Cocaine and serotonin: a role for the 5-HT(1A) receptor site in the mediation of cocaine stimulant effects.

Cocaine induced locomotor stimulant effects are generally attributed to cocaine effects on brain dopamine. In this report, we present evidence that the 5-hydroxytryptamine(1A) (5-HT(1A)) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and the 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cycylhexanecarboxaminde maleate (WAY 100635) can enhance or block, respectively, the locomotor stimulant effects induced by cocaine. In two separate experiments, rats administered cocaine (10 mg/kg) exhibited a locomotor stimulant effect and decreased grooming behavior compared to saline treated rats. Pretreatment with the 5-HT(1A) agonist, 8-OHDPAT (0.2 mg/kg) enhanced and pretreatment with the 5-HT(1A) antagonist, WAY 100635 (0.4 mg/kg) eliminated the locomotor stimulant effect of cocaine. Neither the 8-OHDPAT nor WAY 100635 effects were attributable to effects on the behavioral baseline. The 8-OHDPAT and WAY 100635 had opposite effects on grooming behavior. 8-OHDPAT decreased and WAY 100635 increased grooming. Neither treatment, however, affected the grooming suppression induced by cocaine. Ex vivo biochemical measurements indicated that neither 8-OHDPAT or WAY 100635 affected brain dopamine metabolism or cocaine availability in brain. Both treatments affected 5-HT metabolism and altered the effect of cocaine on 5-HT metabolism. 8-OHDPAT increased and WAY 100635 decreased cocaine effects on 5-HT metabolism. Cocaine and 8-OHDPAT but not WAY 100635 increased corticosterone. Altogether, these findings indicate that the 5-HT(1A) receptor site may be an important target for the development of pharmacotherapies for the treatment of cocaine abuse.

8-OH DPAT can restore the locomotor stimulant effects of cocaine blocked by haloperidol.

In the first experiment, separate groups of rats (n = 7) were treated with either saline, cocaine (10 mg/kg), haloperidol (0.1 mg/kg), or cocaine (10 mg/kg) plus haloperidol (0.1 mg/kg). Locomotor behavior was measured in an open-field environment, and cocaine induced a reliable locomotor stimulant effect compared to saline-treated animals. Haloperidol produced a progressive decline in locomotion over the 5 test days. Haloperidol also blocked cocaine stimulant effects compared to cocaine-treated animals. In the second experiment, five groups (n = 7) of animals were treated either with saline, cocaine (10 mg/kg), 8-OH DPAT (0.2 mg/kg), 8-OH DPAT (0.2 mg/kg) plus haloperidol (0.1 mg/kg), or 8-OH DPAT (0.2 mg/kg) plus haloperidol 0.1 mg/kg plus cocaine (10 mg/kg). Over the course of 5 days of treatment, cocaine induced a locomotor stimulant effect. Saline and 8-OH DPAT animals did not differ in terms of locomotion. The 0.1 mg/kg haloperidol plus 0.2 mg/kg 8-OH DPAT treatment decreased locomotion compared to the saline group, but the group given 0.2 mg/kg 8-OH DPAT plus 0.1 mg/kg haloperidol plus cocaine (10 mg/kg) exhibited a locomotor stimulant effect equivalent to the cocaine group. In a third experiment, it was found that the 0.2 mg/kg 8-OH DPAT treatment did not enhance the locomotor stimulant effect of cocaine. Thus, the 8-OH DPAT treatment was able to restore a cocaine locomotor stimulant effect in animals treated with haloperidol without directly enhancing the locomotor stimulant effects of cocaine. In Experiments 2 and 3, entries into the central zone of the open field were measured. Cocaine reliably increased central zone entries. The 8-OH DPAT treatment, however, selectively blocked this behavioral effect of cocaine suggesting a qualitative influence of 5-HT(1A) receptors upon cocaine, independent of locomotion activation by cocaine. Ex vivo measurements of dopamine and 5-hydroxytryptamine metabolism in limbic tissue were consistent with the established effects of cocaine, haloperidol, and 8-OH DPAT upon dopamine and 5-hydroxytryptamine neurotransmission. In addition, measurement of cocaine brain concentration indicated that neither haloperidol or 8-OH DPAT affected cocaine concentration in brain.

The 5-HT(1A) antagonist WAY 100635 can block the low-dose locomotor stimulant effects of cocaine.

Cocaine treatments of 2.5, 5.0, 10.0 and 15.0 mg/kg induced dose-dependent increases in locomotor behavior. This cocaine-induced increase in locomotion was blocked if the animals were administered the selective 5-HT(1A) antagonist, WAY 100635 (0.4 mg/kg) prior to the cocaine treatment. The 0.4-mg/kg dose of WAY 100635 did not affect locomotor behavior or alter cocaine availability in brain.

Issues in the pharmacological modification of cocaine conditioning: evidence that the stimulus properties of drugs can interact with contextual cues to activate or inactivate cocaine conditioned stimuli.

Cocaine conditioned stimuli are capable of eliciting cocaine craving in individuals with a history of cocaine use. As a consequence, there have been a number of attempts using animal models to identify pharmacological treatments which can attenuate cocaine conditioned effects. The emphasis in these studies has been to employ drug doses which do not have response effects that could directly alter the conditioned drug response. A drug treatment may not have a response effect but still have drug stimulus effects which could interact with and modify the cocaine conditioned stimulus. In order to experimentally investigate this important issue, two experiments are reported. In one experiment, rats were co-administered 0.1 mg/kg MK-801 either with cocaine (10 mg/kg) or with saline; in the other experiment 3.0 mg/kg buspirone was co-administered with either cocaine (10 mg/kg) or with saline. The MK-801 and buspirone treatments did not affect spontaneous activity levels or alter the unconditioned cocaine stimulant effect. In tests for conditioning, however, the effects of buspirone and MK-801 depended upon their association with cocaine. If MK-801 and buspirone had no association with cocaine then these drugs inactivated the cocaine conditioned stimulant response. If MK-801 and buspirone had been co-administered with cocaine, then, in saline conditioning tests, no cocaine conditioning was observed. If the conditioning tests were conducted following MK-801 or buspirone treatment, however, cocaine conditioning was elicited. Altogether, these studies demonstrate that the stimulus properties of drugs can interact with contextual stimuli to inactivate or activate cocaine conditioned stimuli. In the search for drugs which may prevent cocaine craving, therefore, the stimulus properties of drugs provide an important mechanism for the modification of cocaine conditioned stimuli.

Evidence for N-methyl-D-aspartate receptor mediation of cocaine induced corticosterone release and cocaine conditioned stimulant effects.

The role of the N-methyl-D-aspartate (NMDA) receptors in cocaine conditioning and sensitization of locomotor activity was studied in four groups of Sprague-Dawley rats. A sub-motoric dose of the NMDA antagonist MK-801 (0.1 mg/kg, i.p.) was employed using a novel dual-compartment Pavlovian drug conditioning paradigm. The animals were placed sequentially in two different test environments in which locomotor activity was monitored. In the first compartment, the animals always received a non-drug test for 20 min. Upon completion of this test, the animals received either saline, cocaine (10 mg/kg i.p.), MK-801 or MK-801 plus cocaine depending on group assignment and were then placed immediately into the second compartment and again tested for 20 min. A total of six non-drug and six drug tests were conducted every other day over a 12-day period. Across all drug/saline treatment and post-treatment tests for conditioning, there were no statistical differences in locomotor activity among the saline and drug treatment groups in the non-drug test environment. In the drug/saline associated environment, however, cocaine had a reliable stimulant effect on locomotion when administered alone or in combination with MK-801. Following a 1-day and again after 21-days of withdrawal, all animals were administered a non-drug test for conditioning in which no injections were administered. On both tests, all groups had equivalent activity levels in the non-drug environment. In the drug/saline environment, only the cocaine group of the three drug treatment groups exhibited conditioned hyperlocomotion. Importantly, MK-801 blocked conditioned hyperlocomotion in the combined cocaine+MK-801 group. MK-801 did not alter serum or brain cocaine concentration or the cocaine effects on dopamine metabolism in limbic brain tissue. The co-administration of MK-801 with cocaine, however, blocked the corticosterone release effect of cocaine. Thus, the NMDA receptor site appears critical for cocaine induced conditioning and for corticosterone release.

Cocaine stimulant effects vary with cocaine levels in medial prefrontal cortex.

Rats treated with 10 mg kg-1 cocaine exhibited hyperlocomotion. Individual variation in the magnitude of this response was not correlated with serum cocaine concentration. Brain cocaine concentration, particularly in the medial prefrontal cortex, was highly correlated with the cocaine-induced locomotor stimulant effect. These findings indicate that variation in the uptake of cocaine into the brain is a critical variable in determining individual variation in its stimulant effects.

A new method to assess Pavlovian conditioning of psychostimulant drug effects.

Experimental studies of psychoactive drugs by pavlovian drug-conditioning methods, which originally began with investigations of drug-induced responses mediated by the autonomic nervous system, have now been expanded to include drug-induced response effects expressed as modulations of spontaneous motoric behaviors. In the latter application, however, equivalent behavioral response outcomes in post-treatment tests for conditioning can occur following a psychostimulant drug treatment either through drug interference effects on habituation processes, drug-induced stress effects and/or by pavlovian conditioning of the drug-induced motoric activation effect. Current methodologies for the study of pavlovian conditioned drug effects and/or drug sensitization cannot distinguish among these possibilities. This methodological inadequacy was addressed by a modification of the conventional paired-unpaired treatment protocol. In the new protocol, the animal is sequentially placed into two test compartments with the drug treatment administered in conjunction with placement into the second test compartment. This design permits a differentiation of a pavlovian conditioned drug responses from non-conditioned drug effects through continuous measurement of the non-drug behavioral baseline in both the drug and non-drug control treatment groups combined with multiple response measurements and post-treatment tests for conditioning at variable post-conditioning intervals. The present study details the use of the new modified pavlovian protocol with repeated cocaine (10 mg/kg) treatment. A cocaine conditioned response at 1, 7, and 21 days post-conditioning was identified and distinguished from habituation and stress effects.

Conditioned cocaine induced hyperactivity: an association with increased medial prefrontal cortex serotonin.

Two sets of contextual stimuli, only one of which was associated with drug treatment, were employed in a new paradigm to assess the conditioned effects of ten cocaine (20 mg/kg) treatments on motoric behavior. Two matched groups of Sprague-Dawley rats were sequentially placed into two similar but distinct test compartments. The drug treatment was administered immediately prior to placement into the second test compartment in one group (paired group) but 2 h later in the other group (unpaired group). Changes in the non drug behavioral baseline were assessed in the non drug compartment immediately prior to each drug treatment and provided the referent baseline for determining stimulus specificity of the observed behavioral effects in the drug compartment. Both groups had equivalent activity levels in the non-drug compartment. In the drug compartment, however, the paired group showed an overall cocaine stimulant effect expressed as a marked increase in distance traversed in the drug box. Additionally, the repeated cocaine treatment induced a conditioned drug effect as revealed by the higher level of motor activity in the paired compared to the unpaired treatment group exclusively in the drug compartment in two post-treatment non-drug tests for conditioning after 1-day and 21-day withdrawal and non-testing intervals. The biochemical assay results showed no significant group differences in DA and dopamine metabolites, DOPAC, HVA and 3-MT, in striatal, limbic or cortical tissue. No differences were observed either in NE or plasma corticosterone levels. Importantly, the analysis for serotonin revealed higher levels of 5-HT and 5-HIAA selectively in the prefrontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential temporal dynamics of serum and brain cocaine: relationship to behavioral, neuroendocrine and neurochemical cocaine induced responses.

Rats administered cocaine 10 mg/kg i.p. exhibited hyperlocomotion which occurred within 5 min post injection. Subsequently, rats were injected with 10 mg/kg cocaine and brain and serum concentrations of cocaine were measured at 5, 10, and 20 min post injection. Within this time frame, cocaine concentration in limbic brain tissue was maximal at 5 min post injection and then declined substantially by 20 min post injection. In contrast, serum cocaine concentration increased from 5 to 20 min post injection. Neurochemical effects of cocaine upon limbic dopamine turnover and plasma corticosterone had a time course similar to serum cocaine. Brain cocaine concentrations paralleled the locomotor stimulant cocaine response whereas cocaine neuroendocrine effects paralleled serum cocaine concentrations. These findings point to the importance of brain cocaine concentration determinations in neurobehavioral studies of cocaine.

Apomorphine sensitization effects: evidence for environmentally contingent behavioral reorganization processes.

Apomorphine-induced behavioral sensitization was investigated with a Pavlovian conditioning paradigm. Rats were administered apomorphine (2.0 mg/kg SC) daily for 7 days either paired or unpaired with a 10-min test environment placement. Initially, apomorphine induced hypolocomotion, but by treatment day 5, hyperlocomotion developed. Utilizing a videoimage analysis program which quantitated angular movement, it was determined that the increase in locomotion induced by repeated apomorphine treatment was due to an increase in rotational locomotion. Critically, rotation per se did not increase, but rather wide angle rotation toward the periphery of the test environment increased. Furthermore, a directional bias of rotation developed and stabilized which was unrelated to the animal's initial asymmetry bias. This emergence of a new locomotion pattern in conjunction with hyperlocomotion pointed to the need to reconceptualize behavioral sensitization phenomena into a new framework consistent with a progressive change in behavioral structure. Behavioral reorganization is presented as an alternative formulation to that of behavioral sensitization, as a drug-environment interactive process which is more compatible with the behavioral dynamics that emerge with repeated intermittent dopaminergic psychostimulant drug treatment.

Activation of an apomorphine behavior pattern by cocaine: a new behavioral test for drug substitution.

In current tests for drug substitution using the 2-choice operant bar press paradigm, an animal can be trained to respond differentially between an interoceptive drug state stimulus vs. saline. Despite the long history and extensive number of investigations, the interpretation of such test results, nevertheless, is limited by number of potential sources of stimulus drug effects which can occur with repeated drug administration but which cannot be distinguished by this paradigm: (1) local effects at the injection site; (2) peripheral effects; (3) central activity effects; and/or (4) sensory-motor dysfunctional effects. By using a video-image analysis of behavior in an intact animal model and a pavlovian drug treatment protocol, new, spontaneous but environmentally contingent and stable behavior patterns emerge selectively in the paired treatment group with repeated drug administration which can be used as a behavioral marker to assess dose-response effects and drug substitution test results with a novel drug. A study with repeated administration of the DA agonist apomorphine and with a drug substitution assessment by a cocaine drug test is presented as a reference example to illustrate the new response-based methodological approach to the study of central mechanisms mediating the stimulus and response effects of drugs. Additionally, the observed efficacy of cocaine to activate a complex acquired behavioral pattern unique to repeated apomorphine treatment supports a critical role for dopaminergic mechanisms in the mediation of cocaine induced stereotypy.

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)

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.

Conditioning, attention, and the CS-US interval. A theoretical statement of relations.

A revised version of the Rescorla-Wagner (1972) mathematical model is presented. A metatheoretical assumption of an attentional process, the added revision, is conceived as an independent alpha-salience growth factor determining both rate of association and performance. Conditioned stimulus-unconditioned stimulus (CS-US) correlation, and CS-US interval (two primary conditioning parameters) are incorporated in the mathematical model as alpha-salience growth rate and as alpha-salience and association asymptote factors, respectively. In this manner, the long-standing issue of necessary and sufficient factors in classical conditioning is resolved. An empirical assessment of the model's parameters has been included.

Forward and backward classical conditioning of the flexion reflex in the spinal cat.

Effects of forward and backward conditioned-unconditioned stimulus (CS-US) intervals on classical conditioning of the flexion reflex were examined in a cat spinal preparation. Interstimulus intervals (ISIs) ranging from +3.0 to -3.0 sec were employed in 9 experimental groups and the results compared with those of an explicitly unpaired control group. Forward conditioning produced an asymmetrical, inverted U-shaped gradient relating magnitude of conditioning to ISI for both acquisition and extinction. The optimum ISI was 1.0 sec. Backward ISIs also produced excitatory conditioning, with optimal conditioning at -0.25 sec. Unlike forward conditioning, backward conditioning produced little sign of retention during extinction trials. The results, which parallel in several ways those of ISI effects in studies of intact animals, support the hypothesis that backward and forward conditioning may be fundamentally different phenomena, under the control of different neural processes.

Necessary and sufficient factors in classical conditioning.

The issue of necessary and sufficient factors (pairing-contiguity vs. contingency-correlation) in classical (Pavlovian) excitatory conditioning is examined: first, in terms of definitional (logical) and manipulational requirements of "necessary" and "sufficient"; second, in terms of Boolean logic test models indicating experimental and control manipulations in tests of pairing and contingency as necessary and sufficient factors; and, third, by a selective review of reference experiments showing appropriate experimental and control manipulations of pairing and contingency indicated in the Boolean logic test models. Results of examination show pairing-contiguity as the sole necessary and sufficient factor for excitatory conditioning, while contingency-correlation is conceptualized as a modulating factor controlling minimal-maximal effects of pairing-contiguity. Reservations and diagnostic experiments are indicated to assess effects of uncontrolled conditioned stimulus--unconditioned stimulus (--CS--US) probability characteristics (e.g., p (CS--US)/p (--CS--US) in truly random (TR) schedule manipulations). Similar analysis of conditioned inhibition reveals insufficient evidence to support a choice among current alternatives.