understood, most conditioned physiological responses to drugs can be seen to conform to the conditioning paradigm developed by Pavlov.
Part 2: Conditioned Behaviors
A useful paradigm for the behavioral evaluation of conditioned drug effects is ► conditioned activity. Pickens and Crowder (1967) were among the first to report that environmental stimuli paired with the psychomotor-stimulant drug ► amphetamine produced conditioned locomotor activity in rats. In this paradigm, the CR is not a specific operant but rather a general increase in locomotion, rearing, and other related behaviors in the drug-associated environment.
The procedure involves injecting animals with a drug and then placing them into a distinct environment for a period of time (e.g., 1 h). After several drug-environment pairings, experimental animals are injected with saline and again placed into the test environment. The animals that received drug-environment pairings are observed to be more active than control animals with a similar history of placement in the environment and a similar history of drug injections but without having received the drug in the test environment (Fig. 1). Therefore, the effect of increased activity in rats having received environment-
Conditioned Drug Effects. Fig. 1. Locomotor activity (count per 60 min) typically observed during conditioning based on cocaine (10 mg/kg; left side) and test of conditioned activity (right side). Three groups (n =18 per group): saline controlled, unpaired (saline in conditioning environment; cocaine in homecage), paired (cocaine in conditioning environment; saline in homecage). *Significantly greater than unpaired and saline groups by analysis of variance followed by pairwise comparisons, p < 0.05.
drug pairings can be attributed to the association of environmental stimuli with the effects of the drug rather than a previous history of drug treatment. Conditioned activity has been demonstrated with a number of drugs including amphetamine, ► cocaine, ► nomifensine, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), quin-pirole, ► apomorphine, morphine, and etorphine.
The conditioning procedure used in this paradigm is often referred to as Pavlovian, where the drug is the US, the distinctive environment is the CS, and the increased activity in response to the drug is the UR. Increased activity during the CS alone is the CR. In spite of this apparent similarity, some research has shown that the CR does not strongly resemble the UR as is usually assumed in Pavlovian conditioning. In particular, behaviors not manifested during the drug-conditioning phase have been reported on the drug-free test day. For example, rats that received the dopamine reuptake inhibitor nomi-fensine on conditioning days were observed to gnaw on the drug-free test day, but gnawing was never produced by the nomifensine. In another study, the pattern of cocaine-induced turning during the drug-free test day did not resemble the pattern of turning observed on conditioning days. Based on these reports, Martin-Iverson and Fawcett (1996) examined whether behaviors of rats placed in an environment previously paired with amphetamine or the direct dopamine D2-like receptor agonist PHNO, looked like the drug-induced behaviors. The authors found that out of the 11 behavioral measures increased by amphetamine on conditioning days, only four were increased on the drug-free test day. The total duration of sniff, head movement, snout contact, and stand were significantly greater than that of control animals. Furthermore, rearing behavior was increased on the drug-free test day but this was not so during conditioning. The authors argued that some of the behaviors observed during the test session represented an increase in scanning of the test environment as a result of a change in that environment due to the absence of the drug cue. The drug-free day may alter the affective state of the animal by removing an anticipated rewarding stimulus; this in turn, might lead to a frustrative affective state that is behaviorally activating. Similar differences in behaviors observed during conditioning and test sessions were seen when PHNO was the drug used for conditioning. Out of 19 behaviors increased by PHNO during conditioning only three were significantly increased when compared with control rats in the test. Thus, behaviors evoked by an environment previously paired with either amphetamine or PHNO are not always the same as those produced by the drugs used for conditioning.
Ahmed et al. (1998) tested whether three variables known to affect the acquisition of Pavlovian conditioning would interfere with conditioned activity using amphetamine. The authors examined sensitivity to CS-US temporal order, to unsignaled occurrences of the drug US between CS-US pairing trials and CS-alone test, and to the US preexposure effect. With respect to the first, the acquisition of a Pavlovian CR is abolished if the US is presented simultaneously or before the CS. In the case of conditioned activity however, a 25 or 50 min drug US-CS delay during the six pairing sessions had no significant effect. Second, in Pavlovian conditioning, unpaired presentations of a US alone between CS-US pairings lead to a diminished CR in the test. Conditioned activity was not influenced by the number of unsignaled amphetamine injections given between the pairings of the CS and the drug US. Third, according to Pavlovian conditioning, pre-exposing the animal to the US alone usually has a detrimental effect on the acquisition of a CR. However, the acquisition of conditioned activity was not influenced by 10 days of preexposure to amphetamine prior to CS-US conditioning. Therefore, research argues that conditioned activity based on drug stimuli is not controlled by the same variables that control Pavlovian conditioning.
It has been suggested that conditioned activity can be understood as involving ► reward-related incentive learning (Beninger 1983; Beninger and Olmstead 2000). In this view, the environment paired with the rewarding properties of the drug acquires an increased ability to elicit approach and other responses during conditioning that manifests as a conditioned activity during testing. All drugs that elicit conditioned activity share a common feature: they all exhibit facilitative effect on the ► meso-telencephalic dopamine reward system especially in the striatal regions of the mammalian brain. Further, it has been shown consistently that conditioned activity does not develop if dopamine function is blocked during conditioning. Drugs that block dopamine transmission at D1- and/or D2-like receptors block the acquisition of conditioned activity. Classical Pavlovian learning has been shown to be relatively independent of dopamine; e.g., animals are able to learn CS-US associations under the influence of dopamine receptor blocking drugs. When the dopamine receptor blocker ► pimozide was administered during tone-food pairings, learning of the stimulus-stimulus associations was not blocked but the tone failed to acquire incentive motivational properties and consequently, could not be used as a conditioned reinforcer to control instrumental responding.
Another conditioned behavioral phenomenon that involves reward-related incentive learning, although in the opposite direction, is ► context-dependent catalepsy. Unlike conditioned activity that depends on enhanced dopamine transmission in the striatum, conditioned catalepsy depends on the lack of dopamine transmission in striatal regions. In one version of this paradigm rats were treated with a low dose of ► haloperidol, a dopamine D2-like receptor blocker, for 8 days. Paired rats were injected with haloperidol 1 h before being tested for catalepsy and were injected with saline 30 min after the test. Unpaired rats were injected with saline 1 h before the catalepsy test and then with haloperidol 30 min post test. Control rats received saline 1 h before and 30 min after the test. The dose of haloperidol did not produce catalepsy on the first session; however, a day-to-day increase in catalepsy was observed from day 1 to day 8. On day 9, paired rats were administered saline only and showed context-induced catalepsy in the environment previously paired with haloperidol. The unpaired group did not differ from saline control rats, thus history of haloperidol injections alone could not account for this effect. Conditioned catalepsy shares a number of characteristics with conditioned activity; however, the net effect is not an enhanced activity in the conditioned environment but a decrease in the locomotor output (Schmidt and Beninger 2006).
In the conditioned catalepsy studies, a day-to-day ► sensitization to haloperidol was also seen. This is similar but opposite in direction to the augmentation of behavior observed with repeated administration of psychostimulant or opiate drugs. The context in which the drug is expected facilitates the expression of sensitiza-tion to the effects of both haloperidol and stimulant drugs. Normally, this context-dependency is extinguish-able by repeated exposure to the test environment without the drug. However, retesting animals with haloperidol following extinction resulted in a slight but significant cataleptic response in the paired group and not in the unpaired group. This suggested that haloperidol itselfmay act as an interoceptive cue that was conditioned along with the environment. Thus, sensitization might involve two separate learning components: first, a context-conditioned component that is not expressed following extinction and second, an interoceptive cue-related component that had become associated with the conditioning environment and was not weakened by exposures to that environment while in a drug-free state.
The development of sensitization has been shown to depend on the dopamine activity in the ► ventral tegmen-tal area (VTA) and ► nucleus accumbens. This enhancement is also glutamate dependent. Studies using the glutamate N-methyl-d-aspartate receptor antagonist MK-801 have shown that glutamatergic input to the
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