Continued trends in the conditioned place preference literature from 1992 to 1996, inclusive, with a cross-indexed bibliography.

In light of the overwhelming response to the previous publication in Neuroscience and Biobehavioral Reviews (1993, 17, 21-41) regarding trends in place conditioning (either preference or aversion), the present work constitutes a five-year follow-up to review the empirical research in this behavioral paradigm from 1992 to 1996, inclusively. The behavioral technique has grown as indicated by the number of publications over the last five years which equals those authored over the 35 years covered by our last survey. The previous work used descriptive statistics to explore topical issues, whereas the present work discusses trends since that time and hopes to provide an exhaustive bibliography of the CPP literature, including articles, published abstracts, book chapters and reviews, as well as providing a cross-index of identified key words/drugs tested.

Olfactory bulbectomy disrupts the expression of cocaine-induced conditioned place preference.

The role of the olfactory sense in the expression of cocaine-induced conditioned place preference (CPP) was examined in adult male rats (n = 35) of the N/Nih strain. Consistent with the scientific literature, rats were observed to significantly (p < 0.05) increase (double) the seconds spent in their least-preferred chamber following cocaine-chamber pairings. Subsequently, groups of rats underwent one of three treatments: 1) olfactory bulbectomy (BULBX), 2) sham surgery (SHAM), or 3) sham surgery plus intranasal zinc sulfate perfusion (ZnSO4). Zinc sulfate was used to produce a temporary loss of olfaction. In a separate behavioral measure of olfactory acuity, both BULBX and ZnSO4-treated rats performed at an equally deficient level, in contrast to SHAM-treated rats that were not rendered anosmic. A second conditioned place preference test revealed that the ZnSO4-perfused and SHAM groups did not differ from their original postcocaine preference measurements. In contrast, the BULBX group spent significantly fewer seconds in the cocaine-paired chamber. After a 14-day interval, a third preference test revealed that SHAM and ZnSO4-treated rats displayed an equivalent preference for the cocaine-paired chamber (at 2.7 times above baseline). Interestingly, the seconds spent in the cocaine-paired chamber by BULBX rats did not differ from their baseline (e.g., precocaine exposure). These results suggest that bulbectomy disrupts the expression of cocaine-induced place preference. Interpretations of data from BULBX rats involving the production of an anhedonic condition and the relevance of olfactory bulbectomy as an animal model of anhedonic depression are discussed.

Blockade of cocaine-induced conditioned place preference: relevance to cocaine abuse therapeutics.

Conditioned place preference/aversion testing is a behavioral method believed capable of measuring the affective (positive, neutral or negative) properties of psychoactive drugs. Cocaine injections in rats reliably produces a positive place preference. Drugs that attenuate or block this effect of cocaine have obvious potential for developing treatments to address cocaine addiction as well as to add to the scientific understanding of the mechanism of cocaine's action at the cellular level. To date, six drugs have been reported to block the expression of a cocaine-induced conditioned place preference (CPP) and this review evidences the cocaine-induced CPP blockage by the two potent L-type calcium channel blockers, isradipine and nifedipine, the two serotonin-3 receptor antagonists, MDL72222 and ICS205-930, the delta opioid receptor selective antagonist naltrindole, and lastly, a mixed opioid agonist-antagonist buprenorphine. Additional evidence relating to the blockade of other cocaine behavioral effects by these putative blockers is addressed, where appropriate, from studies employing other procedures such as drug stimulus discrimination, self-administration, electrical brain stimulation and increases in locomotor activity. The significance of these findings is discussed in the context of their relevance to the development of treatment regimens to allow for cessation of cocaine abuse.

Nicotine place preference using the biased method of conditioning.

1. The objective of the experimentation was to determine whether nicotine (NIC, 0.8 mg/kg subcutaneously administered) would produce a conditioned place preference (CPP) in rats confined for thirty min to their less-preferred side in a three compartment apparatus, or an aversion when another group of rats were confined to their more preferred side. 2. On the non-drugged test day following eight conditioning trials, the rats spent more time in the compartment paired with NIC that was initially less-preferred, whereas animals that were conditioned with NIC in their preferred compartment had no significant change in time spent in that side. 3. Subsequently, locomotor activity was measured during a 30 min test session following the injection of NIC at the dose tested in CPP (0.8 mg/kg). A possible common mechanism on NIC-induced CPP and locomotor stimulation, as they may be regulated by mesolimbic dopamine neurons is discussed.

Deficits in shock-induced freezing and naltrexone enhancement of freezing in fawn hooded rats.

When a rat is returned to a context associated with mild electric foot shock (1 mA/0.75 s), the environmental cues elicit a species-specific defensive behavior termed freezing. Genetically divergent strains of rats given identical shock conditioning differ in the degree of freezing observed. The acquisition of freezing appears to be mediated, at least in part, by endogenous opioids since the duration that a rat spends freezing is increased by pretreatment prior to training with naltrexone (NTX), an opioid receptor antagonist. The objective of the present studies was to compare the shock-induced freezing and its enhancement with NTX in two unique strains of rats, viz., N/Nih and Fawn Hooded (FH), with that seen in the more commonly employed Sprague-Dawley strain (SPD). Age-matched female rats from these three strains were observed for freezing after shock conditioning. Separate groups of rats from each strain were treated with NTX (7.0 mg/kg) prior to shock. Vehicle (VEH; 0.9% saline)-treated SPD and N/Nih rats were observed freezing for approximately 30% of the testing duration, whereas FH rats froze for only 15% of the test duration. NTX-treated SPD and N/Nih rats displayed an equivalent 130% increase in freezing in comparison to their respective saline controls. Freezing in NTX treated FH rats did not differ from VEH. Collectively, these results suggest that the level of freezing and NTX enhancement of freezing in the N/Nih rat strain are equivalent to SPD. In comparison, FH rats show deficits in freezing and are insensitive to NTX enhancement of freezing.

Isradipine produces neither a conditioned place preference nor aversion.

Isradipine (ISR) has been reported to block cocaine-induced conditioned place preference. Using this procedure, the pairing of this L-type calcium blocker, at doses of 2.5, 5.0 and 10 mg/kg, with a preferred (cue-distinct) environment was investigated. In a separate experiment, ISR injection (10 mg/kg) was paired with the less-preferred environment to determine whether ISR produces a place preference. Testing in the non-drugged state revealed that ISR conditioning failed to affect side preference in both experiments. The neutral affective properties of ISR may be relevant to the development of cocaine use/abuse treatment regimens.

Place preference for the psychostimulant cathinone is blocked by pretreatment with a dopamine release inhibitor.

1. The objective of Exp. 1 was to determine whether intracerebroventricular (ICV) injection of cathinone CATH (8.0-32 micrograms) would produce a dose-dependent conditioned place preference (CPP) and/or activation in rats. Results indicate that rats conditioned with 16 or 32 micrograms doses of CATH significantly increased the time spent in their less preferred side, whereas rats conditioned with the 8.0 micrograms dose failed to show any shift from baseline preference. The 16 and 32 micrograms doses of CATH also significantly (p < .004) increased activity by more than 65% of baseline. 2. Exp. 2 was designed to determine whether ICV pretreatment with a dopamine release inhibitor CGS 10746B (CGS; 15 micrograms/rat) would block place conditioning produced by CATH. The results demonstrate that CGS pretreatment effectively blocked CATH-induced place conditioning and the CATH-induced elevation of activity.

Calcium channel blockade attenuates angiotensin II-induced drinking in rats.

Lateral ventricular administration of angiotensin II (ANG II) produces potent dipsogenic effects in water-sated rats. ANG II seems to require functional voltage-gated calcium channels on neurons throughout circumventricular brain sites to exert its effects. Although there are at least three types of calcium channels, only L-type calcium channel-blocking drugs have been reported to decrease drinking. (4-(4-Benzofurazanyl)-1-4-dihydro-2,6-dimethyl-3,5-pyridine-dic arb oxylic acid methyl 1-methyl-ethyl ester) [PN 200-110; isradipine (ISR)], a selective L-type calcium channel blocker, has been shown to attenuate significantly the intake of sweetened water in water-sated rats following either peripheral or ICV administration, but ISR does not affect plain-water intake in water-deprived rats. The present experiment was designed to determine whether ISR would attenuate ANG II-induced drinking that is not either motivated by palatability or dependent on deprivation. Rats, each fitted with chronic indwelling ventricular cannulae, were pretreated with ISR (0.3, 3.0, and 30 micrograms/rat; ICV). ANG II (40 ng/rat; ICV) was administered 10 min later and rats were allowed free access to water for 15 min. Injections of ANG II plus saline and ANG II plus the ISR vehicle (dimethyl sulfoxide) did not attenuate ANG II-induced polydipsia, whereas ANG II+ISR (0.3 and 3.0 micrograms) attenuated ANG II-induced drinking to 62 and 22% of control, respectively. Results with the 30-micrograms dose were not different from the 3.0 dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Extinction of cocaine-induced place approach in rats: a validation of the "biased" conditioning procedure.

It has often been demonstrated that when a rat is conditioned in a cue-specific environment that has been repeatedly paired with cocaine injections, it will spend more time in that environment than it does in a saline-paired environment. This behavioral procedure is commonly known as the conditioned place preference (CPP)-test. At present, a firm theoretical understanding of the mechanisms underlying the production of a CPP are unknown. It is insufficient merely to know that a CPP can result after repeated drug pairings. Rather, it is necessary that the procedure is validated within a learning theory framework. The objective of the present study was, therefore, to establish that what is observed in place preference studies was, indeed, conditioning. This was accomplished by determining whether a cocaine-induced increase in time spent in a drug-paired environment was subject to attenuation following extinction trials. Rats were tested for their initial bias in spending more time in one of two stimulus-specific chambers of a place-conditioning apparatus. On four occasions, rats were injected with 2.5 mg/kg cocaine and confined to their less-preferred chamber whereas, on four alternating sessions, they were conditioned with saline (vehicle) in their preferred chamber. Subsequent testing in the nondrugged state revealed that these rats displayed a significant increase in the time spent in their initially least-preferred environment compared to baseline measurements. Following establishment of this cocaine-induced CPP, the rats were injected only with saline and conditioned for an equal number of sessions (i.e., four).(ABSTRACT TRUNCATED AT 250 WORDS)

Trends in place preference conditioning with a cross-indexed bibliography; 1957-1991.

The purpose of this work is to present a perspective of the conditioned place preference (CPP) test by offering an overview of the empirical research from 1957-1991. The intent is not to extensively analyze the controversies inherent to any behavioral technique but rather to present a survey of research using a descriptive statistics approach to explore topical issues. The objectives of this work are three-fold: (a) to provide an exhaustive bibliography of the CPP literature including articles, journal abstracts, book chapters and critical reviews; (b) to provide a cross-index of identified key words/drugs tested; and (c) to give an overview of selected procedural issues underlying CPP testing.

Intake of sweet water attenuates restraint-stress-induced potentiation of morphine analgesia in rats.

The analgesia induced in rats by morphine is potentiated by restraint-stress exposure and is reduced in rats that have been consuming a sweet solution. The purpose of the present study was to determine whether the potentiation of morphine-induced analgesia following restraint immobilization would be attenuated in rats consuming a sweet solution. Groups of rats were maintained on unsweetened water or allowed 2 h of daily access to a solution of saccharin and glucose (SG). Half of the rats in each of these groups were subjected to 1 h of restraint stress (groups RS and RS+SG) and the other half in each group were not stressed (groups NS and NS+SG). Rats then underwent 1 h of RS treatment or were nonstressed (NS). The next day all rats were injected subcutaneously with morphine (0.0, 4.0, 8.0, or 16 mg/kg) and analgesia was assessed using the tail flick assay. ED50S (mg/kg) were calculated for each treatment group; NS = 5.8, RS = 1.6, NS+SG = 6.4, and RS+SG = 4.4. Our results demonstrate that RS potentiated morphine-induced analgesia in rats given access to SG as well as non-SG exposed rats that displayed ED50S 1.5 and 3.9 times lower than their respective controls. RS-treated rats that consumed SG solution had significantly lower tail flick latencies than did non-SG exposed rats. Additionally, tail flick latencies of rats in the nonstressed and NS+SG groups did not significantly differ. We conclude that the brain mechanism(s) responsible for RS-induced potentiation of morphine antinociception are attenuated by intake of a sweet solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Increases in the locomotor activity of rats after intracerebral administration of cathinone.

There is a widespread practice among people living in Eastern Africa and Southern Arabia of chewing the leaves of the Khat shrub so as to produce pharmacological effects that are practically indistinguishable from those produced by amphetamine (AMPH). Cathinone (CATH) has been identified as the psychostimulant constituent of this plant and, although the locomotor elevating effects of centrally administered AMPH and cocaine (COC) in rats are well known, there is a paucity of data regarding CATH. Three experiments were, therefore, conducted to measure locomotor activity following central administration of CATH in rats. The first experiment determined the dose-dependent effects of CATH on activity following intracerebroventricular (ICV) administration. As psychostimulant effects are believed, at least in part, to be mediated by dopaminergic systems, in Experiment 2 CATH was injected into the dopamine nerve terminals of the nucleus accumbens. Experiment 3 examined the effects of CATH injection into the dopamine cell body region of the substantia nigra, and activity was measured. Results of the ICV injection of CATH revealed a dose-dependent increase of activity. The highest dose tested (64 micrograms) yielded a 117% increase in activity when compared to baseline, whereas a 20 micrograms bilateral nucleus accumbens (NA) injection of CATH increased activity fivefold. These findings evidence the hypothesis that the effects of CATH are dopaminergically mediated. Substantia nigra (SN) injections of CATH were without effect.

Psychostimulant-induced activity is attenuated by two putative dopamine release inhibitors.

Centrally administered amphetamine (AMPH), cathinone, (CATH), or cocaine (COC) have each been shown to produce elevated activity in rats and this effect is dose responsive. The question remains whether these psychostimulants share a common mechanism of action (i.e., do these psychostimulants act by releasing dopamine to increase activity levels?). Experiments were, therefore, conducted to measure the spontaneous activity of these three centrally administered psychostimulants in rats following pretreatment with two putative dopamine release inhibitors, viz., 5-(4-methyl-1 piperazinyl)imidazol(2,1-b) (1,3,5)-benzothiadiazepine maleate [CGS 10746B (CGS); 20 mg/kg)] and 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicar boxylic acid methyl 1-methyl-ethyl ester [isradipine (ISR); 2.5 mg/kg)]. Rats fitted with chronic indwelling ventricular cannulae received a single dose of ICV-administered CATH (32 micrograms), AMPH (16 micrograms), COC (100 micrograms), or vehicle. Selection of these ICV doses of stimulant drugs was based upon results obtained in preliminary studies that indicated similar elevations of activity. ICV administration of each of these drugs/doses was preceded (20 min) by peripherally administered CGS, ISR, or vehicle. Results show that ICV CATH (32 micrograms), AMPH (16 micrograms), COC (100 micrograms) equieffectively elevate activity (two- to threefold) and that, in each case, this increase was significantly attenuated by pretreatment with CGS or ISR.

A single restraint stress exposure potentiates analgesia induced by intrathecally administered DAGO.

In rats, restraint exposure potentiates the magnitude and duration of analgesia following both the peripheral and intracerebroventricular administration of several opioid agonists as compared to non-stressed controls. It has been suggested that the site of action whereby restraint leads to potentiated opioid analgesia is located supraspinally. However, the possible contribution of spinal analgesic mechanisms also warrants investigation. Thus, the purpose of the present study was two-fold: (1) to determine whether a single exposure to restraint stress would result in the dose-dependent potentiation of analgesia following the intrathecal (i.t.) administration of the mu (mu)-receptor selective opioid agonist [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO) and (2) to quantify the degree of analgesia in restrained vs. non-restrained rats using the tail-flick and hot-plate analgesic assays. Using rats implanted with chronic i.t. cannula, dose- and time-course curves were observed following the i.t. administration of DAGO. The results demonstrate that both the duration and magnitude of analgesia was significantly potentiated in restrained rats compared to non-restrained controls. Restraint-treated rats receiving 0.15-0.6 micrograms of DAGO i.t. showed 1.3-1.5-fold potentiation of analgesia in the tail-flick assay and a 2.3-5.6-fold potentiation using the hot-plate assay. Restraint immobilization potentiated the magnitude and duration of DAGO-induced analgesia administered by the i.t. route as measured by the tail-flick and hot-plate assays. These data suggest that spinal analgesic mechanisms significantly contribute to the enhanced analgesic potency of opioids in subjects exposed to restraint stress.

Direct microinjection of cathinone into the rat brain produces discriminative stimuli.

Rats were trained to discriminate IP administration of 800 micrograms/kg cathinone using a food-motivated, two-lever discrimination procedure. Following training, 800 micrograms/kg cathinone discrimination was produced (generalized) by lower cathinone doses in a dose-responsive manner after IP administration; an ED50 value of 330 micrograms/kg was calculated. Subsequently, guide cannulae were implanted into the lateral ventricle and bilaterally into the nucleus accumbens. After recovery, injections were made via cannulae that extended 0.5 mm past the tip of the guide cannulae. ICV administration of 256 micrograms cathinone/rat produced discriminative responding on the cathinone-appropriate lever to the same degree as did the peripherally administered training dose of cathinone. Decreasing ICV doses produced decreased discriminative performance and allowed the calculation of an ED50 value of 90.5 micrograms. Likewise, administration of 64 micrograms cathinone/nucleus accumbens (for a total of 128 micrograms/rat) substituted for the IP training dose of cathinone. These results evidence the central mediation of the cathinone-induced discriminative stimulus cue and show that administration of cathinone into the nucleus accumbens is sufficient to produce these stimuli. Thus, these data suggest that receptors in the nucleus accumbens are important for the discrimination of this psychostimulant.

Attenuation of drinking sweetened water following calcium channel blockade.

Recent reports cite results that both cocaine-induced conditioned place preference and activity stimulation are attenuated by pretreatment with the calcium channel blocker isradipine (ISR) in rats. By blocking voltage-dependent L-type calcium channels, ISR may regulate neural dopamine release that, in turn, decreases the putative rewarding effects mediated by dopaminergic mechanisms. It is known that nonfluid deprived rats avidly consume sweetened fluids; this suggests that the sweet taste is rewarding. Three experiments were conducted to determine the effects of ISR on drinking sweetened and nonflavored water. Experiment 1 was designed to test whether ISR would attenuate the intake of a palatable solution in a dose-dependent manner. To this end, ISR was administered both peripherally (3.0-30 mg/kg) and centrally (0.3-30 micrograms/rat) prior to a solution of saccharin and d-glucose (S + G) being made available to rats (15 min/day) and intake was recorded. ISR produced dose-dependent decreases (38%-81%) in S + G intake dependent on the route of administration. In Experiment 2, water intake was measured in 18 h water-deprived rats following ISR (10 mg/kg) administration as well as comparing S + G drinking. The effect of two ISR vehicles, dimethyl sulfoxide and Tween 80, upon fluid intake was also determined. ISR injection did not attenuate water intake in 18 h water-deprived rats and the choice of vehicle did not affect the ISR-induced attenuation of S + G drinking. In Experiment 3, a single dose (30 micrograms) of ICV administered ISR, that attenuated S + G intake by approximately 44%, did not attenuate water intake in 18 h water-deprived rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of learned helplessness by central administration of quaternary naltrexone.

Prior research has established that escape impairment resulting from prior inescapable shock (IS) could be reversed by the peripheral administration of the opiate antagonist naltrexone (NTX), but not the quaternary form of naltrexone (QNTX), which when systemically administered, does not readily pass the blood-brain barrier. As it was unclear whether the failure of systemically administered QNTX to reduce shuttle escape deficits following exposure to IS could be attributed to reasons other than the restricted access of QNTX to receptor sites in the brain, rats were affixed with chronic indwelling ventricular cannulae to allow direct brain administration of QNTX. The present experiment found a significant attenuation of the escape deficit produced by prior inescapable shock following the intracerebroventricular (ICV) administration of QNTX (10 micrograms/rat). These data provide further evidence of a mediational role for central opiate receptors in the expression of escape interference following inescapable shock.

Place conditioning reveals the rewarding aspect of social interaction in juvenile rats.

Rewards, as diverse as food, sweetened solutions, copulation, electrical brain stimulation, and drugs abused by humans, have been shown to condition place preferences in rats. Juvenile rats will readily learn to traverse a T-maze for the opportunity to interact with another similar-aged rat. This suggests that play behavior is rewarding. Experiment 1 examined whether play (as quantified by rough-and-tumble pinning) would act as a sufficient reward to condition a place preference (CPP). Experiment 2 examined whether pairings with a nonplaying partner would decrease the time spent in the preferred side and thus suggest a conditioned place aversion (CPA). In Experiment 1, dominant juvenile rats were given free access to a CPP apparatus and a side preference for one of the two physically distinct sides was determined. Dominant rats were then conditioned twice daily over four days in the CPP apparatus. They spent their first session confined in their preferred side with a scopolamine-treated partner (that rendered the partner unable to respond to play solicitations) and during the second session, dominant rats were confined to their less preferred side with a submissive play partner. The number of dorsal contacts, as well as frequency and duration of pinning, were recorded. Following conditioning, side preference was redetermined. A similar procedure was used in Experiment 2 except that the subjects underwent conditioning on their less-preferred side without a play partner. Results of Experiment 1 demonstrated that the dominant rats significantly increased (198.6%) the time spent on the originally less-preferred side after play conditioning.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation of morphine analgesia in rats given a single exposure to restraint stress immobilization.

Rats exposed to restraint stress and injected with morphine show significantly greater increases in tail-flick latency compared to unstressed rats. However, it is not necessary for rats to be restrained at the time of testing to elicit a potentiated analgesic response to morphine. We reported recently that analgesia induced by 4.0 mg/kg morphine was significantly potentiated in rats that had been restrained for only 1 h at 24 h prior to testing. One purpose of the present study was to extend this observation by determining the ability of a single exposure to restraint stress to potentiate dose-dependently morphine (0.0, 2.0, 4.0, and 8.0 mg/kg)-induced analgesia in the tail-flick test. A second purpose was to assess the generality of the phenomenon by determining whether prior restraint would potentiate the analgesic effect of morphine in another common analgesic assay, the hot-plate test. Dose- and time-course (20-120 min) curves for morphine were generated in rats exposed to one of two treatments: no restraint stress (NS) and a single exposure to 1 h of restraint (RS). Rats subjected to 1 h of restraint and tested 24 h later displayed significant time- and dose-dependent potentiation (1.3-2.0-fold) of morphine-induced analgesia compared to unstressed rats in both the tail-flick and hot-plate tests. These results demonstrate that a single period of restraint is sufficient to activate the mechanisms responsible for potentiation of morphine-induced analgesia and that the degree to which stress modified morphine's analgesia can be demonstrated using both the tail-flick and hot-plate assays.

Reducing the time needed to conduct conditioned place preference testing.

The objective of the present experiment was to demonstrate whether four days of twice-a-day conditioned place conditioning produces a preference that is equivalent to that produced by using eight days of once-a-day training. Two doses of the amphetamine-like stimulant drug cathinone (0.2 and 1.6 mg/kg) were selected to demonstrate the effectiveness of twice-a-day (morning-vehicle; afternoon-drug pairings) conditioning. The 0.2 mg/kg dose of cathinone failed to affect the expression of place preference, whereas the 1.6 mg/kg dose produced a significant (p less than 0.002) shift in CPP from baseline when compared to previous measurements. These results demonstrate that twice-a-day pairings over four days effectively shorten the total duration of training without changing the development of place preference produced by once-a-day over eight conditioning day schedule.