Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.
The formalin test is increasingly used as a model of injury-produced pain but there is no generally accepted method of pain rating. To examine the properties of various pain rating methods we established dose-response relations for formalin injected in the plantar surface of one hind paw, and the analgesic effects of morphine and amphetamine using the most frequently reported behavioural measures of pain (favouring, lifting, licking and flinching/shaking of the injured paw) and combinations of these. Licking, elevation and favouring of the injected paw showed a biphasic response at all formalin doses. Flinching varied in form across the time course of formalin, and the biphasic nature of the behaviour was not as apparent. In untreated rats all these behaviours were infrequent. Flinching and favouring were increased after injection of local anaesthetic into the paw but remained negligible relative to the effect of formalin. Grooming other than that directed to the injected paw was elevated in a dose-dependent manner by formalin. Intercorrelations between the behaviours were different for the initial response and the second phase. Correlational analysis indicated that no single behavioural measure was a strong predictor of formalin, morphine and amphetamine dose. A simple sum of time spent licking plus elevating the paw, or the weighted pain score of Dubuisson and Dennis (1977), were superior to any single measure (r ranging from 0.75 to 0.86). Addition of flinching and favouring to the combined pain score using multiple regression did not increase variance explained. Depending on the measure used, a sedative dose of pentobarbital produced apparent analgesia, hyperalgesia or no effect. The interphase depression of pain, as well as the analgesic effects of morphine and amphetamine, were all associated with increased motor activation. Power analysis indicated that using a moderate dose of formalin and a combined pain score gave the greatest power to detect differences in pain. It was also found that pain scores increase with ambient temperature and that rat strains may differ in formalin pain sensitivity.
Experiment 1 examined whether microinjections of morphine (1 microg in 0.5 microl over 1 min x 2 pairings) into 13 different CNS sites produced a conditioned place preference (CPP). Injections into the lateral ventricles (LV), ventral tegmental area (VTA), or periaqueductal gray (PAG) produced a CPP; injections 1 mm dorsal to the PAG or VTA, or into the caudate putamen, medial frontal cortex, hippocampus, lateral nucleus of the amygdala, lateral hypothalamus, pedunculopontine tegmental nucleus, posterior hypothalamus, ventral palladium, or nucleus accumbens septi (core or shell) did not. In Experiment 2, morphine 0.2 microg produced a CPP when injected into the VTA but not in the PAG, while 5.0 microg was effective in both sites. The CPP induced by systemic morphine (4 mg/kg x 1 pairing) was blocked by naloxone methiodide (NM) injected (2 nmol in 0.5 microl) into the VTA. PAG injections of 2 nmol reduced, and 5 nmol NM eliminated, the CPP. The results confirm that morphine injections into the VTA or the PAG are rewarding, that blockade of opioid receptors in either site disrupts a morphine-induced CPP, and that the VTA is more sensitive to both effects.
The neurosphere assay can detect and expand neural stem cells (NSCs) and progenitor cells, but it cannot discriminate between these two populations. Given two assays have purported to overcome this shortfall, we performed a comparative analysis of the distribution and frequency of NSCs and progenitor cells detected in 400 m coronal segments along the ventricular neuraxis of the adult mouse brain using the neurosphere assay, the neural colony forming cell assay (N-CFCA), and label-retaining cell (LRC) approach. We observed a large variation in the number of progenitor/stem cells detected in serial sections along the neuraxis, with the number of neurosphereforming cells detected in individual 400 m sections varying from a minimum of eight to a maximum of 891 depending upon the rostral-caudal coordinate assayed. Moreover, the greatest variability occurred in the rostral portion of the lateral ventricles, thereby explaining the large variation in neurosphere frequency previously reported. Whereas the overall number of neurospheres (3730 ؎ 276) or colonies (4275 ؎ 124) we detected along the neuraxis did not differ significantly, LRC numbers were significantly reduced (1186 ؎ 188, 7 month chase) in comparison to both total colonies and neurospheres. Moreover, approximately two orders of magnitude fewer NSC-derived colonies (50 ؎ 10) were detected using the N-CFCA as compared to LRCs. Given only 5% of the LRCs are cycling (BrdU ؉ /Ki-67 ؉ ) or competent to divide (BrdU ؉ /Mcm-2 ؉ ), and proliferate upon transfer to culture, it is unclear whether this technique selectively detects endogenous NSCs. Overall, caution should be taken with the interpretation and employment of all these techniques. STEM CELLS 2008;26:979 -987 Disclosure of potential conflicts of interest is found at the end of this article.
The pedunculopontine tegmental nucleus (PPTg) is believed to play important roles in reward and learning. We examined the effect of PPTg lesions (0.5 microl of 0.1 M NMDA injected bilaterally over 10 min) on the learning of an operant response for opiate reward. In 14 adult male Long-Evans rats, bilateral lesions of the PPTg disrupted the acquisition of responding for intravenous heroin (0.1 mg/kg infused at a rate of 0.25 ml/28 sec) on a fixed ratio-1 (FR-1) schedule of reinforcement. The 12 remaining lesioned animals increased their heroin intake over the acquisition sessions but did not reach the response levels of sham-lesioned animals on the 15th and final session. The sham- and PPTg-lesioned animals that learned the FR-1 task exhibited similar patterns of responding during extinction and reacquisition sessions. When tested on a progressive ratio (PR) schedule of reinforcement, however, PPTg-lesioned animals had lower break points than sham-lesioned animals. Asymmetric lesions, which destroyed the majority of the nucleus in one hemisphere only, did not produce any behavioral deficits. Rats that were lesioned after training also did not show deficits in responding under either FR or PR schedules. These findings suggest that PPTg lesions reduce the rewarding effect of opiates but do not disrupt the ability either to learn an operant response or the response requirements of a PR schedule.
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