate samples were collected before and after drug administration and levels of extracellular dopamine and its metabolites were measured using HPLC. Acute nicotine administration increased levels of extracellular dopamine and its metabolites in the NAcc. Pre-treatment with intra-habenular AuIB or 18-MC prevented nicotine-induced increases in accumbal dopamine. Neither drug had an effect on nicotine-induced increases in dopamine metabolites, suggesting that α3β4 receptors do not play a role in dopamine metabolism. The effect of intra-habenular blockade of α3β4 receptors on NAcc dopamine was selective for acute nicotine: neither AuIB nor 18-MC prevented increases in NAcc dopamine stimulated by acute d-amphetamine or morphine. These results suggest the mesolimbic response to acute nicotine, but not to acute administration of other drugs of abuse, is directly modulated by α3β4 nicotinic receptors in the MHb, and emphasize a critical role for habenular nicotinic receptors in nicotine's reinforcing effects.     

The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity.

1. The effects of acute and subchronic nicotine and (+)-amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely-moving rats by use of in vivo microdialysis. 2. In rats which had been habituated to the test apparatus for approximately 80 min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4 mg kg-1) caused a dose-dependent increase (P less than 0.01) in spontaneous activity and evoked significant increases (P less than 0.05) in the extracellular levels of DOPAC and HVA. 3. Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg-1) resulted in increased basal levels of dopamine (P less than 0.01) and decreased basal levels of DOPAC (P less than 0.05) in the NAc dialysates. 4. Pretreatment with nicotine (0.1 or 0.4 mg kg-1 daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant (P less than 0.05). 5. If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg-1) resulted in significant increases (P less than 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged (P less than 0.05) the dopamine response to a challenge dose of nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Lobeline attenuates locomotor stimulation induced by repeated nicotine administration in rats

Lobeline inhibits [3H]nicotine binding to rat brain membranes and nicotine-induced [3H]dopamine release from superfused rat striatal slices, indicating that lobeline acts as a nicotinic receptor antagonist. To determine whether lobeline also inhibits the effects of nicotine in vivo, the present study assessed the effect of lobeline pretreatment on nicotine-induced hyperactivity and sensitization. For 12 consecutive days, rats were injected subcutaneously with lobeline (3 mg/kg) or saline, followed 10 min later by nicotine (0.3 mg/kg) or saline injection, and activity was monitored. To determine if lobeline inhibits induction of sensitization to nicotine, 1 or 28 days later, rats were pretreated with saline followed by nicotine or saline. Lobeline attenuated nicotine-induced hyperactivity when both drugs were administered repeatedly. Although an initial injection of lobeline produced hypoactivity, tolerance to this effect developed. Importantly, tolerance did not develop to the lobeline-induced attenuation of nicotine hyperactivity. Lobeline attenuated the induction of sensitization to nicotine 1 day, but not 28 days, after the cessation of lobeline treatment. These results demonstrate that systemic administration of lobeline attenuates the locomotor-activating effects of repeated nicotine injection and the sensitization to nicotine, consistent with lobeline inhibition of nicotinic receptors and/or neurotransmitter transporters.     

The effects of nicotine on locomotor activity and dopamine overflow in the alcohol-preferring AA and alcohol-avoiding ANA rats

The aim of the study was to investigate the importance of the interaction between central dopaminergic and cholinergic mechanisms for ethanol reinforcement. This was done by comparing the effects of nicotine on locomotor activity and release of dopamine in the nucleus accumbens of the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding alko non-alcohol (ANA) rats. Nicotine was administered acutely (0.25, 0.50 or 0.75 mg/kg, s.c.) or repeatedly once daily (0.5 mg/kg, s.c.) for 8 days. An acute dose of nicotine increased locomotor activity and the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) measured with in vivo microdialysis suggesting stimulation of dopamine release by nicotine. No difference in the stimulation of locomotor activity or in the increase in the extracellular concentrations of dopamine or its metabolites by nicotine was found between the rat lines. The concentrations of nicotine in the plasma were also identical. The rats treated repeatedly with nicotine showed a progressive increase in locomotion. On the challenge day, 1 week after termination of nicotine or saline injections, rats previously treated with nicotine were activated more by nicotine than saline-treated rats. This behavioral sensitization was not accompanied by an increase in the amplitude of the neurochemical response to nicotine, but the duration of the increase in the levels of DOPAC was longer in the nicotine than saline-treated animals. The increases in locomotor activity and metabolite levels were, however, similar in both rat lines. These data suggest that differences in the interaction of central dopaminergic and cholinergic mechanisms probably do not contribute to the difference in ethanol self-administration between the AA and ANA rat lines.     

Nicotine and epibatidine alter differently nomifensine-elevated dopamine output in the rat dorsal and ventral striatum

We studied the effects of nicotine and epibatidine given in combination with dopamine uptake inhibitor, nomifensine, on striatal extracellular dopamine and its metabolites by using brain microdialysis in freely moving rats. Nomifensine (3 mg/kg) elevated extracellular dopamine in the caudate-putamen, and clearly more in the nucleus accumbens. In the caudate-putamen, nicotine (0.5 mg/kg) and epibatidine (0.6 microg/kg but not 3.0 microg/kg) enhanced nomifensine's effect on dopamine. The effect of nomifensine on accumbal dopamine was enhanced by nicotine, but inhibited by epibatidine at 0.6 microg/kg. The larger dose of epibatidine had no effect. Thus, the effects of the smaller epibatidine dose (0.6 microg/kg) on the dopamine output in the caudate-putamen but not in the accumbens resemble those of nicotine 0.5 mg/kg. Discrepancies in the effects of epibatidine and nicotine are most probably due to differences in their affinities to nicotinic receptor subtypes regulating dopamine release. Further, different responses to low concentrations of epibatidine between the brain areas suggest that there are differences in the nicotinic regulation of nigrostriatal and mesolimbic dopaminergic pathways.     

Chronic desipramine and fluoxetine differentially affect extracellular dopamine in the rat prefrontal cortex

The effect of chronic administration of desipramine or fluoxetine (10 mg/kg IP once a day for 2 weeks) on extracellular noradrenaline, serotonin and dopamine in the rat prefrontal cortex was studied by transcerebral microdialysis. Chronic desipramine increased extracellular noradrenaline and dopamine by three-fold as compared to saline controls. Acute challenge with 10 mg/kg desipramine increased by more than three-fold extracellular noradrenaline and dopamine in saline controls, but failed further to increase extracellular noradrenaline and dopamine in rats chronically administered desipramine. Chronic fluoxetine more than doubled the extracellular concentrations of serotonin but failed to change the extracellular concentrations of dopamine as compared to saline controls. Challenge with 5 mg/kg fluoxetine while almost doubling extracellular serotonin and dopamine concentrations in saline controls, failed further to increase extracellular serotonin and did not change extracellular dopamine in rats chronically exposed to fluoxetine. In contrast, challenge with 10 mg/kg desipramine normally increased extracellular dopamine in rats chronically exposed to fluoxetine. Therefore, chronic fluoxetine is associated with normal presynaptic dopamine transmission in the prefrontal cortex as a result of tolerance to fluoxetine-induced increase of extracellular dopamine; in contrast, chronic desipramine is associated with an increase of pre-synaptic dopamine transmission in the prefrontal cortex up to a level that cannot be further elevated by acute desipramine challenge. The results suggest that prefrontal cortex dopamine plays a different role in the antidepressant properties, of desipramine and fluoxetine.     

Evidence that mesoaccumbens dopamine and locomotor responses to nicotine in the rat are influenced by pretreatment dose and strain

RATIONALE: Sensitisation of the mesoaccumbens dopamine response to nicotine has been implicated in the development of nicotine dependence. This study explored the doses of nicotine that elicit the response in two strains of rats that differ in their baseline levels of activity. METHODS: Male Sprague-Dawley and Lister hooded rats were pretreated with daily subcutaneous injections of (-)-nicotine for 7 days at doses ranging from 0.03 mg/kg to 0.90 mg/kg. Microdialysis studies were performed on day 9 in conscious freely moving rats, placed in an activity box and challenged with 0.4 mg/kg nicotine. RESULTS: The acute administration of nicotine to drug-naive rats stimulated dopamine overflow in the accumbal shell but not the core. Sprague-Dawley rats, pretreated with nicotine (0.03 mg/kg/day and 0.10 mg/kg/day) showed increased basal overflow of dopamine in the accumbal core. Pretreatment with 0.10 mg/kg/day or 0.30 mg/kg/day, but not 0.03 mg/kg/day or 0.90 mg/kg/day, also caused sensitisation of the response to a nicotine challenge on the test day. Sensitisation of the locomotor response to nicotine exhibited a simple dose-response relationship, with the largest sensitisation being observed in animals pretreated with 0.90 mg/kg/day. In Lister hooded rats, pretreatment with nicotine reduced basal dopamine overflow in the accumbal core and did not cause sensitisation to a subsequent challenge with nicotine. CONCLUSIONS: Sensitisation of the mesoaccumbens dopamine response to nicotine is influenced by pre-treatment dose and the strain of rats used. It is not related directly to the expression of sensitised locomotor responses to the drug and, therefore, may be implicated in other psychopharmacological properties of the drug, including dependence.     

Mecamylamine blocks the development of tolerance to nicotine in rats: implications for the mechanisms of tolerance

 Chronic injections of nicotine in rats produce upregulation of nicotinic cholinergic receptors. It has been proposed that this upregulation is a reflection of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicotinic receptors, does not prevent upregulation produced by nicotine injections. This suggests that receptor activation is not a prerequisite for nicotine-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of tolerance to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicotine did block the development of tolerance to nicotine-induced antinociception (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.66 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no evidence that after six pairings of mecamylamine with nicotine, the cues associated with mecamylamine delivery took on conditioned antagonistic properties. These findings suggest that, unlike the receptor upregulation that results from either continuous or repeated nicotine administration, the tolerance following a short series of intermittent nicotine injections is dependent on receptor activation. Received: 20 May 1998 / Final version: 23 July 1998     

Blockade of nicotine-induced locomotor sensitization by a novel neurotensin analog in rats

Neurotensin is a tridecapeptide with anatomic and functional relationships to dopaminergic neurons. Previously we showed that one of our brain-penetrating neurotensin analogs, NT69L (N-met-L-Arg, L-Lys, L-Pro, L-neo-Trp, L-tert-Leu, L-Leu), blocks cocaine- and D-amphetamine-induced hyperactivity in rats. We have now performed a similar study in rats sensitized to nicotine over 15 days of administration. Male Sprague-Dawley rats were randomly assigned to receive daily injections for 15 days with one of the following combinations: saline/nicotine (0.35 mg/kg), NT69L (1 mg/kg)/nicotine, saline/saline, or NT69L/saline with a 30-min period between injections. On day 15 each group was given saline/nicotine or NT69L/nicotine and tested in an activity chamber. One-time administration of NT69L attenuated nicotine-induced activity with an ED(50) of 1.6 microg/kg. Rats injected with nicotine over the 15 days had a significant increase in locomotor activity, consistent with nicotine-induced locomotor sensitization. A single injection of NT69L on day 15 prior to nicotine markedly decreased nicotine-induced hyperactivity. Although daily injections of NT69L lessened its effect, statistically significant reductions in hyperactivity to nicotine persisted throughout the study. There was no significant difference in activity between rats injected with NT69L/saline and saline/saline. Thus, the activity reduction was not due to sedation. Acute and chronic nicotine injection caused an increase in cytisine binding in prefrontal cortex. NT69L significantly reduced the increase caused by acute but not chronic injection of nicotine. Nicotine injection resulted in an increase in dopamine levels in the striatum and dopamine and norepinephrine levels in the prefrontal cortex. NT69L lowered the norepinephrine and dopamine levels in the prefrontal cortex but did not affect striatal dopamine. The present study is the first report, to our knowledge, of a possible role for neurotensin in the development of nicotine dependence, and suggests that neurotensin analogs such as NT69L may be explored as treatment for nicotine and other psychostimulant abuse.     

Effect of acute nicotine administration on striatal dopamine output and metabolism in rats kept at different ambient temperatures

1. The effect of ambient temperature on the nicotine-induced (0.3, 0.5 or 0.8 mg kg(-1) s.c.) changes of the striatal concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was studied in freely-moving rats by in vivo microdialysis. 2. At the ambient temperature of 30 - 33 degrees C, but not at 20 - 23 degrees C, nicotine doses of 0.5 (P<0. 01) and 0.8 mg kg(-1) (P<0.05) significantly increased the extracellular DA concentration. The nicotine doses of 0.5 and 0.8 mg kg(-1) increased the DA metabolite levels similarly at both ambient temperatures studied (P相似文献   

MDMA Elicits Behavioral and Neurochemical Sensitization in Rats

Rats were treated with repeated injections of saline or one of two doses of (±)3,4-methylenedioxymethamphetamine (MDMA; 5 or 20 mg/kg, SC). Rats pretreated with either of the two repeated MDMA treatment regimens demonstrated an augmented increase in motor activity to an injection of MDMA made 12 days after the last repeated injection compared with either the first MDMA injection or MDMA given to animals pretreated with repeated saline. Furthermore, animals pretreated with the highest dose of repeated MDMA revealed a greater behavioral response to cocaine (15 mg/kg, IP). Microdialysis was conducted in the nucleus accumbens and the capacity of MDMA (5 mg/kg, SC) to elevate extracellular dopamine content was augmented in rats pretreated with repeated MDMA compared with the animals pretreated with repeated saline. These data reveal repeated MDMA administration produces behavioral sensitization and enhanced dopamine transmission in the nucleus accumbens of rats.     

Evidence of cross-tolerance between behavioural effects of nicotine and cocaine in mice

Rationale. Studies have reported that chronic exposure to nicotine does not alter the effects of cocaine on locomotor activity, and vice versa. However, the apparent lack of effect of one drug on the behavioural response to the other may be due to an exclusive focus on locomotor activity as the target behaviour. Objective. To test whether repeated pretreatment with nicotine causes tolerance or sensitization to cocaine's effects on diverse behaviours: locomotion, rearing, grooming, and immobility. Similarly, the effects of repeated cocaine treatment on the acute response to nicotine were also tested. Methods. Mice were pretreated with 14 injections of nicotine (0.3 mg/kg), cocaine (5 mg/kg) or saline, the injections being given once daily, except for three breaks of two days each. Two days after the final pretreatment injection, mice were given a challenge injection of saline, cocaine (3 or 5 mg/kg) or nicotine (0.3 or 1 mg/kg), and observed in a large test cage for 40 min using a time-sampling procedure. Results. Repeated administration of either drug produced some tolerance to subsequent challenge with the same dose of the drug. Prior nicotine exposure significantly attenuated cocaine-induced decreases in grooming and increases in rearing, but did not significantly affect other behaviours. In contrast, prior cocaine exposure failed to alter nicotine's effects on any behaviour. Conclusions. Cross-tolerance between nicotine and cocaine (but not vice-versa) can be demonstrated if several behaviours are observed; measures of locomotor activity are less sensitive to the effect. The asymmetrical pattern of cross-tolerance may be due to differential inhibition of dopamine uptake by the two drugs. Electronic Publication     

Acute stress or corticosterone administration reduces responsiveness to nicotine: implictions for a mechanism of conditioned tolerance

We have shown that conditioned tolerance develops to some of the behavioral and endocrine effects of nicotine in rats. Other investigators have suggested that tolerance to multiple nicotine injections in mice may be due, in part, to elevated plasma corticosterone (CORT) levels, since repeated nicotine injections are associated with elevated CORT,chronically elevated CORT reduces nicotine responsiveness and adrenalectomy disrupts nicotine tolerance. Three experiments tested the feasibility of this hypothesis, as a mechanism for conditioned nicotine tolerance in rats, by determining whetheracute administration of CORT or manipulations that increase adrenocortical activity reduce nicotine responsiveness. In experiment 1, male rats were injected IP with CORT (1 mg/kg), vehicle (ETOH + distilled water) or no injection 10 min before nicotine (0.75 mg/kg, SC) and tested for nicotine-induced analgesia every other day for 10 days. A significant reduction in withdrawal latencies was obtained for CORT pretreated rats compared to animals given only nicotine. A similar reduction was produced by the vehicle pretreatment, which itself induced an elevation of endogenous CORT. Experiments 2 and 3 established that similar effects could be produced by doses of CORT as low as 0.125 mg/kg or by exposure to a novel environment which also elevated CORT levels. Results also suggest that a conditioned release of endogenous CORT was triggered by stimuli associated with nicotine delivery. These data are consistent with the hypothesis that a conditioned release of CORT could contribute to the development of tolerance to some of nicotine's effects. The possibility that other neuroendocrine mediators might be involved in addition to or instead of CORT, is also discussed.