BEHAVIOR ANALYSIS in NEUROSCIENCE - PART 4 potx

92 Methods of Behavior Analysis in NeuroscienceImportant to the study of drug effects on behavior is the understanding that drugs function as stimuli to control behavior.1 Based on the p

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Conditioned Place Preference 85

Visual Cues — Vision cues are a poor choice for albino rodents, but pigeons are

an excellent subject for visual cues Rats prefer a dark environment vs a light environment The use of different shapes and colors are good variables for pigeons

or primates, while simple light and dark choices are appropriate for rodents The preferred chamber design for rodents is a patterned design, not a solid black or white configuration which increases the strong preference for the dark environment

Olfaction — Olfaction is one of the best exteroceptive cues (no odor, female

or male scent, and food) for rodents

It is worth noting that failure to clean the chambers after each test session, during habituation and during training, has the potential to confound results

Auditory Cues — Developmental rodent studies utilizing powerful exterocep-tive cues often use recordings of ultrasonic chatter between mother and pup Tones and clicking sounds provide means of creating distinct auditory environments

Tactile Cues — One should allow for a wide range and degree of specificity between chambers by using different flooring materials (solid floor [smooth, tex-tured], spaced bars, wire mesh, wood chips)

IV Experimental Designs

Drugs with powerful reinforcing properties (amphetamine, cocaine, and morphine) require fewer and shorter conditioning trials then a weaker reinforcing drug (nico-tine) Drugs with a very short half-life may allow a researcher to run a drug session

in the morning and a vehicle session in the afternoon

The number of drug and vehicle training sessions should be equal Number of testing sessions in CPP or CPA is one The test session is in a non-drugged state

Comment — A criticism of CPP or CPA is testing in a non-drug state when conditioning in a drugged state creates the potential of confounding by state depen-dent learning State dependepen-dent learning takes place when an animal is conditioned

to the interaction between exteroceptive cues and interoceptive cues, but then tested with only exteroceptive cues This dilemma potentially arises for weak reinforcing drugs Adding a test session in the drugged state will determine if state dependent learning was a factor in the conditioning Additional test sessions for evaluation of agonist and antagonist are helpful in developing a complete behavioral and pharma-cological profile of the test drugs

In addition to the above considerations, two conditioning techniques can be used in CPP and CPA design, biased and unbiased training In biased conditioning the

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86 Methods of Behavior Analysis in Neuroscience

subject’s baseline preference is first determined for the chosen apparatus before experimental manipulation In unbiased conditioning the subject is trained to asso-ciate the experimental manipulation with a particular environment Both the biased and unbiased conditioning techniques in a two-chamber apparatus require a forced choice decision by the animal Incorporating a three-chamber, four-chamber, or open field apparatus eliminates the potential confound of forced choice The subject of choice for years was the rat, but labs frequently now use the mouse The Syrian hamster and primates have also been used in CPP and CPA.11,12 Thus, there are a variety of approaches that can be used to investigate CPP and the reader is referred

to reviews by Schechter13,14 for additional views of the field

V Training and Testing

Several days of free access to all environments allow the animal to habituate to the apparatus, eliminating novelty as a confounding variable Baseline data should be determined as an average of time spent in each chamber over 3 to 5 days The length

of time necessary to determine baselines depends on the environmental differences between apparatus chambers Distinct environments require fewer baseline sessions while less distinct or ambiguous environments require more baseline sessions Durazzo et al.1 found 20-min habituation sessions just as statistically significant as

Single Alternation Drug Schedule

Drug days Vehicle days WEEK 1 Monday Tuesday

Wednesday Thursday Friday

WEEK 2 Tuesday Monday

Thursday Wednesday Friday

Double Alternation Drug Schedule

Drug days Vehicle days WEEK 1 Monday Wednesday

Tuesday Thursday Friday

WEEK 2 Monday Tuesday

Thursday Wednesday Friday

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40-min habituation sessions Test sessions are generally 30 to 40 min in length In CPP a drug or environmental manipulation thought to have reinforcing properties

is paired with the less preferred environment and vehicle, or no environmental manipulation is paired with the preferred environment

The testingof subjects is performed in a non-manipulated state The percentage of time spent in each chamber is tabulated during the test session If the animal spends more time in the less preferred (baseline data) chamber associated with the experi-mental manipulation, the researcher can infer the experiexperi-mental manipulation had a rewarding effect on the affective state of the animal In CPA a drug or environmental manipulation thought to have aversive properties is paired with the preferred envi-ronment and vehicle or no envienvi-ronmental manipulation is paired with the less preferred environment If the animal spends more time in the preferred (baseline data) chamber associated with vehicle, or no environmental manipulation, the researcher can infer the experimental manipulation had a punishing effect on the affective state of the animal Designs that include a novel chamber do not allow free access to the novel chamber during the habituation period

A variety of other measures can be used to obtain information about the drug being studied Spontaneous activity and location of subject within a chamber can be determined via infrared beams and computer technology.15 In addition, video taping can also be utilized to determine other behavioral characteristics of the subjects under drug and non-drug states

VI Research Objectives: Pharmacological and Neuroscience Objectives

The CPP design is a simple procedure that has the potential for learning more about the positive reinforcing properties of a specific drug This is especially important in research where the goal is to determine mechanisms of drug action using neuro-science approaches It is extremely difficult using brain site techniques (lesions, microdialysis, and other neurophysiolgical procedures) in animals self-administering

a drug or other operant procedures The CPP procedure in many cases is a useful and manageable tool in evaluating drug action at different brain sites

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The CPP design has the potential to evaluate new compounds suspected of having the same effects as a given agent Thus, animal subjects trained with morphine should generalize to meperdine or methadone

A major issue in substance abuse research is the ability to detect new drugs that may be useful as antagonists to drugs such as cocaine that may help cocaine addicts

in their rehabilitation Thus, rats trained to cocaine can be challenged with other agents to determine the relative ability to attenuate cocaine’s reward stimulus In addition, antagonism studies can provide additional information as to how a specific drug is acting (receptor classification)

VII Conclusion

CPP and CPA are behavioral paradigms that are best used with experimental manip-ulations that produce a distinct discriminative stimulus As mentioned previously, a drug may have both rewarding and punishing potential Are you evaluating the rewarding or punishing effect of the drug? Preliminary studies are necessary when

a literature review fails to provide pharmacokinetic information about the test article When deciding upon the “biased” or “unbiased” conditioning method, a researcher might consider combining the two methods, first using the “biased” method where the preferred environment is determined and then using the “unbiased” method where the subjects are split between both environments

References

1 Durazzo, T.C., Gauvin, D.V., Goulden, K.L., Briscoe, R.J., and Holloway, F.A., Cocaine- induced conditioned place approach in rats: The role of dose and route of administration, Pharmacol Biochem Behav. 49, 1001, 1994.

2 Hasenohrl, R.U., Oitzl, M.S., and Huston, J.P., Conditioned place preference in the corral: A procedure for measuring reinforcing properties of drugs, J Neurosci Methods,

30, 141, 1989.

3 Parker, L.A., Place conditioning in a three- or four-choice apparatus: Role of stimulus novelty in drug-induced place conditioning, Behav Neurosci., 106, 294, 1992.

4 Klebaur, J.E and Bardo, M.T., The effects of anxiolytic drugs on novelty-induced place preference, Behav Brain Res., 101, 51, 1999.

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5 Kosten, T.A., Miserendino, M.J., Chi, S., and Nestler, E.J., Fischer and Lewis rat strains show differential cocaine effects in conditioned place preference and behavioral sen-sitization but not in locomotor activity or conditioned taste aversion, J Pharmacol Exp Ther., 269, 137, 1994.

6 Tzschentke, T.M., Measuring reward with the conditioned place preference paradigm:

A comprehensive review of drug effects, recent progress and new issues, Prog Neu-robiol., 56, 613, 1998.

7 Fudala, P.J., Teoh, K.W., and Iwamoto, E.T., Pharmacologic characterization of nico-tine-induced conditioned place preference, Pharmacol Biochem Behav., 22, 237, 1985.

8 Fudala, P.J and Iwamoto, E.T., Further studies on nicotine-induced conditioned place preference in the rat, Pharmacol Biochem Behav., 25, 1041, 1986.

9 Clarke, P.B and Fibiger, H.C., Apparent absence of nicotine-induced conditioned place preference in rats, Psychopharmacol., 92, 84, 1987.

10 Jorenby, D.E., Steinpreis, R.E., Sherman, J.E., and Baker, T.B., Aversion instead of preference learning indicated by nicotine place conditioning in rats, Psychopharmacol.,

101, 533, 1990.

11 Meisel, R.L., Joppa, M.A., and Rowe, R.K., Dopamine receptor antagonists attenuate conditioned place preference following sexual behavior in female Syrian hamsters, Eur.

J Pharmacol., 309, 21, 1996.

12 Pomerantz, S.M., Wertz, I., Hepner, B., Wasio, L., and Piazza, I., Cocaine-induced conditioned place preference in rhesus monkeys, Soc Neurosci., Abstr., 18, 1572, 1992.

13 Schechter, M.D and Calcagnetti, D.J., Trends in place preference conditioning with a cross-indexed bibliography; 1957-1991, Neurosci Biobehav Rev., 17, 21, 1993.

14 Schechter, M.D and Calcagnetti, D.J., Continued trends in the conditioned place preference literature from 1992 to 1996, inclusive, with a cross-indexed bibliography,

Neurosci Biobehav Rev., 22, 827, 1998.

15 Brockwell, N.T., Ferguson, D.S., and Beninger, R.J., A computerized system for the simultaneous monitoring of place conditioning and locomotor activity in rats, J Neu-rosci Meth., 64, 227, 1996.

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-6 Chapter

Intravenous Drug Self-Administration in Nonhuman Primates

Leonard L Howell and Kristin M Wilcox

Contents

I Introduction

II Surgical Procedures III Schedules of Drug Delivery

A Initial Training

B Fixed-Ratio Schedules

C Fixed-Interval Schedules

D Second-Order Schedules

E Progressive-Ratio Schedules

IV Research Application and Data Interpretation

V Discussion References

I Introduction

The abuse of psychoactive drugs such as cocaine and heroin has spanned several decades and continues to be widespread in the U.S Currently, research efforts have focused on the development of therapeutics to treat drug abuse Drug self-adminis-tration studies have done much to help us understand the behavioral and pharmaco-logical mechanisms underlying drug abuse An understanding of these mechanisms will in turn aid in the development of effective therapeutic agents

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Important to the study of drug effects on behavior is the understanding that drugs function as stimuli to control behavior.1 Based on the principles of operant conditioning, presentation of a stimulus as a consequence of behavior may either increase or decrease the probability that a behavior will occur again.2 If a stimulus increases the probability that a behavior will recur, then that stimulus is defined as

a positive reinforcer.2 Stimuli such as food and water function as positive reinforcers, and data from self-administration studies indicate that drugs also function as positive reinforcers Drug self-administration procedures in animals have been used exten-sively to evaluate the reinforcing effects of drugs The first studies examining the reinforcing effects of drugs in the 1950s and 1960s focused on morphine self-administration in morphine-dependent animals.3,4 Later studies demonstrated that dependence was not necessary to initiate self-administration.5,6 Since these early studies, self-administration procedures have been used as a model of drug taking that can be studied under controlled laboratory conditions and applied to human drug use

Drug self-administration studies in animals have contributed substantially to our knowledge of the neuropharmacological mechanisms controlling drug abuse For example, studies with opioids have shown that drugs with high affinity for µ opioid receptors function as positive reinforcers,7,8 whereas opioids with high affinity for κ opioid receptors generally do not.8,9 Additionally, the self-administration of psychomotor stimulants and opioids has been found to be affected by the adminis-tration of antagonists either systemically or centrally (cf,10,11) If administration of

an antagonist shifts the dose-response function for a self-administered drug to the right, then it can be assumed that the site of action of the antagonist is important for the reinforcing effects of the drug.12-15 In addition to the administration of antagonists, self-administration of drugs has been affected by lesions of certain brain neurotransmitter systems (cf,10,11) Studies have also found that animals will self-administer drugs directly into certain brain areas, suggesting a neuropharmacological mechanism for their reinforcing effects (cf,10)

Over the years, drug self-administration procedures in animals have been found

to be valid and reliable for determining the abuse liability of drugs in humans It is well established that animals will self-administer most drugs that are abused by humans.16,17 In particular, studies in nonhuman primates have made a significant contribution to the field of drug abuse research Nonhuman primates are ideal subjects since they are phylogenetically more closely related to humans than are other species Thus, we can apply information obtained from nonhuman primates

to problems of human drug abuse with greater accuracy This chapter will discuss methods of self-administration in nonhuman primates, including different prepara-tions and schedules of drug reinforcement While the focus will be primarily on self-administration of psychoactive stimulants such as cocaine, the methodology and general principles apply to other pharmacological classes including opiates, benzo-diazepines, and alcohol

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FIGURE 6.1

A cumulative record of lever pressing maintained in three squirrel monkeys under a second-order FI 600-second schedule of cocaine (0.1 mg/injection) intravenous self-administration with FR 20 components.

A red light illuminated the test chamber during the 600-second FI, and every 20th response during the

FI changed the red light to white for 2 seconds The first FR completed after the 600-second FI elapsed produced a drug injection and changed the red light to white for 15 seconds Abscissa: time Ordinate: cumulative number of responses Pen deflection on the time axis indicates the end of the interval and the beginning of a timeout The response pen reset vertically upon completion of each FI or when the pen reached the top of the paper.

C

S-104

15 Minutes

S-106

S-102 COCAINE (0.1 mg/infusion)

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response rate increases with drug dose In contrast, the descending limb of the curve reflects a nonspecific disruption of operant behavior as excessive drug accumulates over the session, and response rate decreases with drug dose In addition, an inverse relationship has been obtained between infusion duration and reinforcing effects.35,36 The longer the infusion time required to deliver a constant volume of drug solution, the less effective the drug functions as a reinforcer

A study by Glowa et al.37 illustrates the use of an FR schedule of drug self-administration to characterize the effectiveness of a dopamine reuptake inhibitor to alter the reinforcing effects of cocaine in rhesus monkeys A standard tethered-catheter, home-cage system was used for intravenous drug delivery.5 Animals were trained to self-administer cocaine under an FR 10 schedule of drug delivery during 90-minute daily sessions Pretreatment with the high-affinity dopamine reuptake inhibitor, GBR 12909, dose-dependently decreased rates of cocaine-maintained responding, and the effect was larger when lower doses of cocaine were used to maintain responding Moreover, the rate-decreasing effects of GBR 12909 were greater on cocaine-maintained responding than on food-maintained responding under

a multiple schedule of drug and food delivery The results obtained were consistent with previous reports demonstrating that drugs with dopamine agonist effects can

FIGURE 6.2

A cumulative record of lever pressing maintained in a rhesus monkey under a progressive-ratio schedule

of cocaine (0.1 mg/kg/injection) self-administration over a daily session The daily session consisted of five components, each made up of four trials at a particular response requirement The response require-ment began at an FR of 120 and doubled in subsequent components (i.e., 120, 240, 480, 960, 1920) A trial ended with a drug injection or the expiration of a limited hold The session ended if the limited hold expired two consecutive times Abscissa: time Ordinate: cumulative number of responses The response pen reset vertically upon completion of the FR or when the pen reached the top of the paper.

90-31

15 Minutes

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Intravenous Drug Self-Administration in Nonhuman Primates 99

decrease cocaine-maintained responding.38,39 This type of drug interaction has been attributed to a satiation of cocaine-maintained responding by pretreatment with a drug having dopaminergic effects The latter approach to cocaine medication devel-opment has been referred to as substitute agonist pharmacotherapy.40 Hence, response-independent delivery of a dopamine reuptake inhibitor may have decreased cocaine self-administration by substituting for the reinforcing effects of response-produced cocaine This interpretation is supported by studies showing that GBR

12909 will substitute for cocaine as a reinforcer in squirrel monkeys.41-43

Note that Glowa et al.37 incorporated several important design features in their self-administration study First, multiple unit doses of cocaine were self-administered

on separate occasions in order to establish a complete dose-effect curve for cocaine Hence, pretreatment effects of GBR 12909 could be assessed over a broad range of cocaine doses Second, multiple pretreatment doses of GBR 12909 were adminis-tered in order to establish dose-dependency of pretreatment effects and to identify the optimal pretreatment dose that lacked overt behavioral toxicity Lastly, the specificity of pretreatment effects on cocaine-maintained behavior was assessed by comparing drug effects on food-maintained behavior The multiple schedule which alternated cocaine and food as maintaining events during separate components was well-suited for this application Moreover, cocaine dose was manipulated to match response rate to that obtained during the food component of the multiple schedule The finding that GBR 12909 suppressed cocaine-maintained responding at doses that had little or no effect on food-maintained responding under identical schedules and comparable response rates provides convincing evidence that GBR 12909 selec-tively attenuated the reinforcing effects of cocaine

A study by Woolverton44 provides another example of cocaine self-administration under an FR schedule in rhesus monkeys The objective was to characterize the effectiveness of dopamine antagonists to alter the reinforcing effects of cocaine A standard tethered-catheter, home-cage system was used for intravenous drug delivery Animals were trained to self-administer cocaine under an FR 10 schedule of drug delivery during 2-hour daily sessions When responding was stable, the animals were pretreated with the D1 antagonist, SCH 23390, or the D2 antagonist, pimozide Inter-mediate doses of pimozide generally increased cocaine self-administration, whereas SCH 23390 either had no effect or decreased cocaine self-administration High doses

of both antagonists decreased the rate of cocaine self-administration, but also produced pronounced catalepsy Hence, the latter effects could not be attributed to a selective interaction with the reinforcing effects of cocaine The author concluded that the selective increase in responding maintained by cocaine following pimozide pretreat-ment suggested a role for the D2-receptor in cocaine self-administration

Strengths of the Woolverton44 study design included multiple unit doses of cocaine and multiple pretreatment doses of both dopamine antagonists Extinction

of cocaine self-administration when saline was substituted for cocaine was also characterized Note that response rate for cocaine increased following pretreatment with the D2-selective antagonist The latter effect is interpreted as a behavioral compensation to overcome the attenuation of the reinforcing effects of cocaine by pimozide Since drug intake is a direct function of response rate under FR schedules,

an increase in rate will result in greater session intake of cocaine which may

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