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1.
RATIONALE: The pedunculopontine tegmental nucleus (PPTg) has been implicated in the self-administration of drugs, particularly nicotine, which acts directly through the PPTg in addition to targeting midbrain dopamine neurons. The direct action of nicotine in PPTg may be through GABAergic mechanisms that have been shown to influence nicotine self-administration preferentially compared to cocaine. OBJECTIVE: The purpose of these experiments was to examine several pharmacological manipulations that alter neuronal activity in the PPTg for their specificity or generality in nicotine versus cocaine reinforcement. METHODS AND RESULTS: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the muscarinic agonist carbachol (0.1-1.0 microg), the micro opioid agonist DAMGO (0.005 and 0.05 microg), tetrodotoxin (5 ng) and neostigmine (0.5 nmol) each reduced the self-administration of nicotine and cocaine maintained on an FR5 schedule of reinforcement. The muscarinic antagonist scopolamine (0.1-1.0 microg) and the opioid antagonist CTOP (1 microg) did not affect self-administration, but reversed the effects of the respective agonist when co-administered with it. Carbachol and DAMGO were also tested in self-administration maintained on a progressive-ratio schedule; each agonist again reduced both nicotine and cocaine self-administration. CONCLUSIONS: PPTg manipulations are able to alter established self-administration of nicotine, which acts at the level of the ventral tegmental area and the PPTg itself, and cocaine, which acts through the mesolimbic dopamine system. These data suggest that the PPTg is an important substrate in drug dependence. 相似文献
2.
Rationale The brainstem pedunculopontine tegmental nucleus (PPTg) is proposed to mediate hypothalamic self-stimulation reward via cholinergic
activation of the ventral tegmental area (VTA). However, to date there is little direct evidence to support this hypothesis.
Objectives To further study the role of PPTg in hypothalamic self-stimulation reward.
Methods By using in vivo microdialysis, the levels of extracellular acetylcholine (ACh) in the PPTg and VTA were detected during lateral
hypothalamic (LH) self-stimulation in rats. Rate–frequency curve shift procedure was used to evaluate the effects of nonselective
muscarinic antagonist scopolamine (1∼100 μg/μl) and nicotinic antagonist mecamylamine (5∼100 μg/μl) microinjected into the
PPTg on the rewarding efficacy of LH self-stimulation. Subsequently, the drugs were injected into the PPTg, and the extracellular
ACh in the VTA was measured.
Results LH self-stimulation produced a concurrent ACh release in the PPTg and VTA. Intra-PPTg injection of scopolamine (100 μg/μl)
significantly reduced the frequency threshold for LH self-stimulation reward, but nicotinic antagonist mecamylamine did not
shift the threshold. However, mecamylamine (10, 25 μg/μl) injected into the PPTg robustly diminished the nicotine-potentiated
LH self-stimulation reward. The extracellular ACh in the VTA was dramatically increased by intra-PPTg scopolamine (10, 100 μg/μl),
but not by mecamylamine.
Conclusions Results confirm that PPTg plays an important role in brain stimulation reward by modulating the cholinergic activity of the
VTA. The PPTg muscarinic receptors contribute to an inhibitory modulation of reward effects by self-stimulation, whereas nicotinic
receptors seem to be more involved in nicotine potentiation of brain stimulation reward. 相似文献
3.
The aim of this study was to assess the effects of a single dose of nicotine (NIC, 0.3 or 1.0 mg/kg, s.c.), after survival times of 30, 60 or 120 min, on immediate early gene expression in the pedunculopontine mesencephalic tegmentum (PMT), using Fos-immunocytochemistry. Either doses of NIC strongly increased Fos-immunoreactivity in both the pedunculopontine tegmental nucleus (PPTg) and the laterodorsal tegmental nucleus (LDTg), as compared to the saline controls, at 30 min and 60 min. In comparison, the effects of NIC-induced Fos expression in the caudate-putamen (CP) were not as strong as the ones observed in the PPTg and LDTg. In fact, at 30 min the 0.3 mg/kg dose of NIC did not induce Fos-expression, unlike the PPTg and LDTg. The CP response was more noticeable in the mediodorsal than in the laterodorsal region. Double-labelling studies using Fos-immunoreactivity and NADPH-diaphorase histochemistry for cholinergic cells in the PPTg and LDTg revealed that, in general, cholinergic neurons had Fos negative nuclei, although double-labelled neurons were occasionally seen in the PPTg. In conclusion, systemically administered NIC activates the neuronal population of the PPTg and the LDTg possibly by directly targeting nicotinic receptors that may be located in non-cholinergic neurons. We postulate that activation of these non-cholinergic neurons modulates the activity of cholinergic cells in the PMT, which in turn may alter dopamine release in the mesolimbic system. 相似文献
4.
Rationale Nicotine has two effects on reinforcement in traditional self-administration paradigms. It serves as a primary reinforcer
by increasing the probability of behaviors that result in nicotine delivery. However, nicotine also potently enhances behaviors
that result in the delivery of nonpharmacological reinforcers.
Objectives The present study sought to dissociate these two effects of nicotine on reinforcement.
Methods For one group of rats (2 lever), a nonpharmacological reinforcer [visual stimulus (VS)] was available for pressing one lever.
Nicotine infusions were available for pressing a different lever. A second group (NIC + VS) received more traditional self-administration
training; both the VS and nicotine were delivered for pressing a single active lever. Control groups received either nicotine
infusions (NIC only) or VS presentations (VS only) for pressing the active lever.
Results Nicotine alone was a weak reinforcer; the VS alone was slightly more reinforcing than nicotine. When these two reinforcers
were combined (NIC + VS), response rates were synergistically increased. For the 2-lever group, responding on the nicotine
lever was weak, matching the response rates of rats receiving nicotine alone. However, responding on the VS lever was potently
enhanced in this group; equaling the response rates for rats receiving both reinforcers for making a single response (NIC
+ VS).
Conclusions These data indicate that the reinforcement-enhancing effects of nicotine are very potent even when only moderate quantities
of the drug are self-administered. Moreover, they provide the first demonstration that the reinforcement-enhancing and primary
reinforcing effects of nicotine can be dissociated behaviorally. 相似文献
5.
The effect of the selective D1 antagonist, SCH 23390, and the selective D2 antagonist, spiperone, was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Both SCH 23390 and spiperone pretreatment increased responding up to doses of 10.0 µg/kg, and decreased responding at higher doses. Since rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy, behavior maintained by cocaine was also investigated under a progressive-ratio schedule. The breaking point obtained under this schedule is used as a measure of the efficacy of the reinforcer and this value is not exclusively determined by response rate. With the progressive-ratio schedule, both SCH 23390 and spiperone produced dose-dependent decreases in the highest ratio completed in rats self-administering cocaine. The results obtained using the FR 5 and progressive-ratio schedules suggest that both D1 and D2 receptors are involved in mediating the reinforcing effects of cocaine. 相似文献
6.
The effects of intraperitoneal (i.p.) or intrathecal (i.t.) injection of antagonists of acetylcholine, noradrenaline, serotonin, dopamine, opioids and GABA on stimulation-produced antinociception (SPA) from the pedunculopontine tegmental nucleus (PPTg) of rats were studied using the tail-flick test. The electrical stimulation of the PPTg produced a strong and long-lasting increase in tail-flick latency. The intensity and duration of the effect were significantly reduced in rats pretreated with i.p. or i.t. atropine (a non-selective muscarinic cholinergic antagonist), or i.t. phenoxybenzamine or WB 4101 (non-selective and selective α 1-adrenergic antagonists, respectively). Intraperitoneal phenoxybenzamine, i.p. or i.t. methysergide or naloxone (non-selective serotonin and opioid antagonists, respectively), or i.t. idazoxan (a selective α 2-adrenergic antagonist) only reduced the duration of the effect. The duration of SPA from the PPTg was increased by i.t. phaclofen (a GABA B antagonist). The effect from the nucleus was not altered following i.t. bicuculline (a GABA A antagonist), or i.p. or i.t. mecamylamine, propranolol or haloperidol (non-selective nicotinic cholinergic, β-adrenergic and dopaminergic antagonists, respectively). Thus, SPA from the PPTg involves the spinal activation of muscarinic and α 1-adrenergic but not nicotinic cholinergic, β-adrenergic and dopaminergic mechanisms. Serotonergic, endogenous opioid and α 2-adrenergic mechanisms are involved in the duration but not in the intensity of the effect. 相似文献
7.
The effects of the noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats
were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on
a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP,
30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed
that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1
mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15
mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across
all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine.
The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher
doses attenuate, the rewarding effects of self-administered cocaine.
Received: 3 January 1996 / Final version: 12 June 1996 相似文献
8.
6-Hydroxydopamine-induced destruction of dopaminergic terminals in the nucleus accumbens have been shown previously to disrupt cocaine and amphetamine self-administration. We sought to determine whether lesions of the DA cell bodies in the ventral tegmental area (VTA) which give rise to the DA innervation of the n. accumbens, would also disrupt cocaine self-administration behavior. Rats were trained to self-inject cocaine (0.75 mg/kg) for 4 hr/day. After a stable baseline was established, one group of rats received bilateral injections of 6-OHDA (4 micrograms/l microliter) into the VTA. Control rats received vehicle injections. When retested on the fifth day post-lesion, all of the 6-OHDA treated animals showed a long lasting reduction in cocaine intake. Three animals did not reinitiate cocaine self-administration after the lesion, although each showed stable post-lesion responding for apomorphine. The surgery had no effect on cocaine self-administration in control animals. These data support the hypothesis that dopaminergic mechanisms are necessary for the normal expression of cocaine self-administration. 相似文献
9.
Rationale: The pedunculopontine tegmental nucleus (PPTg) has been implicated in drug reward, particularly in the development of dependence.
However, little is known of the receptor systems within this nucleus which might be involved. Furthermore, some research suggests
that the PPTg may also be part of the neuronal circuitry involved in established drug-taking behavior. Objective: The objective of these experiments was to examine the role of mu-opioid and nicotinic cholinergic mechanisms in the PPTg
in cocaine self-administration. Methods: Microinfusions of mu-opioid and nicotinic receptor selective compounds were made into the PPTg of rats trained to self-administer
cocaine intravenously, in the vicinity of cholinergic cells which are known to project to the midbrain dopamine neurons of
the ventral tegmental area (VTA). Results: The mu-opioid selective agonist DAMGO, tested at doses of 0, 0.05 and 0.5 μg, produced a dose-related reduction in the number
of cocaine infusions obtained during the 1-h self-administration sessions. The mu-selective antagonist CTOP (0–2 μg) and nicotine
(0–10 μg) did not produce significant changes in cocaine self-administration. Microinfusions of the nicotinic antagonist dihydro-β-erythroidine
(0–30 μg) produced a small but significant increase in cocaine-maintained responding. Conclusions: These data show that mu-opioid mechanisms in the PPTg can influence cocaine self-administration markedly. Moreover, the data
demonstrate that PPTg circuitry can influence drug reward in already-established drug-reinforced behavior, as well as during
the development of dependence (as shown by previous research).
Received: 30 November 1998 / Final version: 25 March 1999 相似文献
10.
The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural subtrates are responsible for the reinforcing actions of these two drugs. 相似文献
11.
Rationale Previous work has indicated a potential role for -aminobutyric acid-B (GABA B) receptor agonists in treating drug addiction in humans. Specifically, GABA B receptor agonists decreased cocaine, heroin and nicotine self-administration in rats.Objectives The purpose of the present studies was to extend previous findings by assessing the effects of additional GABA B receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats.Methods Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABA B receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules.Results Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function ( r=0.61). Both CGP44532 and (–)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule.Conclusion The present data demonstrate that administration of GABA B receptor agonists decreased intravenous nicotine self-administration under both fixed and progressive ratio schedules of reinforcement, possibly reflecting reduced rewarding effects of nicotine. Both baclofen and CGP44532 exhibited specificity for nicotine- versus food-maintained responding on the fixed ratio schedules but not on the progressive ratio schedule (CGP44532 tested only), indicating the potential usefulness of GABA B receptor agonists as therapeutics for smoking cessation. 相似文献
12.
Rationale Immunization of rats against nicotine using a nicotine conjugate vaccine reduces the distribution of nicotine to brain in
rats and attenuates some of nicotine's physiological and behavioral effects. It is not known whether such a vaccine can attenuate
nicotine's reinforcing effects.
Objective The present experiment was conducted to determine whether a nicotine conjugate vaccine could interfere with the acquisition
and maintenance of nicotine self-administration (NSA) in rats given 23 h day −1 access to nicotine.
Methods To examine acquisition of NSA, rats were vaccinated with nicotine or control immunogen prior to being given access to a 0.01 mg
kg −1 infusion −1 nicotine under a fixed-ratio(FR) 1 schedule for week 1, FR 2 for week 2, and FR 3 for week 3. Acquisition of cocaine self-administration
(CSA) was similarly examined to determine the specificity of vaccination effects. To examine maintenance of NSA, rats were
initially trained to self-administer nicotine under an FR 3 schedule, and then vaccinated with nicotine or control immunogen
while NSA continued to be monitored.
Results NSA was significantly lower in vaccinated rats compared to controls during the acquisition protocol, with a 38% decrease in
the number of infusions during the last week of training. The percentage of rats meeting acquisition criteria in the vaccinated
group was lower (36%) than that in the control group (70%), but this difference was not statistically significant. Vaccination
did not affect acquisition of CSA, demonstrating its specificity for nicotine. Maintenance of NSA was significantly reduced
in vaccinated rats as compared to controls after the final vaccine injection, with a mean reduction of 57%. There was no evidence
in either protocol that vaccinated rats attempted to compensate for altered nicotine distribution by increasing nicotine intake.
Conclusion These data suggest that vaccination against nicotine can reduce the reinforcing effects of nicotine in rats and may have therapeutic
potential for the treatment of tobacco dependence. 相似文献
13.
Rationale The pedunculopontine tegmental nucleus (PPTg) is involved in the execution and regulation of a variety of behaviors. Most investigations used brain lesions that have certain disadvantages, such as functional compensation over time.Objectives In the present study, we investigated by temporary, reversible inhibition of neurons the role of the PPTg in sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR) using variable interstimulus intervals (ISI). In a second set of experiments we examined by the same technique the role of the PPTg in a progressive-ratio instrumental response task.Methods Local infusions of the GABA A-receptor agonist muscimol (0.05 g and 0.5 g/0.3 l, or vehicle) were applied through indwelling microinfusion cannulae into the PPTg of freely moving rats. ASR and PPI were measured using acoustic stimuli of 100 dB (pulse) and 80 dB (prepulse) using ISIs of 25, 120, 520 and 1,020 ms. Instrumental behavior (lever pressing for casein pellets) was assessed in a Skinner box. Motor activity was measured in an open field.Results Intra-PPTg infusions of muscimol dose-dependently attenuated PPI at ISIs of 120 ms and 520 ms, but not at longer or shorter ISIs. ASR magnitude in pulse-alone trials was not significantly affected. Intra-PPTg infusion of 0.5 g muscimol reduced the break point of instrumental responding (testing sequence where the rats fail to respond according to an increased ratio of reinforcement). No effects on food-preference and open-field activity were found.Conclusions These findings suggest that GABAergic neurotransmission in the PPTg plays an important role for sensorimotor gating at intermediate ISIs and for response selection under demanding schedules of reinforcement. 相似文献
14.
Summary The effects of the GABA A agonist, muscimol, and of the enantiomers of the GABA B agonist, baclofen, on the release of endogenous GABA from slices of the rat cerebral cortex, striatum and hippocampus were measured by means of a HPLC method with electrochemical detection. Moreover, the effect of the GABA A antagonist, bicuculline, and of the frequency of stimulation were studied in cortical slices. The amount of endogenous GABA released per impulse from cortical slices decreased by about 50% when the frequency was increased from 0.25 Hz to 1 Hz. This might indicate that GABA inhibited its own release. (–)-Baclofen at 1 and 10 M, but not its (+)-enantiomer, markedly inhibited the release of endogenous GABA, to a similar extent in all 3 areas investigated. The effect of (–)-baclofen was dependent on the frequency of stimulation: at lower frequencies (0.25 and 0.5 Hz) it was more marked than at a higher one (4 Hz). This would be expected from the results showing that the release of endogenous GABA decreases with increasing frequency, which suggests that this amino acid inhibits its own release. Muscimol at 10 M, on the other hand, was ineffective in all 3 areas at a stimulation frequency of 0.5 Hz. Bicuculline (10 M) at 4 Hz, at which autosuppression of GABA release is maximal did not enhance the release of endogenous GABA from cortical slices. With cerebellar or nigral slices, no adequate stimulation-induced release of endogenous GABA could be obtained under comparable conditions. These data are compatible with, but do not prove the existence of GABAB-type presynaptic autoreceptors modulating the release of this amino acid. More definite conclusions may possibly be drawn when a GABAB antagonist becomes available, which is expected to enhance GABA release under appropriate conditions.Presented in part at the 3rd Brit. Meeting on Electrochemical detection in Pharmacology and Neurochemistry, Cambridge, March 30–April 1, 1987Send offprint requests to P. C. Waldmeier 相似文献
15.
Rationale The nucleus accumbens (NAC) is theorized to be a critical element of the neural circuitry that mediates relapse to cocaine seeking. Evidence suggests that the NAC is a functionally heterogeneous structure, and the core (NACc) and shell (NACs) regions of the NAC may play a differential role in stimulus-induced motivated behavior. Thus, determination of the involvement of NAC subregions in conditioned cue-induced reinstatement of cocaine seeking is warranted.Objectives The present study compared the effects of GABA agonist-induced inactivation of the NACc versus NACs on conditioned cue-induced reinstatement of cocaine seeking behavior.Methods Rats were trained to lever press for cocaine infusions (0.20 mg/infusion, IV) paired with presentations of a light-tone stimulus complex. Responding was then allowed to extinguish prior to reinstatement testing. Reinstatement of cocaine seeking (i.e. responses on the previously cocaine-paired lever) was measured in the presence of response-contingent presentation of the light-tone stimulus complex following microinfusion of muscimol+baclofen (Mus+Bac, 0.1/1.0 mM, respectively, 0.3 l/side) or vehicle into the NACc or NACs. The effects of these manipulations on locomotor activity were also examined.Results Mus+Bac-induced inactivation of the NACc abolished, whereas inactivation of the NACs failed to alter, conditioned cue-induced reinstatement of operant responding relative to vehicle pretreatment. Time course analyses of the effects of these manipulations on locomotion versus operant responding confirmed that the effects of Mus+Bac on reinstatement were not due to suppression of general activity.Conclusions The functional integrity of the NACc, but not the NACs, is necessary for conditioned cue-induced reinstatement of cocaine seeking behavior. 相似文献
16.
RationaleNicotine withdrawal is characterized by depression-like symptomatology that may be mediated by dysregulations in norepinephrine transmission. These aversive aspects of nicotine withdrawal and the rewarding effects of nicotine play major roles in maintaining nicotine dependence.ObjectivesThe aim of this work was to evaluate the effects of desipramine (DMI), a preferential norepinephrine reuptake inhibitor and antidepressant, on preclinical models of nicotine dependence in rats.Materials and methodsA rate-independent current-intensity discrete-trial threshold intracranial self-stimulation procedure was used to assess brain reward function during nicotine withdrawal induced by cessation of nicotine infusion via subcutaneous osmotic mini pumps (3.16 mg/kg/day, base). Nicotine withdrawal was also measured by somatic signs of withdrawal. DMI was administered acutely (2 or 5 mg/kg, salt) during nicotine/saline withdrawal. In other naïve rats, chronic DMI treatment via mini pump (15 mg/kg/day, salt) began after 7 days of nicotine/saline exposure and continued during administration of nicotine/saline for 14 days and during nicotine/saline withdrawal. Additional rats acquired intravenous nicotine- or food-maintained responding, were prepared with DMI/vehicle-containing mini pumps, and self-administered nicotine or food during 12 days of DMI/vehicle exposure.ResultsAcute DMI administration had no effect on threshold elevations observed in nicotine-withdrawing rats. Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding.ConclusionsThe results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal and may alter the rewarding effects of nicotine and food. 相似文献
17.
The effect of GABA agonists and antagonists on K +-stimulated [ 3H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was affected in a quite different manner in the pars compacta and in the pars reticulata. Muscimol markedly inhibited the release from the pars compacta but had no effect on the release from the pars reticulata. Baclofen inhibited the release from the pars reticulata without affecting the release from the pars compacta. Bicuculline itself facilitated the release from the pars compacta but inhibited the release from the pars reticulata. Picrotoxin facilitated the release from the pars compacta and had no effect in the pars reticulata. The results suggest that the release of GABA from GABAergic terminals in the substantia nigra of the rat brain is modulated by GABA A autoreceptors in the pars compacta and by GABA B receptors in the pars reticulata. 相似文献
18.
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. 相似文献
19.
Microinfusions of the opioid subtype-selective agonist DAMGO and antagonist CTOP into the ventral tegmental area (VTA) were
used to examine the role of mu opioid receptors in this area of the mesolimbic dopamine system in regulating cocaine reinforcement.
Long-Evans rats were trained to self-administer cocaine intravenously and prepared with intracranial cannulae directed to
the VTA. At doses of cocaine on the descending limb of the cocaine dose-response curve, the mu-selective agonist DAMGO produced
a dose-related decrease in cocaine self-administration when delivered by microinfusion into the VTA. At a dose of cocaine
on the ascending limb of the self-administration dose-response curve, DAMGO microinfusions produced an increase in responding
for the drug. The mu-selective antagonist CTOP produced small effects on cocaine self-administration. A kappa-selective agonist
and antagonist (U50,488 and norbinaltorphimine, respectively) produced either no effects or small effects that did not show
consistent trends with dose. These experiments suggest that the mu agonist DAMGO is able to shift the dose-response curve
for cocaine self-administration to the left. This effect appears to be specific for mu as compared to kappa agonists. These
data are consistent with the known differential distribution of opioid receptor subtypes within the VTA, and with the effects
of opioid compounds in the VTA on dopamine release in the mesolimbic synaptic field. The data show that a mu opioid mechanism
in the somatodendritic region can alter reinforcement processes for cocaine, which acts predominantly at the terminal field
of dopamine cells.
Received: 8 May 1998 / Final version: 13 August 1998 相似文献
20.
In rats trained to self-administer heroin or cocaine intravenously, non-contingent priming injections of heroin or cocaine, respectively, reinstated responding after a period of extinction. In rats similarly trained to self-administer heroin or cocaine intravenously, morphine sulphate was applied centrally to sites in the ventral tegmental area (VTA), the periventricular grey (PVG) and the caudate nucleus following a period of extinction. Self-administration behavior was reinstated by morphine application to sites in the region of the VTA, but not to other sites, in both heroin and cocaine-trained animals. This priming effect of morphine was blocked or attenuated by prior administration of naltrexone, given intraperitoneally. Morphine in the VTA is known to activate mesolimbic dopamine neurons, suggesting that dopamine activity in this system may underline the priming effects of both opiates and stimulants. Furthermore, the fact that the mesolimbic system is implicated in the positive motivational actions of both drug groups, suggests that morphine reinstates drug-taking behavior in these animals by activating appetitive motivational systems of the brain. 相似文献
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