The D8G group was significantly suppressed on only the first day of its treatment with physostigmine and it took 4 sessions and a reduction of the dose of physostigmine to 0.067 mg/kg be
Trang 1IV Discussion
The results of this experiment indicate that, as animals learn to form the association between lever extension/retraction and food pellet delivery during autoshaping they become increasingly resistant to the behaviorally toxic effects of physostigmine As shown above, only the D1G and D4G groups were significantly suppressed, com-pared to the D8G on more than the first day that each of these groups received physostigmine The D8G group was significantly suppressed on only the first day
of its treatment with physostigmine and it took 4 sessions (and a reduction of the dose of physostigmine to 0.067 mg/kg) before the D4G group returned to levels of responding not different from the CG/D13Gs The D1G group remained suppressed virtually throughout the study, even after their dose was also reduced to one third for Session 8 and beyond and even on Session 13, when they received a saline injection This decrease in the number of days of behavioral suppression with
FIGURE 14.3
Percentage of rats in each group achieving the autoshaping criterion of emitting 6 or more ELT during
2 of 3 contiguous sessions By Session 3 (Figure 14.3A) the percentage of rats in the D1G achieving the criterion was significantly below the CG/D13G (0% vs 44%, *p<0.05) These values increased to 11%
vs 78% during Session 6 and 22% vs 89% for Session 9 ( **p<0.01 in both cases) By Session 12 the percentage achieving criterion for these two groups was the same as for Session 9 and is depicted in Figure 14.3B None of the other groups were significantly different from the control group, using this criterion analysis
A
100
90 80 70 60 50 40 30 20 10 0
Treatment Group
*
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Trang 2The suppression of the D1G group, at least after several sessions, is an indication that conditioned aversion/suppression was probably established and maintained Previous studies57,58 have shown that conditioned taste aversion takes place when physostigmine is presented immediately after the presentation of a novel stimulus (saccharine solution) Because this evidence suggests that pairings between a novel stimulus and physostigmine are aversive, it is quite possible that the pairing of the novel environment during the first days of autoshaping with the novel drug, phys-ostigmine, produced conditioned aversion in the D1G group In this case the aversive properties of physostigmine could be acting as a type of unconditioned stimulus which is affecting their behavior This particular group showed the greatest amount
of behavioral suppression, throughout the 13 sessions, and were the only group that experienced the effects of physostigmine and the novel environment of the operant chamber together from the very beginning All of the other groups had previous experience with either the drug or the chamber before the two were paired.
FIGURE 14.4
When an ANOVA was performed upon the session number in which the criterion was attained by each rat, assigning a value of 15 for those rats which had not achieved it by Session 13, the outcome is depicted
in this figure **p<0.025 or better vs all other groups; PLSD following a significant omnibus outcome (F5,48 = 5.26; p<0.001)
0
2
4
6
8
10
12
14
Treatment Group
* *
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Trang 3Surprisingly, even after the dose of physostigmine was dropped on Session 8, the D1G group still showed no evidence of acquisition As was suggested at the begin-ning of this section of the chapter, a high dose of physostigmine which is aversive, and thus acts as an unconditioned stimulus, may also signal a discriminable internal state change as the drug is absorbed, which can also act as a conditioned stimulus.59,60
The animals that received a high dose of the drug for 7 days before the dose was dropped could thus discriminate an internal state change, even after the dose was dropped Although they actually may not have been as adversely affected (i.e., by
the high dose) as they had been previously, the expectation of the aversive effects
to follow, and thus the discriminative drug stimulus, was sufficient to elicit the conditioned response (i.e., no performance) This pairing of CS and UCS may be responsible, at least in part, for the lack of autoshaping by the D1G group throughout the 13 sessions.
The PSG’s autoshaping performance was almost identical to the CG/D13G’s through the first 5 sessions Thereafter, their performance dropped to a level
FIGURE 14.5
Autoshaped ELT were significantly depressed by physostigmine (0.2 mg/kg) during the session when first administered, relative to ELT performance during the previous session, for the D4G and D8G The CG/D13G was unaffected by the injection of the cholinesterase inhibitor after 12 autoshaping sessions
*p<0.05; **<0.01
0 2 4 6 8 10
12
Treatment Group(Physostigmine0.2mg/kg)
1 Day Pre-Physostigmine ELT 1st Physostigmine Day ELT
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Trang 4significantly below the control group (i.e., during Sessions 6 and 7), coming back when the dose was decreased It was during the deterioration of their autoshaped performance that their exploratory rearing behaviors were significantly elevated, so
a different sort of interaction between their behavioral and drug histories was acting
to prevent a similar habituation that was observed when the CG/D13G and D4G were injected with saline before and after the sessions These two groups showed very similar exploratory rearing activity as did the PSG during the first autoshaping session but this behavior diminished thereafter, while the PSG, given physostigmine injection after the sessions, showed impaired habituation to the chamber.
Invoking the idea of aversive conditioning, it could be that the number of pairings of the chamber and the drug are determinants of the suppression in the D1G group, and that the D4G group was not as suppressed because they had not had enough pairings of the drug and the chamber for conditioned aversion to take place Yet the HCG had more injections, in addition to the same number of pairings of drug and chamber as did the D1G group but nevertheless showed significant learning Additional studies will have to be undertaken to more fully interpret the bases for the PSG’s and the HCG’s drug-behavior interactions, which deviate substantially from the other groups’ performance.
FIGURE 14.6
Regression analyses of average ELT for groups injected prior to sessions (D1G, D4G, D8G, CG/D13G)
vs the day the first injection of physostigmine was administered, for Session 9 (Figure 14.6A), Session
11 (Figure 14.6B), and Session 13 (Figure 14.6C)
0
1
2
3
4
5
6
7
8
9
10
y = 408x + 3.047, r = 864; p=0.0712
First Injection Day (Physostigmine,0.2mg/kg)
A
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Trang 5Some of the research upon which this chapter is based, and its preparation, was supported in part by the Office of Naval Research N00014-86-K-0407 and USPHS grants RO1 ES 00760; RO1 DA 01880; T37 DA 07097; R37 DA 04979 Technical assistance by D Rosenfeld is likewise acknowledged and appreciated.
References
1 Brown, P L and Jenkins, H M., Auto-shaping of the pigeon’s key-peck Journal of Experimental Analysis of Behavior, 11, 1, 1968.
2 Terrace, H S., Introduction: Autoshaping and two-factor learning theory In: Autoshap-ing and ConditionAutoshap-ing Theory, Locurto, C M., Terrace, H S., and Gibbon, J., Eds.,
Academic Press, New York, 15, 1981
3 Locurto, C M., Terrace, H S., and Gibbon, J., Eds., Autoshaping and Conditioning Theory, Academic Press, New York, 1981.
4 Cunningham, C L., Ostroff, R L., and Harris, D F., Thermoregulation and performance
of heat-reinforced autoshaped key pecking in chicks Behavior and Neural Biology,
51, 54, 1989
5 Carroll, M E and Lac, S T., Autoshaping i.v cocaine self-administration in rats:
effects of nondrug alternative reinforcers on acquisition Psychopharmacology, 110, 5,
1993
6 Janak, P H., Rodriguez, W A., and Martinez, Jr., J L., Cocaine impairs acquisition of
an autoshaped lever-touch response Psychopharmacology, 130, 213, 1997.
7 Aubert, A., Vega, C., Dantzer, R., and Goodall, G., Pyrogens specifically disrupt the
acquisition of a task involving cognitive processing in the rat Brain Behavior and Immunity, 9, 148, 1995.
8 Sparber, S B., Is prenatal induction of tyrosine hydroxylase associated with postnatal
behavioral changes? In: Maturation of Neurotransmission Vernadakis, A., Giacobini
E., and Filagamo, G., Eds., S Karger, Basel, 200, 1978
9 Lydiard, R B and Sparber, S B., Postnatal behavioral alterations resulting from
prenatal administration of dl-alpha-methylparatyrosine Developmental Psychobiology,
10, 305, 1977
10 Sparber, S B., Postnatal behavioral effects of in utero exposure to drugs which modify catecholamines and/or serotonin In: Drugs and the Developing Brain, Vernadakis, A.
and Weiner, N., Eds., Plenum Press, New York, 81, 1974
11 Bollweg, G and Sparber, S., Ritanserin blocks DOI-altered embryonic motility and
posthatch learning in the developing chicken Pharmacology Biochemistry and Behav-ior 55, 397, 1996.
12 Goldstein, L H and Oakley, D A., Autoshaping in microencephalic rats Behavioral Neuroscience, 103, 566, 1989.
13 Poplawsky, A and Phillips, C L., Autoshaping a leverpress in rats with lateral, medial,
or complete septal lesions Behavioral and Neural Biology, 45, 319, 1986.
© 2001 by CRC Press LLC
Trang 614 van Haaren, F., van Zÿderveld, G., van Hest, A., de Bruin, J P., van Eden, C G., and van de Poll, N E., Acquisition of conditional associations and operant delayed spatial
response alternation: effects of lesions in the medial prefrontal cortex Behavioral Neuroscience, 102, 481, 1988.
15 Sparber, S B., Effects of drugs on the biochemical and behavioral responses of
devel-oping organisms Federation Proceedings, 31, 74, 1972.
16 Rosenthal, E and Sparber, S B., Methylmercury dicyandiamide: Retardation of detour
learning in chicks hatched from injected eggs Life Sciences, 11, 883, 1972.
17 Spyker, J M., Sparber, S B., and Goldberg, A M., Subtle consequences of
methyl-mercury exposure: Behavioral deviations in offspring of treated mothers Science, 177,
621, 1972
18 Hughes, J A and Sparber, S B., d-Amphetamine unmasks postnatal consequences of exposure to methylmercury in utero: Methods for studying behavioral teratogenesis
Pharmacology Biochemistry and Behavior, 8, 365, 1978.
19 Reuhl, K., Delayed expression of neurotoxicity: The problem of silent damage Neu-rotoxicology, 12, 341, 1991.
20 Cohen, C A., Messing, R B., and Sparber, S B., Selective learning impairment of delayed reinforcement autoshaped behaviors caused by low doses of trimethyltin
Psychopharmacology, 93, 301, 1987.
21 Lubow, R E and Moore, A U., Latent inhibition: effects of non-reinforced
pre-exposure to the conditioned stimulus Journal of Comparative and Physiological Psy-chology, 52, 415, 1959.
22 Weiner, I and Feldon, J., The switching model of latent inhibition: an update of neural
substrates Behavioral Brain Research, 88, 11, 1997.
23 Collier, T J., Quirk, G J., and Routtenberg, A., Separable roles of hippocampal granule
cells in forgetting and pyramidal cells in remembering spatial information Brain Research, 409, 316, 1987.
24 Huang, M., Messing, R B., and Sparber, S B., Learning enhancement and behavioral
arousal induced by yohimbine Life Sciences, 41, 1083, 1987.
25 Messing, R B and Sparber, S B., Greater task difficulty amplifies the facilitatory
effect of des-glycinamide arginine vasopressin on appetitively motivated learning Behavioral Neuroscience, 99, 1114, 1985.
26 Messing, R B., Kleven, M S., and Sparber, S B., Delaying reinforcement in an
autoshaping task generates adjunctive and superstitious behaviors Behavioural Pro-cesses, 13, 327, 1986.
27 Messing, R B and Sparber, S B., Des-gly-vasopressin improves acquisition and slows
extinction of autoshaped behavior European Journal of Pharmacology, 89, 43, 1983.
28 Ross, W D., Emmett, E A., Steiner, J., and Tureen, T., Neurotoxic effects of
occupa-tional exposure to organotins American Journal of Psychology, 138, 1092, 1981.
29 Tilson, H A and Sparber, S B., Eds., Neurotoxicants and Neurobiological Function: Effects of Organoheavy Metals John Wiley & Sons, New York, 1987.
30 Cohn, J and MacPhail, R C., Acute trimethyltin exposure produces nonspecific effects
on learning in rats working under a multiple repeated acquisition and performance
schedule Neurotoxicology and Teratology, 18, 99, 1996.
© 2001 by CRC Press LLC
Trang 731 Gerbec, E N., Messing, R B., and Sparber, S B., Parallel changes in operant behavioral adaptation and hippocampal corticosterone binding in rats treated with trimethlytin
Brain Research, 460, 346, 1988.
32 Messing, R B., Bollweg, G., Chen, Q., and Sparber, S B., Dose-specific effects of
trimethyltin poisoning on learning and hippocampal corticosterone binding Neurotox-icology, 9, 491, 1988.
33 Sparber, S B., Bollweg, G L., and Messing, R B., Food deprivation enhances both
autoshaping and autoshaping impairment by a latent inhibition procedure Behavioral Processes, 23, 59, 1991.
34 Solomon, P R., Neural and behavioral mechanism involved in learning to ignore
irrelevant stimuli In: Classical Conditioning, Gormezano, I., Prokasy, W F., and
Thompson, R F., Eds., Lawrence Erlbaum Assoc., Hillsdale, NJ, 117, 1987
35 Swartzwelder, H S., Hepler, H S J., Holahan,W., King, S E., Leverenz, H A., Miller,
P A., and Myers, R D., Impaired maze performance in the rat caused by trimethyltin
treatment: Problem solving deficits and perseveration Neurobehavioral Toxicology and Teratology, 4, 169, 1982.
36 Coveney, J R and Sparber, S B., Phencylidine retards autoshaping at a dose which
does not suppress the required response Pharmacology Biochemistry and Behavior,
16, 937, 1982
37 Sparber, S B., O’Callaghan, J P., and Berra, B., Ganglioside treatment partially counteracts neurotoxic effects of trimethyltin but may itself cause neurotoxicity in rats:
Experimental results and a critical review Neurotoxicology, 13, 679, 1992.
38 Bollweg, G., Balaban, C D., Berra, B., and Sparber, S B., Potential efficacy and toxicity of GM1 ganglioside against trimethyltin-induced brain lesions in rats:
Com-parison with protracted food restriction Neurotoxicology, 16, 239, 1995.
39 Deutsch, J., Higher nervous function: The psychological basis of memory Annual Review of Physiology, 24, 259, 1962.
40 Deutsch, J., The cholinergic synapse and the site of memory Science, 174, 788, 1971.
41 Davis, K L., Hollister, L E., Overall, J., Johnson, A., and Train, K., Physostigmine:
Effects on cognition and effects in normal subjects Psychopharmacology, 51, 23,
1976
42 Davis, K L., Mohs, R C., Tinklenberg, J R., Pfefferbaum, A., Hollister, L E., and Kopell, B S., Physostigmine: improvement of long-term memory processes in normal
humans Science, 201, 272, 1978.
43 Davies, P and Maloney, A J F., Selective loss of central cholinergic neurons in
Alzheimer’s Disease Lancet, 2, 1403, 1976.
44 Roberts, G W., Crow, T J., and Polak, J M., Location of neuronal tangles in
soma-tostatin neurones in Alzheimer’s Disease Nature, 314, 92, 1985.
45 Yamamoto T and Hirano A., Nucleus Raphe Dorsalis in Alzheimer’s Disease:
Neu-rofibrillary tangles and loss of large neurons Annals of Neurology, 17, 573, 1984.
46 Mohs, R C., Davis, B M., Johns, C A., Mathé, A A., Greenwald, B S., Horvath,
T B., and Davis, K L., Oral physostigmine treatment of patients with Alzheimer’s
Disease American Journal of Psychiatry, 142, 28, 1985.
47 Muramoto, O., Sugishita, M., and Ando, K., Cholinergic system and constructural
praxis: a further study of physostigmine in Alzheimer’s Disease Journal of Neurology, Neurosurgery, and Psychiatry, 47, 485, 1984.
© 2001 by CRC Press LLC
Trang 848 Caltagirone, C., Gainotti, G., and Masullo, C., Oral administration of chronic physos-tigmine does not improve cognitive or mnesic performances in Alzheimer’s Presenile
Dementia International Journal of Neuroscience, 16, 247, 1982.
49 Jenike, M A., Albert, M S., Heller, H., Gunther, J., and Goff, D., Oral physostigmine treatment for patients with presenile and senile dementia of the Alzheimer’s type: a
double-blind placebo-controlled trial Journal of Clinical Psychiatry, 51, 3-, 1990.
50 Jotkowitz, S., Lack of clinical efficacy of chronic oral physostigmine in Alzheimer’s
Disease Annals of Neurology, 14, 690, 1983.
51 Peters, B H and Levin, H S., Effects of physostigmine and lecithin on memory in
Alzheimer’s Disease Annals of Neurology, 6, 219, 1979.
52 Schwartz, A S and Kohlstaedt, E V., Physostigmine effects in Alzheimer’s Disease:
relationship to dementia severity Life Sciences, 38, 1021, 1986.
53 Cox, T and Tye, N., Effects of physostigmine on the acquisition of a position
discrim-ination in rats Neuropharmacology, 12, 477, 1982.
54 Leaf, R C and Muller, S A., Effects of scopolamine on operant avoidance acquisition
and retention Psychopharmacologia, 9, 101, 1966.
55 Stratton, L D and Petrinovich, L., Post trial injections of an anticholinesterase drug
and maze learning in two strains of rats Psychopharmacologia, 5, 47, 1963.
56 Rech, R H., Effects of cholinergic drugs on poor performance of rats in a shutttle box
Psychopharmacologia, 12, 371, 1968.
57 Parker, L A., Hutchinson, S., and Riley, A L., Conditioned flavor aversions: A toxicity
test of the anticholinesterase agent, physostigmine Neurobehavioral Toxicology and Teratology, 4, 93, 1982.
58 Romano, J A., King, J M., and Penetar, D M., A comparison of physostigmine
and soman using taste aversion and nociception Neurobehavioral Toxicology and Teratology, 7, 243, 1985.
59 Locke, K W., Gorney, B., Cornfeldt, M., and Fielding, S., Characterization of the
discriminative stimulus effects of physostigmine in the rat Journal of Pharmacolology and Experimental Therapeutics, 250, 241, 1989.
60 Tang A H and Franklin S R., Discriminative stimulus properties of physostigmine in
rats European Journal of Pharmacology, 153, 97, 1988.
61 Sivam, S P., Hoskins, B., and Ho, I K., An assessment of comparative acute toxicity
of diisopropylflorophosphate, tabun, sarin, and soman in relation to cholinergic and
GABAergic enzyme activities in rats Fundamental and Applied Toxicology, 4, 531,
1984
62 Sparber, S B and Tilson H A., Environmental influences upon drug-induced
suppres-sion of operant behavior The Journal of Pharmacology and Experimental Therapeutics,
179, 1, 1971
63 Sparber, S B., Tilson, H A., and Peterson, D W., Environmental influences upon
morphine or d-amphetamine induced suppression of operant behavior Pharmacology, Biochemistry and Behavior, 1, 133, 1973.
64 Jarbe, T C U., Laaksonen, T., and Svensson, R., Influence of exteroceptive contextual
conditions upon internal drug stimulus control Psychopharmacology, 80, 31, 1980.
65 Maayani, S., Egozi, Y., Pinchasi, I., and Sokolovsky, M., On the interaction of drugs
with the cholinergic nervous system VI Tolerance to physostigmine in mice Psycho-pharmacology, 55, 43, 1977.
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Trang 9© 2001 by CRC Press LLC
15
Chapter
Assessing Frontal Lobe Functions in Non-Human Primates
Jay S Schneider
Contents
I Introduction
II Assessing Short-Term (Working) Memory
A Delayed Response Tasks
B Delayed Matching-to-Sample
C Delayed Alternation III Assessing Inhibitory Control Functions
A Go/No-Go Tasks
B Discrimination Reversal Tasks
C Object Retrieval Task References
The frontal lobes, which comprise the anterior (precentral) cortical regions of the mammalian brain are functionally diverse and heterogenous structures The entirety
of the frontal cortex, including the prefrontal region (defined as the part of the cortex that receives projections from the mediodorsal nucleus of the thalamus) is motor cortex in the broadest sense.1 The frontal cortex is involved in the generation of skeletal and eye movements as well as in the mediation of a variety of cognitive functions, the temporal organization of behavior, and the expression of emotion Cognitive functions represented in the prefrontal cortex include short-term (working) 0704/C15/frame Page 269 Monday, July 17, 2000 5:37 PM
Trang 10Assessing Frontal Lobe Functions in Non-Human Primates 271
chair restraint prior to attempting any behavioral training or testing The animal should become accustomed to the restraint and be relaxed in the testing situation prior to the initiation of training The experimenter sits on the opposite side of the apparatus at a specified distance from the monkey and outside the view of the monkey The experimenter is hidden behind a two-way mirror so that he/she can observe the monkey's behavior There is a small opening at the bottom of the wall
in front of the examiner so that the experimenter can place the food rewards into the wells on the sliding board The distance between the monkey and the experi-menter should be such that the experiexperi-menter can comfortably push the stimulus tray towards the monkey To initiate a trial, the experimenter raises the opaque screen (attached by a pulley system) that, when raised, allows access to the sliding tray The tray contains recessed food wells and is equipped with identical sliding covers over the wells These can be made out of metal, Plexiglas, or any other sturdy material The covers serve as stimulus plaques that can be displaced by the animal
to obtain rewards (raisins, dried fruit, peanuts) The choice of reward should be arrived at empirically since different animals have different preferences.
Early in the training process, the animals will first need to be trained to displace the well covers to remove the food rewards from the wells This behavior is first shaped by leaving food in open wells and then by progressively covering the wells until the monkeys learn to displace the covers to retrieve the food Once this behavior
FIGURE 15.1
Standard version of a Wisconsin General Testing Apparatus (WGTA), showing the position of the monkey and the experimenter, the stimulus tray, and the one-way vision and opaque screens The WGTA is typically used in testing delayed response, delayed alternation, delayed matching-to-sample, and discrim-ination tasks In some versions of the WGTA, the monkey sits in a restraint chair located in a sound attenuated chamber rather than in a testing cage (From Stuss and Benson: The Frontal Lobes Raven Press, New York, 1986, used with permission Originally published by Harlow: Psychol Rev., 56: 51–65, 1949.)
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