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R J Carey

Publications and source records attributed to R J Carey.

At least 19 recordsLinked to original sources
PubMed1992

Opponent-process theory and drug conditioning: an assessment for conditioned stimulant-induced movement.

Opponent-process theory occupies an important place in drug conditioning because it accounts for conditioned drug effects which are opposite to those induced by the drug itself. It has not been established, however, whether there is an opponent-process component to stimulant drug induced conditioned effects. In the present study the unilateral 6-hydroxydopamine (6-OHDA) rat model was used to examine this issue. Two groups of Sprague-Dawley rats with equivalent 6-OHDA lesions were administered five apomorphine treatments (0.05 mg/kg s.c.) either paired or unpaired to a 10-min test chamber placement. Apomorphine induced vigorous contralateral rotation and suppressed all ipsilateral rotation. While the apomorphine-induced contralateral rotation response can be conditioned to the test environment cues, the critical test of opponent-process theory in the present study was whether the opposite response of ipsilateral rotation would also become conditioned as a latent opponent-process response to the exteroceptive test environment cues associated with the apomorphine drug state. The postacquisition saline test for conditioning showed that the paired group exhibited higher rates of contralateral and ipsilateral rotation compared to the unpaired group. In addition, when the animals were subsequently tested with the dopaminergic receptor antagonist, haloperidol (0.5 mg/kg), unexpectedly, contralateral rotation was enhanced in the paired group, whereas, ipsilateral rotation was suppressed in both groups. While these findings are, in part, compatible with an opponent-process mechanism, the data supported a simpler explanation; namely, the mechanism of differential habituation in the two groups due to a blocking effect of apomorphine on habituation selectively in the paired group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Conditioning, habituation and behavioral reorganization factors in chronic cocaine effects.

Rats were administered cocaine (50.0 mg/kg i.p.) daily for 7 days in a Pavlovian paradigm either immediately prior (paired group) or 30 min following (unpaired group) a 20-min placement in an open field test environment. After 7 days of drug withdrawal, the animals were retested 3 days apart, once with saline and once with cocaine (50 mg/kg). Measurement of locomotion as distance traversed (m) revealed a higher level of locomotion in the paired group on all test trials. Analysis of the paired vs. unpaired differences indicated an antihabituation effect of cocaine rather than a hyperlocomotion or a conditioned locomotor effect. Rotation pattern analysis for each animal showed a new frequency distribution of rotations across four categories of diameter size in the paired but not in the unpaired group by Day 5. This new pattern was characterized by a shift in skewness toward large greater than or equal to 55 cm diameter rotations. These qualitative changes in rotation pattern point to a context specific behavioral reorganization process in response to repeated cocaine drug treatment.

Animals↗
PubMed1992

Factors in amphetamine-induced contralateral rotation in the unilateral 6-OHDA lesion rat model during the first-week postoperative: implications for neuropathology and neural grafting.

Amphetamine induced ipsilateral rotation in rats with chronic unilateral 6-hydroxydopamine (6-OHDA) lesions is a widely accepted line of evidence supportive of dopaminergic mediation of amphetamine effects on motoric behavior. However, there is literature indicating that amphetamine induces contralateral rotation, in the early postoperative phase of a unilateral 6-OHDA lesion. In an attempt to reconcile these opposite amphetamine effects on rotation in terms of dopaminergic mechanisms, a series of 4 experiments were conducted. These studies showed that amphetamine reliably elicits contralateral rotation for up to 7 days postoperative but only ipsilateral rotation thereafter. The amphetamine induced contralateral rotation differed behaviorally in several respects from subsequent ipsilateral rotation induced by amphetamine. It was comparatively more intense; and, while onset of peak rotation was dose dependent, rate of rotation was independent of dose level (0.5, 1.0 and 2.5 mg/kg). Dopamine and dopamine metabolite analyses by HPLC-EC after 3 postoperative intervals (days 3, 6, and 9) indicated a progressive and severe depletion of striatal dopamine in conjunction with elevated dopamine turnover. Importantly, after 6 days postoperative, dopamine was reduced to less than 0.06% after intact hemisphere but yet, amphetamine (1.0 mg/kg) elicited contralateral rotation. It was proposed that amphetamine could release a small amount of dopamine present in a sparse number of residual degenerating terminals and this dopamine, unrestricted by reuptake, could widely access supersensitive dopamine receptors to elicit contralateral rotation. This possibility calls into question amphetamine tests for neural graft efficacy in animal models which use amphetamine induced contralateral rotation as the criterion response.

Amphetamine↗
PubMed1992

Pavlovian conditioning of L-dopa induced movement.

Using the unilateral 6-hydroxydopamine (6-OHDA) substantia nigra pars compacta (SNC) lesion rat model and a Pavlovian conditioning protocol, the present investigation determined that the contralateral rotation response induced by the antiparkinsonian dopaminergic drug L-dopa can become conditioned to exteroceptive test environment stimuli. Two non-drug conditioning tests indicated that contralateral rotation was elicited by the test environment without the presence of L-dopa. This conditioned response had a rotation diameter profile that was qualitatively the same as the L-dopa induced contralateral rotation response. Additionally, drug tests with the combined dopaminergic receptor antagonists, SCH 23390 (0.1 mg/kg) and haloperidol (0.5 mg/kg), at doses sufficient to block spontaneous behavior and L-dopa (20 mg/kg)-induced rotation, revealed that the conditioned contralateral rotation response, unlike L-dopa-induced contralateral rotation, is not affected by D1/D2 receptor blockade. Thus, the conditioned stimuli of the test environment can elicit the contralateral rotation response even in animals rendered akinetic by D1/D2 antagonists. This activation of a conditioned dopaminergic drug response by the situational stimuli, independent of dopaminergic mechanisms, may, therefore, contribute to the untoward overstimulation clinical effects of L-dopa through summation of conditioned and drug-induced effects. Furthermore, the use of conditioning procedures to elicit movement in akinetic animals may provide a new research methodology to investigate the phenomenon of paradoxical kinesia.

Animals↗
PubMed1991

Chronic L-dopa treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance.

Two separate experiments were conducted to assess the behavioral and biochemical effects of chronic L-dihydroxyphenylalanine (L-DOPA) treatment in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this animal model, contralateral rotation provides the behavioral indicator response for L-DOPA activation of the dopamine denervated striatum. Following 30 daily L-DOPA treatments, a subthreshold dose (10 mg/kg) for rotation became suprathreshold and the contralateral rotation induced by a suprathreshold dose (20 mg/kg) became exaggerated. This motoric sensitization to L-DOPA was not reversed by a three-day period of L-DOPA withdrawal. In contrast with the emergence of behavioral sensitization to L-DOPA, biochemical measurements showed that the increase of dopamine metabolite concentrations (DOPAC and HVA) induced by acute L-DOPA treatment became attenuated with chronic treatment. This finding suggests that chronic L-DOPA treatment produces a partial tolerance in the conversion of L-DOPA to extracellular dopamine. The emergence of L-DOPA sensitization-over-stimulation effects was hypothesized to reflect the combined effects of dopamine receptor priming and Pavlovian drug conditioning and to contribute to the emergence of dyskinetic effects of L-DOPA therapy. The partial tolerance observed for dopamine metabolites was hypothesized to represent a decreased conversion of L-DOPA to dopamine which with long-term treatment could progress to an eventual wearing-off effect of L-DOPA therapy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Relationships between indices of behavioral asymmetries and neurochemical changes following mesencephalic 6-hydroxydopamine injections.

Behavioral and neurochemical changes were investigated in rats that had received one of 3 doses of 6-hydroxydopamine (6-OHDA), injected unilaterally into the ventral mesencephalon. The behavioral analysis comprised that of tight turns (diameter less than 30 cm), wide turns (diameter greater than 55 cm), and locomotor activity. 6-OHDA-injected animals were assigned to 3 different groups according to their degree of asymmetry in tight turns, both in spontaneous behavior and after the dopamine receptor agonist apomorphine (0.05 mg/kg). Thus, 6-OHDA-injected animals showed either (i) no spontaneous ipsiversive asymmetry (group 1), or (ii) an ipsiversive asymmetry, from which they did not recover during the three postoperative weeks of testing and which could not be reversed by apomorphine (group 2), or (iii) an even stronger ipsiversive asymmetry from which they did not recover but which could be reversed by apomorphine (group 3). The analysis of wide turns, which might reflect exploratory behavior of the environment, namely thigmotactic scanning, provided further information, as it indicated an asymmetry even in group 1; however, in contrast to the other groups a contraversive asymmetry was observed. Neurochemically, the three experimental groups were clearly different from each other with respect to the degree of neostriatal dopamine depletion, and the increase in dopamine metabolism in the damaged hemisphere as indicated by increased metabolite/transmitter ratios. The ipsiversive asymmetry in tight turns was negatively correlated with dopamine levels in the damaged neostriatum and positively correlated with the increase in metabolism. Furthermore, indications of changes in neostriatal serotonin activity were found. These results are discussed with respect to the necessity of differential measures of behavioral asymmetry, the role of dopaminergic mechanisms of 6-OHDA-induced deficits and mechanisms of recovery. The asymmetries in tight versus wide turns are suggested to reflect the preponderance of a motor deficit in the former case versus that of sensory neglect in the latter. Thus, the analysis of tight versus wide turns may provide distinctive and sensitive indices related to different functional deficits in animal models of hemiparkinsonism.

Analysis of Variance↗
PubMed1991

Pavlovian conditioning between co-administered drugs: elicitation of an apomorphine-induced antiparkinsonian response by scopolamine.

Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.

Animals↗
PubMed1991

Naloxone reverses L-dopa induced overstimulation effects in a Parkinson's disease animal model analogue.

Chronic L-DOPA treatment of Parkinson's disease frequently leads to the development of motoric overstimulation and hyperkinetic movements. To investigate this problem in the laboratory, rats surgically altered by unilateral 6-hydroxydopamine lesions (6-OHDA) were chronically treated with one L-DOPA (10 mg/kg i.p.) injection per day for 20 days. In this 6-OHDA rotation model, the unilateral dopamine denervation results in a profound contralateral sensory-motor neglect and the animals spontaneously rotate in a direction ipsilateral to the dopamine depleted hemisphere. Initially, the L-DOPA treatment did not alter the response bias but after several weeks, the response bias was reversed and the animals rotated in the formerly akinetic direction, contralaterally, at a significantly higher level. Using this overstimulation effect as an analogue of the clinically observed L-DOPA overstimulation, animals were given naloxone in conjunction with the L-DOPA treatment. Naloxone (0.10, 0.25 and 0.50 mg/kg i.p.) produced a dose related decrease in the L-DOPA induced contralateral rotation. Consistent with an expected selective effect on the L-DOPA induced rotation, a dose related increase in ipsilateral rotation was observed. These results suggest that naloxone can attenuate the overstimulation effect of L-DOPA and that this effect is not attributable to non-specific response suppression effects.

Animals↗
PubMed1990

Antiparkinsonian effects of caffeine depend upon pavlovian drug conditioning processes.

Caffeine induces the antiparkinsonian response of contralateral rotation in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions following exposure to the direct-acting dopamine agonist apomorphine. This effect of caffeine has been attributed to a 'priming' effect of apomorphine which enables the supersensitive dopamine receptors to respond to caffeine and other methylxanthines. These studies, however, did not differentiate between conditioning and pharmacological variables. To resolve this issue, a Pavlovian conditioning procedure was employed in which separate groups of 6-OHDA rats were given 0.05 mg/kg (s.c.) apomorphine treatments paired or unpaired with a test environment. The animals in the paired or conditioning treatment groups subsequently exhibited contralateral rotation when tested with caffeine (10 mg/kg, i.p.), whereas animals in the unpaired or 'priming' treatment groups displayed only enhanced ipsilateral rotation. The activation of the conditioned contralateral rotation by caffeine in the paired group occurred even after the response was suppressed by extinction. This preferential activation following extinction of a previously conditioned drug response by caffeine implicates caffeine mechanisms (e.g. adenosine antagonism) in drug conditioning processes.

Animals↗
PubMed1990

Dopamine receptors mediate drug-induced but not Pavlovian conditioned contralateral rotation in the unilateral 6-OHDA animal model.

Following Pavlovian conditioning treatment sessions with apomorphine, animals receiving the paired treatment showed substantial contralateral rotation when placed without drug into the test environment previously paired to the apomorphine (0.5 mg/kg) injection while animals in the unpaired control treatment showed only ipsilateral rotation. Subsequent tests with the D1 antagonist (SCH 23390), or the D2 antagonist (haloperidol) partially suppressed and the combined D1-D2 antagonists completely suppressed the apomorphine-induced response of contralateral rotation. The identical contralateral rotation response occurring as a Pavlovian conditioned response in the paired apomorphine treatment group was not attenuated by dopamine receptor blockade. In both paired and unpaired groups, the spontaneous ipsilateral rotation response was completely blocked. Thus, non-dopaminergic mechanisms mediate conditioned rotation whereas the drug-induced as well as the spontaneous rotation responses require stimulation of striatal dopamine receptors.

Animals↗
PubMed1990

Chronic low-dose haloperidol effects on self-stimulation rate-intensity functions.

Animals responding for biphasic square wave stimulation to the VTA were treated for 26 days with a low dose (0.07 mg/kg) of the neuroleptic haloperidol and tested at 1 h post-injection. Initially the drug induced a pronounced lateral displacement of the baseline rate-intensity function, concomitant with a depression in slope. Over the course of chronic treatment, partial tolerance was observed to the drug-induced increases in threshold concomitant with the onset of a significant suppression in peak response rate. Biochemical tolerance to stimulated dopamine metabolism (as per cent non-drug control) was significant only for mesolimbic (versus neostriatal) regions, in animals receiving haloperidol according to pre- and post-test administration schedules. The observation of sensitization to peak rate reductions parallels previous reports for spontaneous locomotor activity measures and is compatible with depolarization inactivation mechanisms proposed to account for delayed-onset clinical effects. Further, selective biochemical tolerance in mesolimbic regions supports suggestions that mesolimbic dopamine is important as a substrate for subtle low dose neuroleptic effects which may be relevant for studying pharmacotherapeutic treatment issues.

Animals↗
PubMed1990

Reinstatement by caffeine of an extinguished conditioned dopaminergic drug response.

An experimental study of extinction of conditioned drug-induced effects was carried out to determine: 1) duration of the extinction effect; and 2) stability of extinction as determined by a challenge with a stimulant drug. Twelve animals with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions were assigned to paired and unpaired treatment groups (n = 6) in a Pavlovian conditioning paradigm. The paired animals received apomorphine (0.05 mg/kg SC) immediately prior to placement into a test chamber and the unpaired animals received the apomorphine 30 min following test chamber placement. The two groups were matched for apomorphine-induced contralateral rotation prior to the conditioning treatment. Following Pavlovian conditioning, the paired group, but not the unpaired group, exhibited contralateral rotation in a nondrug test trial. This conditioned response underwent extinction after one nondrug extinction trial and the extinction effect persisted for 2 months. When tested with caffeine (10 mg/kg), the paired animals again exhibited substantial contralateral rotation. In contrast, the unpaired animals showed only an increase in ipsilateral rotation in response to the caffeine treatment. The drastically different response to caffeine in the paired and unpaired animals was not due to prior apomorphine exposure per se or due to 6-OHDA lesion-induced differences in striatal dopamine depletion. Rather, the effect of caffeine on rotation behavior was determined by the Pavlovian drug conditioning procedures carried out several months earlier prior to caffeine testing.

Animals↗
PubMed1989

Amphetamine-induced rotation reveals post 6-OHDA lesion neurochemical reorganization.

Early postlesion amphetamine-induced contralateral rotation has been linked to intraneuronal dopamine (DA) accumulation and transmitter release associated with axonal degeneration. Animals in the present study sustained severe unilateral depletion of striatal DA with or without a near-complete loss of ipsilateral mesolimbic DA. Contralateral rotation to 1.0 mg/kg (+)-amphetamine was observed on days 1 and 4 postlesion, and was greatly enhanced in mesolimbic-lesioned animals on day 4. On days 7 and 14, very little contralateral turning was observed and there was an emergence of low-rate ipsilateral rotation. These changes in direction and magnitude of rotational response suggest neurochemical adaptations which continue beyond initial periods of intraneuronal accumulation and degeneration-induced release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Mesolimbic dopamine and early post-6-OHDA lesion enhanced responses to d-amphetamine.

Bilateral lesions of mesolimbic dopamine (DA) reliably produce an attenuated response to amphetamine's locomotor stimulatory effects when administered after two weeks of surgical recovery. Several studies have revealed enhanced amphetamine-induced hyperactivity during the first postlesion week, however. In the present study, animals with bilateral 6-OHDA lesions of nucleus accumbens and olfactory tubercle DA showed an exaggerated response to 1.0 mg/kg amphetamine during this early period but were hypoactive in the absence of drug treatment. Neurochemical assay at 5 days revealed increased DA metabolism in the tubercle. Shifting patterns of postlesion amphetamine response under conditions of reduced mesolimbic DA are suggestive of dynamic adaptations in nondopaminergic systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Application of the unilateral 6-hydroxydopamine rat model of rotational behavior to the study of conditioned drug effects.

In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra apomorphine reliably induces a response of contralateral rotation. The present study shows that this response can readily be conditioned to a test environment which the rats are briefly exposed to during the onset of the apomorphine-induced rotation. This conditioned response can be repeatedly conditioned, extinguished, and differentially conditioned, thereby providing a useful behavioral model for the study of the conditioning of drug-induced movements.

Animals↗
PubMed1988

A behavioral methodology for assessing non-motoric deficits in the dopamine denervated rat.

Tests of sensory-motor functions in rats with deficits in brain dopamine have generally relied on responses mediated by the dopamine-deficient hemisphere for the expression of the animals' behavioral response to stimulation. The present report demonstrates that in rats with unilateral denervation of dopamine neurons, a lateralized attenuation of behavioral response to nociceptive stimulation can be observed when the indicator response is not mediated by the dopamine-deficient hemisphere. Two readily measured responses to footshock, one unconditioned (i.e. ipsiversive turning) and one conditioned (i.e. passive avoidance), were shown to be attenuated when footshock was applied to the body surface contralateral versus ipsilateral to the dopamine-deficient hemisphere. The paradigm of using responses not mediated by the lesion hemisphere to assess behavioral responses to stimuli applied to a lesion hemisphere provides a behavioral methodology for assessing behavioral deficits in sensory processing that are not confounded with lesion-induced motoric deficits.

Animals↗
PubMed1988

Chronic haloperidol-amphetamine interactions and mesolimbic dopamine.

As low-dose amphetamine stimulation of locomotor activity in the rat depends upon a mesolimbic dopaminergic substrate, neuroleptic antagonism of this behavior has been suggested as a model for studying antipsychotic activity. Animals in the present study received 21 days of chronic treatment with 1.0 mg/kg amphetamine, 0.1 mg/kg haloperidol or a combination of these two drugs. On day 21, mesolimbic (but not striatal) dopamine (DA) concentrations were positively related to locomotor activity in an open field. DA metabolites in this region were inversely correlated with the behavior. The combined drug group showed saline-like levels of both behavioral activity and mesolimbic DA. Metabolic indices in this group suggested that increased DA availability partially competed with the neuroleptic receptor blockade in mesolimbic regions. In contrast to tolerance previously observed with cataleptic doses of neuroleptics, 21 days of 0.1 mg/kg haloperidol did not induce behavioral or biochemical tolerance. This finding is consistent with the lack of tolerance development to antipsychotic effects and suggests that animal models incorporating chronic low-dose neuroleptic regimens may be useful for the study of chronic treatment issues.

Animals↗