Behavioral and neurochemical effects following neurotoxic lesions of a major cholinergic input to the cerebral cortex in the rat

The nucleus basalis magnocellularis (NBM) is the name given to a group of cholinesterase-reactive neurons in the ventromedial corner of the globus pallidus of the rat. This cell group appears to be the major extrinsic source of cortical acetylcholine and is believed to be homologous to the nucleus basalis of Meynert in primates. The excitotoxin ibotenic acid (2.4 micrograms/0.4 microliter) was infused bilaterally into the ventromedial globus pallidus. These lesions depleted frontal cortical choline acetyltransferase (CAT) by a third. Neurotoxic lesions of the dorsolateral globus pallidus did not affect cortical CAT activity. Neither lesion affected the rats' performance on a battery of psychomotor tasks or on tests of shock sensitivity. Rats with NBM lesions were mildly impaired in the acquisition of a one-way active avoidance response, but did not differ from the other groups on extinction of the task. The NBM lesioned rats exhibited a severe deficit in the retention of a passive avoidance response. This effect was visible both 24 hours and one hour after training. Experimental controls suggested that the poor performance of the NBM lesioned rats involves a deficit in learning and/or memory of the training trial. Lesions of the dorsolateral globus pallidus also produced an impairment of passive avoidance retention, but this impairment was not as severe as that following NBM lesions. These results are discussed as they relate to the behavioral role of cholinergic innervation of the cortex, and the development of animal models for disorders involving cortical cholinergic deficiencies, including senile dementia of the Alzheimer's type.     

Nicotine-induced catecholamine synthesis after lesions to the dorsal or ventral noradrenergic bundle

The role of projections from coerulear (A6) and lateral tegmental (A1-A5) noradrenergic cell groups in the induced catecholamine response to (-)-nicotine was studied following lesions to the dorsal (DNAB) or ventral (VNAB) noradrenergic bundle by 6-hydroxydopamine. The lesions produced large reductions in basal noradrenaline levels in hippocampus (after DNAB lesions) and hypothalamus (after VNAB lesions), while not affecting basal levels of dopamine or 5-hydroxytryptamine. Vehicle and sham operated controls showed a significant increase in DOPA accumulation in response to (-)-nicotine (0.8 mg/kg s.c.) following inhibition of amino acid decarboxylase. In DNAB lesioned rats, the response induced by (-)-nicotine in both the hippocampus and hypothalamus was significantly attenuated, whereas in VNAB lesioned rats the induced response was still evident. The effect of (-)-nicotine was also studied in the nucleus accumbens and was found not to be affected by either lesion. These data suggest that increases in catecholamine synthesis in the hippocampus and hypothalamus reflect increased noradrenaline synthesis, and that this effect occurs specifically in noradrenergic projections originating in the locus coeruleus.     

Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: New evidence for central dopaminergic-noradrenergic interactions

A series of experiments examined the effects of lesions of the dorsal noradrenergic bundle (DNAB), induced by 6-hydroxydopamine (6-OHDA), on the behavioural response to systemic and intra-accumbens amphetamine, using a rat analogue of Leonard's 5-choice serial reaction time task for humans. Although the 6-OHDA DNAB lesion produced a profound depletion of cortical noradrenaline (NA) (to around 5% of control levels) it did not impair any aspect of performance on this task. Both systemic and intra-accumbens amphetamine increased behavioural measures of impulsivity of responding, but neither impaired discriminative accuracy in the sham-operated control rats. However, the DNAB lesioned rats did show a discriminative impairment following both low doses of systemic amphetamine, and intra-accumbens amphetamine. The latter effect was antagonised by systemic administration of the specific dopaminergic (DA) antagonist alpha-flupenthixol. The DNAB lesion did not alter the effect of amphetamine on any other behavioural measure, including speed and impulsivity of responding. These results suggest that although DA and NA participate in qualitatively different behavioural processes, the effects of DNAB lesions on attentional processes depend on the level of DA activity within the nucleus accumbens.     

Selective memory loss following nucleus basalis lesions: long term behavioral recovery despite persistent cholinergic deficiencies

Rats were trained for several months to perform a radial arm maze task and then given either sham or ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), the primary cholinergic projection to the neocortex. The lesion produced a profound and apparently selective disturbance in memory for recent events. Further testing revealed that although the memory deficit persisted for several weeks, a gradual but complete recovery eventually occurred. Moreover, when these functionally recovered rats were later tested on a passive avoidance task that is normally sensitive to lesions of the NBM, no deficit was found. Thus, the post-lesion recovery of function generalized to a different memory test, upon which no post-lesion practice had been given. Post-mortem determinations revealed that the lesions caused marked neurodegeneration of the NBM, and decreases in both cortical choline acetyltransferase activity and high affinity choline uptake, but had no effect on density of muscarinic receptors. No evidence of neuronal recovery or neurochemical compensatory changes in the cholinergic system was found in the cortical projection areas, lesion site, or in parallel cholinergic systems terminating in the hippocampus or olfactory bulb. These results support the idea that the cortically-projecting cholinergic cells of the NBM normally play an important role in mediating recent memory. However, they also demonstrate that any simple relationship between the function of this brain region and the mediation of recent memory is unlikely. Finally, the results of this study direct attention toward issues related to the mechanisms involved with the recovery of function, and the extent to which degeneration of this brain area may contribute directly to the severe disturbance of cognitive function associated with certain neurodegenerative diseases (e.g., Alzheimer's, Pick's and Parkinson's disease).     

Serotonin influences the behavioral recovery of rats following nucleus basalis lesions.

The present study investigated the effects of serotonergic depletion upon the performance of rats with lesions of the nucleus basalis magnocellularis (NBM) in a nonspatial memory task. NBM lesions were made by injections of ibotenic acid. Serotonin was depleted by systemic injections of p-chloroamphetamine (PCA). After four weeks of testing, the choice accuracy of PCA rats was not different from that of control rats (CON), while the choice accuracy of NBM rats and rats with combined treatment (NBM + PCA) was significantly lower than CON rats, but not different from each other. After prolonged testing, performance improved in NBM rats, but not in NBM + PCA rats indicating that simultaneous loss of both cholinergic and serotonergic neurotransmission produced a significantly longer lasting behavioral deficit than the loss of cholinergic neurotransmission alone.     

Forebrain norepinephrine: role in controlled information processing in the rat.

A series of experiments examined the effects of 6-hydroxydopamine (6-OHDA)-induced depletion of forebrain norepinephrine (NE) on the performance of a visual detection (spatial localization) task. The behavioral paradigm used was an analogue of Leonard's 5-choice serial reaction time task for humans. The 6-OHDA lesion of the dorsal noradrenergic bundle (DNAB) produced a 98% depletion of the NE content in the neocortex, and a much smaller depletion (32%) of the NE content in the hypothalamus. As reported previously, performance of visual discrimination was unaffected by DNAB lesions, even when the discrimination was made more difficult by decreasing the intensity of the visual stimuli. However, the lesion produced a significant decrease in accuracy and a significant increase in omissions when a burst of loud white noise was presented just prior to the onset of the visual discriminanda. Similarly, a significant decrease in discriminative accuracy was produced in the rats with forebrain NE depletion by systemic administration of the psychomotor stimulant, d-amphetamine (0.2 to 0.8 mg/kg). In both of these experiments, the lesion-induced discrimination impairment was not magnified by reducing the brightness of the visual discriminanda, suggesting that the behavioral impairment was not caused by a decreased ability to detect the visual stimuli. In addition, the lesion impaired discriminative accuracy when the visual discriminanda were presented at an unpredictable rate. The implications of these behavioral impairments produced by forebrain NE depletion for theories of catecholamine involvement in attentional processes and arousal are discussed in terms of a possible role for the DNAB in controlled or "effortful" processing.     

THA improves word priming and clonidine enhances fluency and working memory in Alzheimer's disease.

We investigated the effects of a single administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA, 25 and 50 mg, orally), and an alpha 2-agonist, clonidine (0.5 and 2 micrograms/kg, orally), on neuropsychologic performance in two groups of patients with Alzheimer's disease (AD). Clonidine enhanced a spatial working memory and verbal fluency, but had no effect on spatial span or word priming. THA enhanced word priming, but had no effect on other performance measures. Our data suggests that degeneration of the LC noradrenergic system and the cholinergic cells of the basal forebrain have different functional consequences during the progression of AD. Finally, a combined treatment with noradrenergic and cholinergic drugs might produce a qualitatively broader effect on cognitive functions than either of the treatments alone, and more effectively attenuate clinical dementia.     

Effects of THA on passive avoidance retention performance of intact, nucleus basalis, frontal cortex and nucleus basalis + frontal cortex-lesioned rats.

Unilateral quisqualic acid lesions of the nucleus basalis magnocellularis (NBM) produced marked choline acetyltransferase depletion (-67% ipsilateral to lesion) and impaired passive avoidance (PA) retention at 24 hours. Pretraining injections of tacrine (THA: 1, 3 and 5 mg/kg), an anticholinesterase, failed to facilitate PA retention in intact rats. However, the retention performance of NBM-lesioned rats was improved by pretraining administration of THA at 3 mg/kg but not at either 1 or 5 mg/kg. Frontal cortex lesioning did not impair PA retention, and THA at 3 mg/kg had no effect on the PA retention of frontal cortex-lesioned rats. THA at 3 mg/kg failed to improve retention performance of NBM + frontal cortex-lesioned rats. After 10 days of chronic treatment with THA, NBM lesion-induced PA retention deficits were partially restored at both 3- and 5-mg/kg doses. The results suggest that 1) the insult to cholinergic neurons in the NBM may be involved in the PA memory consolidation deficit induced by nonselective quisqualic acid lesioning; 2) the beneficial effects of THA on NBM lesion-induced PA retention deficit occur in a narrow dose range; 3) the alleviating effects of THA on NBM lesion-induced PA memory deficits are blocked by frontal cortex lesions; and 4) the dose-response window for THA-induced PA retention performance improvement is broadened by repeated treatment.     

Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert

Monkeys with bilateral ibotenic-acid lesions of the nucleus basalis of Meynert, an area rich in cholinergic neurons that innervate the cerebral cortex, were compared with unoperated control monkeys on a recognition memory task. Although animals with large lesions had substantial reductions of cortical choline acetyltransferase activity, none showed impairment in the task. Lesion effects were observed, however, when performance was assessed following administration of a muscarinic receptor blocker (scopolamine) or a cholinesterase inhibitor (physostigmine). Although scopolamine produced dose-related impairments in both groups, this effect was greater in the experimental animals. Conversely, whereas physostigmine produced modest improvement in performance in the control group, no such improvement was observed in the experimental animals. The altered sensitivity to the mnemonic effects of cholinergic agents in the experimental group suggests that the cholinergic neurons of the nucleus basalis of Meynert contribute to recognition memory.     

Reversal of visual attention dysfunction after AMPA lesions of the nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT<Subscript>1A</Subscript> receptor antagonist WAY 100635

Rationale. Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease (AD). In addition to memory dysfunction, attentional functions are also impaired in AD. Objective. We investigated the extent to which the cholinesterase inhibitor donepezil reversed the attentional performance deficit in nucleus basalis magnocellularis (NBM) lesioned rats. We also examined the effects of a selective and potent 5-HT_1A receptor antagonist, WAY 100635, on the attentional deficit of NBM lesioned rats. Methods. We injected α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the NBM to selectively destroy cholinergic neurons projecting to the neocortex. Attentional functions were examined using the 5-CSRT task, in which hungry rats were required to locate brief visual targets presented randomly in one of five locations in a specially designed chamber. Results. AMPA lesions of the NBM caused marked reductions in choline acetyltransferase activity (ChAT) ranging from 30 to 46% in medial areas of the cortex (medial-frontal and cingulate) and from 58 to 72% in more lateral areas (anterior-dorso-lateral and parietal). AMPA lesioned rats made fewer correct responses (choice accuracy), longer latency to correct response and an increase in the number of premature and perseverative responses. These impairments showed some recovery over the next 12 weeks. Reducing the duration of the visual stimulus reinstated the impairments in choice accuracy. The anticholinesterase inhibitor donepezil at 1.0 mg/kg but not 0.5 mg/kg reversed the impairments in choice accuracy and correct response latency. The premature and perseverative over-responding of AMPA lesioned rats remained unchanged. A dose of 0.1 mg/kg WAY 100635 to AMPA-lesioned rats improved their choice accuracy but did not shorten correct response latencies. The number of premature responses was reduced by WAY 100635 but perseverative over-responding was not affected. Conclusions. The attentional impairments induced due to cortical cholinergic dysfunction may be ameliorated by cholinergic treatments such as cholinesterase inhibitors. In addition, 5-HT_1A receptors and the cortical cholinergic system exert balanced opposition in regulating attentional performance in the rat. Blockade of 5-HT_1A receptors may be useful to treat some aspects of attentional dysfunction in AD. Electronic Publication     

N-(n-propyl)-n-(3-fluoro-4-pyridinyl)-1h-3-methylindol-1-amine hydrochloride (HP 184): In vitro spontaneous release of acetylcholine and norepinephrine

It has been shown that a single injection of N-(n-propyl)-N-(3-fluoro-4-pyridinyl-1H-3-methylindol-1-amine hydrochloride) (HP 184) (0.6-4.8 mg/kg, or 2-15 μmoles/kg, sc) reversed passive avoidance deficits in rats with combined cholinergic and noradrenergic lesions. This report describes the effects of HP 184 on NE and ACh release from rat brain slices. In contrast to 4-aminopyridine (4-AP), tyramine, or veratridine, HP 184 only enhanced spontaneous release and had no effect on electrical stimulation (ES). Chromatographic analysis showed that the spontaneous release from [³H]choline-loaded striatal slices correlated with increased release of ACh, not choline efflux. HP 184 also enhanced ACh spontaneous release in the absence of both extracellular calcium and functional vesicles (as defined by ES and vesamicol). In frontal cortical slices, HP 184 caused [³H]NE release in a calcium independent fashion different from that induced by veratridine, and was not affected by uptake blockers. In contrast to the cholinergic profile, the [³H]NE release induced by HP 184 required intact storage vesicles, since release was blocked by reserpine pretreatment. The results show that HP 184 can release both NE and ACh in vitro, and, coupled with the dual lesion results, suggest it may have use in diseases involving cholinergic and noradrenergic deterioration. © 1993 wiley-Liss, Inc.     

Behavioral recovery following bilateral lesions of the nucleus basalis does not occur spontaneously

Recent studies have shown that rats given bilateral ibotenic acid lesions of the nucleus basalis (NBM) exhibit significant impairments on tasks requiring recent or trial-specific memory. However, despite the persistence of cholinergic deficiencies in the cortical projection area, the memory impairments gradually recover over a period of several months of training. Moreover, in one study, the behavioral recovery on a radial arm maze retention task was shown to generalize to a completely different behavior paradigm (passive avoidance) on which the animals had received no prior experience. The present study was performed to determine the extent to which this generalized recovery of performance on memory tasks is dependent upon extensive post-lesion training. Rats were given ibotenic acid lesions of the NBM and were then passively detained in their home cages for six months. Contrary to animals which had received post-surgical radial arm maze experience, the animals detained in their home cages displayed a significant retention impairment when tested on the passive avoidance task, suggesting that the experience the animals receive is an important factor for whether post-lesion functional recovery occurs. This study also confirms that the loss of cholinergic markers following bilateral, NBM lesions persists for at least several months, or longer.     

Selective immunolesioning of the basal forebrain cholinergic neurons in rats: effect on attention using the 5-choice serial reaction time task

Abstract Rationale. Excitotoxic lesions of the nucleus basalis magnocellularis (nbm) in rats produce deficits in performance of the 5-choice serial reaction time (5CSRT) task, suggesting that basal forebrain cholinergic projections to the neocortex play an important role in visuospatial attention. However, non-selective damage induced by excitotoxins may have confounded the interpretation of the specific contribution of the corticopetal cholinergic neurons of the nbm to attentional processes. Objective. The purpose of the present study was to produce selective immunolesions of the cholinergic neurons of the nbm in order to examine more precisely the role of the cholinergic projections of the basal forebrain on attentional performance in a 5CSRT task. Methods. Rats received bilateral injections of the selective cholinergic immunotoxin 192 IgG-saporin (0.067 μg/μl, 1 μl) into the nbm after baseline training in the 5CSRT task. Performance of sham and nbm lesion groups was then assessed during baseline and increased task difficulty conditions. Results. Contrary to results previously reported, accuracy of responding and behavioral inhibition were unaffected by the immunotoxin. Rats with nbm lesions showed, however, significant increases in omissions relative to control rats, most markedly during sessions with increased difficulty of signal detection, e.g., decreased stimulus intensity or duration. Magazine and correct latencies were unaffected, suggesting that the lesion-induced omissions were not due to changes in motivation. Omissions were highly correlated with percentage of choline acetylcholine transferase depletion. Reduced premature responses were also observed when the target stimulus was made less predictable. Conclusions. Although the 192 IgG-saporin lesion produced a different array of behavioral deficits than previously reported, these effects nevertheless are consistent with an important role of the basal forebrain cholinergic system in attentional function, in particular with accurate timing of stimulus presentation and target detection. Electronic Publication     

Physostigmine improves water maze performance following nucleus basalis magnocellularis lesions in rats

Bilateral excitotoxic lesions of the nucleus basalis magnocellularis in rats were used along with testing in the water maze task to assess whether inhibition of acetylcholinesterase with physostigmine would reverse the lesion-induced impairment. Rats were lesioned bilaterally in stages using ibotenic acid and then behaviorally tested 3 weeks after surgery. Lesioned animals were administered one of three doses of physostigmine (0.06, 0.19, or 0.32 mg/kg) or vehicle solution 15 min prior to water maze testing. Sham lesioned animals injected with vehicle solution served as an untreated control group. Animals were tested for 5 consecutive days followed by 2 days off and then tested for 5 additional days. The rats were then sacrificed and their frontal cortex was assayed for choline acetyltransferase. The nucleus basalis magnocellularis lesion caused approximately a 27% depletion of choline acetyltransferase in the frontal cortex of these animals. The lesion also impaired the performance of the rats given vehicle solution as compared to untreated controls. Two doses (0.06 and 0.19 mg/kg) of physostigmine improved performance relative to lesioned controls. The lower dose, 0.06 mg/kg, improved performance more than the 0.19 mg/kg dose of physostigmine. The highest dose of physostigmine impaired water maze performance relative to lesioned controls. These data are discussed in relation to the cholinergic hypothesis of Alzheimer's disease and the potential therapeutic use of physostigmine.     

Enhanced behavioral response to nicotine in an animal model of Alzheimer's disease

Three groups of rats received either kainic acid or vehicle in the ventral pallidum or no operation, and were then tested in photocell activity cages following recovery from surgery. Locomotor activity was measured following injections of saline, nicotine (0.1, 0.2, 0.4 mg/kg) or d-amphetamine (0.5, 1.0 mg/kg). The lesioned rats showed an enhanced locomotor response after injections of nicotine compared with sham operated or unoperated controls. In contrast, both lesioned and control rats showed increased activity after amphetamine; this effect was not influenced by the lesion. Since these lesions are known to produce neurochemical and cellular changes resembling those seen in human Alzheimer's disease, this increased response to nicotine might also be found in Alzheimer's patients and serve as the basis for a diagnostic test.     

The effect of magnocellular basal forebrain lesions on circadian locomotor activity in the rat

Locomotor activity (LMA) was assessed in rats given ibotenic acid lesions in the nucleus basalis magnocellularis (group NBM) or sham surgery (group OC). Two weeks after surgery, rats were monitored for 8 hours during the middle of either the 12 hr light (day) or 12 hr dark (night) period of the diurnal cycle. Six behavioral measures of LMA were examined: horizontal activity, vertical activity (rearing), distance travelled, movement time, movement velocity (distance/time) and revolutions (turning behavior). During the day, no statistically significant differences between the NBM and OC groups were observed in any of the measures. At night, both NBM and OC groups generally were more active than during the day, and the NBM group generally was more active than the OC group. Because the diurnal LMA of rats with NBM lesions was not significantly affected during the day, when laboratory animals are usually tested, hypotheses regarding lesion-induced locomotor abnormalities cannot be invoked to account entirely for the impaired performance observed in NBM rats on tasks designed to measure learning and memory.     

The effect of selective noradrenergic lesions upon the stimulation by noradrenaline of inositol phospholipid breakdown in rat hippocampal miniprisms

The breakdown of inositol phospholipid (PI) stimulated by hippocampal noradrenaline in rat miniprisms in vitro was used as an index of alpha 1-adrenoceptor function after selective noradrenergic denervation. Selective denervation was produced by microinjections of 6-hydroxydopamine (6-OHDA) into either the dorsal noradrenergic bundle (DNAB) or the locus coeruleus (LC), or by systemic treatment with the noradrenergic neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine). Fourteen days after these treatments, there was a large depletion of cortical noradrenaline but no change in the stimulation of hippocampal PI breakdown by noradrenaline. It is concluded that selective noradrenergic denervation under the conditions used here does not lead to hippocampal alpha 1-adrenoceptor supersensitivity as assessed by noradrenaline-stimulated PI breakdown.     

Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats

To provide a more specific test of memory impairments following lesions to central cholinergic systems, rats were trained on an operant delayed matching task. Ibotenic acid lesions of the nucleus basalis produced a disruption of performance at all delay intervals (a parallel downward shift in the delay-performance curve). By contrast, fimbriafornix transections had no effects at short delays, but produced a progressively greater impairment as the delays lengthened (an increased downward slope of the delay-performance curve). Scopolamine produced a dose-dependent disruption of performance, apparent at the shortest delays but greater at longer delays, that was similar to the two lesion deficits combined, whereas physostigmine induced a mild but significant enhancement of performance. The results support the hypothesis that disruption of hippocampal circuitries, including cholinergic afferents via the fimbria-fornix, produces short-term or working memory impairments, whereas disruption of the cortical cholinergic system implicates more stable long-term aspects of task performance. Peripherally administered cholinergic drugs produce both types of effect and thus may influence both systems.     

Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats

Donepezil is a member of a new class of centrally acting cholinesterase inhibitors which preferentially inhibit acetylcholinesterase rather than butyrylcholinesterase. The effects of donepezil on learning impairments were investigated in some hypocholinergic models in rats. In nucleus basalis magnocellularis (NBM)-lesioned rats, donepezil alleviated deficits in passive avoidance response at a dose of 0.125 mg/kg and higher, while tacrine had only a tendency toward improved performance. Donepezil at 0.5 mg/kg effectively counteracted acquisition impairments in the water maze task induced by lesions of the medial septum; tacrine had no significant effects on impairments in this task. Scopolamine caused an increase of errors in the 8-arm radial maze. Donepezil significantly decreased scopolamine-induced errors in the radial maze at 0.5 mg/kg, whereas tacrine decreased errors at 2 mg/kg. These results suggest that donepezil can clearly minimize learning impairments induced by treatments that cause central cholinergic deficiencies in rats. These findings support the clinical efficacy of donepezil in Alzheimer's disease.     

远志皂苷对β-淀粉样肽和鹅膏蕈氨酸引起胆碱能系统功能降低的影响

目的观察远志皂苷对拟痴呆模型大鼠胆碱能系统功能的作用。方法在大鼠脑内右侧基底核内联合注射β-淀粉样肽1～40片段(β-AP_1～40)和鹅膏蕈氨酸建立大鼠拟痴呆模型,用避暗法测定模型动物的学习记忆能力,用放射配体结合分析法测定胆碱乙酰转移酶活性和M受体密度,用改良Ellman法测定脑组织乙酰胆碱酯酶活性。结果给模型大鼠连续ig远志皂苷60 d后,远志皂苷能明显提高拟痴呆大鼠的学习记忆能力,显著升高脑内M受体密度和增强胆碱乙酰转移酶活性,能有效地抑制脑胆碱酯酶活性。结论远志皂苷对老年性痴呆的胆碱能系统功能减退有一定的改善和治疗作用。