Effects on spontaneous and cocaine-induced behavior of pharmacological inhibition of noradrenergic and serotonergic systems.

Cocaine-induced increases in dopamine (DA) contribute importantly to cocaine effects on behavior but, the role of concomitant increases in norepinephrine (NE) and serotonin (5-HT) is less well understood. In order to selectively block the increases in NE and 5-HT evoked by cocaine, autoreceptor preferring low doses (0.01, 0.025 and 0.05 mg/kg) of the a2 agonist, Clonidine or the 5-HT1A agonist, 8-OHDPAT were given as pretreatments 20 min prior to saline or cocaine (10.0 mg/kg) in separate groups of rats (N=10). With pharmacological stimulation of NE and 5-HT autoreceptors, release of these neurotransmitters would be suppressed and, therefore, less available for re-uptake blockade by cocaine. With increasing dose levels, Clonidine had marked inhibitory effects on spontaneous and cocaine-induced locomotion, grooming and rearing. 8-OHDPAT pretreatment also suppressed spontaneous locomotion, grooming and rearing; but, in contrast, did not reduce the cocaine locomotor stimulant effects. 8-OHDPAT, however, did suppress central zone entry and rearing in cocaine treated rats. Using ex vivo methods, we found that 8-OHDPAT selectively reduced 5-HT metabolism in the medial frontal cortex (MFC) and subcortical limbic brain. Clonidine selectively reduced NE metabolism in the MFC, but decreased both DA and 5-HT metabolism in the subcortical limbic brain without affecting NE metabolism. This diverse and broad spectrum of Clonidine effects upon neurotransmitters and behavior is striking and points-up the important, complex and integrative role of NE in brain function. While both Clonidine and 8-OHDPAT can substantially attenuate a number of cocaine behavioral effects, these inhibitory effects appear to be secondary to reductions in the behavioral baseline rather than reversals of cocaine effects.

Stimulus gated cocaine sensitization: interoceptive drug cue control of cocaine locomotor sensitization.

Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats (N=10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoreceptor preferring low doses of either the 5-HT1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D1/D2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific brain receptor targets rather than in terms of global environmental situational cues.

Pharmacological inhibition of DA- and 5-HT activity blocks spontaneous and cocaine-activated behavior: reversal by chronic cocaine treatment.

Recently it was shown that the combined pretreatment with low autoreceptor preferring dose levels of apomorphine (0.05 mg/kg) and 8-OHDPAT (0.05 mg/kg), which decrease dopaminergic and serotonergic activity, induces a profound behavioral inhibition and also blocks the stimulant effects of cocaine. In two experiments, we report that the acute blockade of spontaneous and cocaine locomotor stimulant effects by pretreatment with 8-OHDPAT (0.05 mg/kg) plus apomorphine (0.05 mg/kg) is dose-dependently (0.0 2.5, 5.0, and 10.0 mg/kg cocaine) reversed with repeated cocaine treatments. Using a paired vs. unpaired Pavlovian conditioning protocol, we found that this reversal by cocaine (10 mg/kg) of the inhibition by the combined 8-OHDPAT plus apomorphine pretreatment occurred for the paired but not the unpaired cocaine treatment. The findings suggest that this reversal of behavioral inhibition is mediated by the transformation of the drug cues generated by 8-OHDPAT and apomorphine into cocaine-conditioned stimuli which can activate behavior.

Acute and chronic cocaine behavioral effects in novel versus familiar environments: open-field familiarity differentiates cocaine locomotor stimulant effects from cocaine emotional behavioral effects.

Cocaine is a potent stimulant drug, but its stimulant effects can be substantially modulated by environmental novelty versus familiarity. In this report, we varied exposures to a novel environment as a way to assess the impact of environmental familiarity versus novelty upon the locomotor activation induced by acute and chronic cocaine treatments. In experiment 1, the effects of 1 (PE1) versus 0 (PE0) pre-exposures to the test environment were compared for their impact upon the locomotor stimulant, central zone entry and grooming effects induced by an acute cocaine (10 mg/kg) treatment. In experiment 2, the effects of 10 (PE10) versus 0 (PE0) pre-exposures upon the cocaine effects were compared. Experiment 3 assessed the effects of nine cocaine treatments (10.0 mg/kg) initiated in a novel environment (PE0) versus familiar environment (PE10). In all experiments, cocaine had a potent locomotor stimulant effect in a novel environment, which was attenuated by environmental familiarity such that in PE10 groups, cocaine did not reliably induce an acute locomotor stimulant effect. Environmental novelty/familiarity, however, did not reliably alter cocaine effects upon central zone penetration, grooming behavior, or the neurochemical effects induced by cocaine. In the chronic treatment regimen, the PE0 group exhibited a tolerance-like decrease in locomotor activation, but the PE10 group exhibited a sensitization-like increase in locomotor activation. Despite the marked directional changes in the locomotor stimulant effects of cocaine treatments, initiated in a novel (PE0) versus familiar (PE10) environment, the same asymptotic levels of locomotor activation were achieved. In contrast, the behavioral measures of central zone activity progressively increased with repeated treatments regardless of whether the environment was initially novel (PE0) or familiar (PE10). Thus, habituation factors can profoundly alter the locomotor stimulant effects of cocaine and can induce pseudo-tolerance phenomena. In contrast, central zone activity undergoes sensitization-like effects independent of habituation state and therefore appears to represent a more fundamental behavioral effect of cocaine. In that, central zone penetration in an open-field is linked to emotional processes; this finding is of substantial importance in understanding the effects of repeated cocaine usage.

Evidence that the 5-HT1A autoreceptor is an important pharmacological target for the modulation of cocaine behavioral stimulant effects.

The psychostimulant effects of cocaine critically depend on the serotonergic (5-HT) system, of which the 5-HT1A receptor is an essential component. We recently showed divergent contributions of various pre- and postsynaptic 5-HT1A receptor populations to the behavioral effects of cocaine. Here, we further investigate the role of 5-HT1A autoreceptors in the acute and chronic stimulant effects of cocaine using 5-HT1A receptor ligands in autoreceptor preferring doses. In experiment 1, four groups of rats (N = 10) received either saline or the 5-HT1A agonist, 8-OHDPAT (0.05 mg/kg) 20 min prior to a saline or cocaine (10 mg/kg) injection on 9 consecutive days. In experiment 2, six groups (N = 10) were given either saline, the 5-HT1A antagonist, WAY 100635 (0.05 mg/kg) or 8-OHDPAT (0.05 mg/kg) plus WAY 100635 (0.05 mg/kg) 20 min before a saline or cocaine (10.0 mg/kg) treatment on 9 consecutive days. Initially, both the 8-OHDPAT and WAY 100635 pretreatments completely blocked the locomotor stimulant effects of cocaine whereas the combined 8-OHDPAT plus WAY 100635 pretreatment had no effect. In saline treated groups, neither the WAY 100635 nor the 8-OHDPAT plus WAY 100635 pretreatment influenced spontaneous activity levels, whereas the 8-OHDPAT alone severely reduced spontaneous activity. These effects persisted over the course of the 9 test sessions. A different pattern of results was obtained for the cocaine treatment groups. With repeated treatments, the WAY 100635 treatment always blocked the locomotor activation effect of cocaine, whereas the effects of 8-OHDPAT were transformed from an inhibition to an enhancement of cocaine locomotor stimulation. The combined 8-OHDPAT plus WAY 100635 pretreatment did not affect the stimulant effect of cocaine. These findings demonstrate that low dose autoreceptor preferring treatments with a 5-HT1A agonist and antagonist can strongly modify the behavioral stimulant effects of cocaine and suggest that the 5-HT1A autoreceptor may be an important pharmacological target for the development of treatments for cocaine addiction.

Evidence for Pavlovian conditioning of cocaine-induced responses linked to emotional behavioral effects.

The pairing of cocaine treatments with a specific test environment typically leads to cocaine-conditioned drug effects. In this study, we first pre-exposed rats 10 times to an open-field environment to establish an habituation asymptote in locomotor activity prior to the initiation of cocaine treatments. Two groups (N=10) equated for locomotion, grooming, central zone penetrations and rearing behavior were used. One group received five pairings of cocaine (10.0 mg/kg) and the second group five pairings of saline injections with placements in the open-field environment. Subsequently, both groups received a saline test to detect possible cocaine-conditioned behavioral effects. During the cocaine treatment phase, cocaine enhanced locomotion and central zone penetrations but decreased rearing and grooming. On the conditioning test, the cocaine group exhibited enhanced central zone penetrations and decreased grooming as compared to the saline group. There were no group differences in locomotion or rearing. When within group comparisons were performed between behavioral responses on the pre-conditioning test vs. the conditioning test, the saline group scores were essentially unchanged. In contrast, the cocaine group exhibited higher central zone penetrations and decreased grooming without changes in locomotion or rearing. In that a cocaine conditioning test can also be viewed as a cocaine withdrawal test, two additional experiments were conducted using an unpaired conditioning protocol to test for withdrawal effects without conditioning. These results indicated that the central zone and grooming effects observed in the conditioning protocol were not withdrawal effects. Altogether, these findings provide support for Pavlovian conditioning of cocaine-induced changes in emotion-related behavioral responses.

Dopaminergic and serotonergic autoreceptor stimulation effects are equivalent and additive in the suppression of spontaneous and cocaine induced locomotor activity.

We used the D(2) receptor agonist, apomorphine (APO) and the 5-HT(1A) receptor agonist, 8-OHDPAT (8OH) in a low dose range to stimulate autoreceptors and in this way assess the separate and combined effects of reduced DA and 5-HT activity upon spontaneous and cocaine induced locomotor behavior. Two separate experiments were conducted. In the first experiment, separate groups of rats (N=10) were tested with either saline, 8OH, APO or 8OH plus APO (0.01, 0.025, 0.05 mg/kg). At 0.05 mg/kg, 8OH and APO induced similar dose related decreases (up to approximately 50%) in locomotor activity. The combined 8OH plus APO treatment induced dose-related decreases in locomotion (approximately 90%). At the 0.05 mg/kg dose level, the drug treatments given separately blocked cocaine induced increases in activity and the 8OH and APO inhibitory effects were again additive. In the second experiment, separate groups (N=10) received saline, 0.05 mg/kg APO, 0.05 mg/kg 8OH or 0.05 mg/kg APO plus 0.05 mg/kg 8OH. As in the first experiment, the 8OH and APO given separately reduced locomotor activity by approximately 50% and when given together, locomotor activity was virtually eliminated (reduced 80-90%). When the combined APO/8OH group also received the 5-HT(1A) antagonist, WAY 100635 (0.05 mg/kg), the effect on activity was equivalent to 0.05 mg/kg APO alone. Ex vivo neurochemical measurement of dopamine (DA) and serotonin (5-HT) metabolism confirmed that the APO decreased DA turnover, 8OH decreased 5-HT turnover and the combined treatment reduced both the DA and 5-HT turnover. Thus, for both spontaneous and cocaine induced locomotor behavior, the low dose 8OH and APO treatments suppressed locomotor activity and these effects were additive. These findings indicate that DA and 5-HT systems contribute separately to motoric activation. These results suggest that it is important to consider both DA and 5-HT contributions to disorders of motoric impoverishment such as Parkinson's disease as well as to hyperkinetic states such as those induced by stimulant drugs.

The 5-HT1A receptor and behavioral stimulation in the rat: effects of 8-OHDPAT on spontaneous and cocaine-induced behavior.

RATIONALE: The contribution of the 5-HT(1A) somato-dendritic autoreceptor populations to spontaneous and cocaine-induced locomotion is unclear. OBJECTIVES: To use a low dose range of +/-8-hydroxy-2-(di- n-propylamino)tetralin (8-OHDPAT) to preferentially stimulate 5-HT(1A) autoreceptors and a medium 8-OHDPAT dose range to stimulate both 5-HT(1A) autoreceptors and postsynaptic receptors as pretreatments prior to either saline or cocaine. METHODS: In experiment 1, either a medium dose of 8-OHDPAT (0.4 mg/kg) or a low dose (0.05 mg/kg) was given as pretreatments 20 min before five separate 20-min open-field tests. In experiment 2, the pretreatments were changed to a low dose range of 8-OHDPAT (0.01-0.05 mg/kg), with or without WAY 100635 (0.01-0.05 mg/kg). In experiment 3, the 8-OHDPAT pretreatments (0.01, 0.025 or 0.05 mg/kg) were administered 20 min prior to saline or cocaine (10 mg/kg) tests. In experiment 4, a medium dose range (0.2-0.3 mg/kg) was given 20 min prior to saline or cocaine (10 mg/kg) tests. RESULTS: Experiment 1 showed that 8-OHDPAT (0.4 mg/kg) tended to increase locomotor activity but that pretreatment with 0.05 mg/kg severely suppressed locomotor activity. In experiment 2, 8-OHDPAT in the low dose range inhibited locomotor activity and this effect was reversed by co-administration of WAY 100635. Experiment 3 showed that the low-dose 8-OHDPAT pretreatment reduced locomotor activity in saline but not cocaine tests. In experiment 4, 8-OHDPAT in the medium dose range enhanced locomotor activity in cocaine tests. CONCLUSIONS: It is suggested that the facilitatory effect of 8-OHDPAT on cocaine-induced locomotor stimulation is mediated by inhibition of 5-HT(1A) somato-dendritic autoreceptors.

Response to novelty as a predictor of cocaine sensitization and conditioning in rats: a correlational analysis.

RATIONALE: An animal's response to novelty has been suggested to be a predictor of its response to drugs of abuse. The possible relationship between an individual's behavioral response to novelty and its subsequent behavioral response to cocaine has not been subjected to a detailed correlational analysis. OBJECTIVE: To use a repeated cocaine treatment protocol to induce cocaine sensitization and conditioned cocaine locomotor stimulant effects and to assess the relationship of these effects to pre-cocaine locomotor behavior in a novel environment. METHODS: In two separate experiments, rats were given a 20-min test in a novel open-field environment. Subsequently, the rats were given a series of additional tests in conjunction with either saline or cocaine (10 mg/kg) treatments to induce cocaine sensitization and conditioned effects. RESULTS: The repeated cocaine treatments induced cocaine behavioral sensitization and conditioned effects. Correlational analyses showed that the initial 20-min novel environment test proved to be a strong predictor of an animal's subsequent saline activity level but did not predict the rats' behavioral acute and sensitized response to cocaine. When change in activity was used as the dependent variable, initial activity level was reliably negatively correlated with activity changes on cocaine tests as well as cocaine conditioning tests. CONCLUSIONS: The negative correlation between initial activity in a novel environment and the change in activity induced by cocaine indicates that low responders to environmental novelty tend to have the strongest response to cocaine. These results appear consistent with the classic initial value and response rate dependent analyses of stimulant drug effects.

Cocaine-conditioned behavioral effects: a role for habituation processes.

Cocaine has potent locomotor stimulant effects in rodents, which seemingly can become conditioned to test environment cues. In two experimental protocols, we measured the effects of cocaine on locomotor activity and grooming behavior, and subsequently tested whether these cocaine effects became conditioned to contextual cues. In the first experiment, three groups of rats received 14 injections of either saline or cocaine (10 mg/kg) paired or unpaired to the test environment. Cocaine increased locomotion and decreased grooming during treatment and on the conditioning test. Over the course of the treatment phase, however, the saline- and cocaine-unpaired groups but not the cocaine paired group developed progressively lower locomotion and higher grooming scores indicative of substantial habituation effects. To examine whether the cocaine may have impaired the acquisition of habituation effects rather than induce a Pavlovian cocaine conditioned response, an additional experiment was conducted in which two additional non-habituation saline and cocaine control groups were added to the experimental design. On a conditioning test, the two non-habituation control groups were equivalent in activity and grooming behavior to the cocaine-paired group. The findings were consistent with a failure by cocaine-paired animals to acquire habituation effects, which could transfer to the non-cocaine state. The connection between cocaine and novelty/habituation may have substantial importance for understanding cocaine effects.

The selective serotonin(1A)-receptor antagonist WAY 100635 blocks behavioral stimulating effects of cocaine but not ventral striatal dopamine increase.

An increase in the extracellular dopamine (DA) concentration is generally accepted as an important neurochemical mediator of the behavioral effects of cocaine. Cocaine induced increases in serotonergic (5-HT) activity also appears to be involved in these effects. Here we describe the effects of the 5-HT(1A)-receptor antagonist WAY 100635 on the behavioral and neurochemical effects of cocaine. In-vivo microdialysis was used in behaving rats to measure extracellular concentration of DA in the nucleus accumbens (Nac). Four groups of animals received one of the following drug combinations: WAY 100635 (0.4 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), WAY 100635 (0.4 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 20 min apart. The pretreatment with WAY 100635 significantly attenuated the locomotor stimulant effects of cocaine without altering the DA overflow in the Nac. WAY 100635 itself did not modify locomotion or the extracellular DA concentration in the Nac. These results indicate that (1) the 5-HT(1A)-receptor is an important component in the mediation of cocaine locomotor stimulant effects, and (2) an increase in the extracellular DA concentration in the Nac might be a necessary but is not a sufficient condition for the locomotor stimulant effects of cocaine.

8-OHDPAT effects upon cocaine unconditioned and conditioned behaviors: a role for drug stimulus effects.

The effects of the 5-HT1A agonist, (+/-)-8-hydroxy-dipropylaminotetralin (8-OHDPAT) upon the unconditioned and conditioned behavior induced by cocaine were assessed in rats. Separate groups (n=7) received saline, cocaine (10 mg/kg), 8-OHDPAT (0.2 mg/kg), or 8-OHDPAT (0.2 mg/kg) plus cocaine (10 mg/kg) for eight treatment sessions (two per week) in which the rats were tested for 20 min in an open-field. On the eighth treatment session, cocaine enhanced locomotion and rearing but decreased grooming. 8-OHDPAT also decreased grooming and, when given in combination with cocaine, enhanced locomotion but attenuated cocaine-induced rearing. The two 8-OHDPAT groups differed substantially from each other and from the cocaine group in terms of locomotion during the drug treatment phase. Subsequently, all groups received a series of conditioning tests in which they received saline, 0.1, 0.2, or 0.4 mg/kg 8-OHDPAT prior to testing. Groups which had received either 8-OHDPAT or cocaine prior to the conditioning tests exhibited equivalent conditioned effects on the saline conditioning test. When conditioning tests were conducted with 8-OHDPAT, however, only the group which had previously received the combined 0.2 mg/kg 8-OHDPAT plus cocaine treatment exhibited a conditioned response and this effect only occurred at the 0.2 8-OHDPAT dose level. These observations indicate the important influence of the stimulus properties of drugs for the study of drug conditioning and for understanding drug interactions with cocaine.