Mark S. Kleven

Effects of repeated injections of cocaine on D1 and D2 dopamine receptors in rat brain

In order to determine if chronic administration of cocaine produced long-lasting alterations in dopamine receptor binding, rats were treated with single daily injections of cocaine (0, 10, or 20 mg/kg) for 15 consecutive days and killed either 20 min or 2 weeks after the last injection. The density of D1 binding sites in frontal cortex was either unchanged (10 mg/kg) or slightly increased (20 mg/kg) 20 min after the last daily injection, but was decreased 2 weeks later. D1 sites in striatum were decreased both immediately and 2 weeks after the injection regimen. Decreases in D1 binding site density in nucleus accumbens were observed only immediately after the last injection. In contrast to these effects on D1 binding sites, D2 binding sites were decreased in striatum and frontal cortex and increased in the nucleus accumbens 20 min after repeated cocaine, but were unaffected 2 weeks after repeated cocaine. Computer-assisted analysis of the saturation isotherms revealed that chronic administration of cocaine did not affect the affinity (Kd) of the radioligands used to label D1 or D2 sites. These findings suggest that repeated administration of cocaine results in long-term decreases in D1 binding sites in striatum and frontal cortex and transient decreases in D2 binding sites. Furthermore, cocaine caused opposite, transient effects on D1 and D2 site density in nucleus accumbens.

Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey

In order to determine if repeated injections of cocaine produced long-lasting alterations in catecholaminergic binding sites, rhesus monkeys were treated with saline (1.0 ml/15 kg) or cocaine (3.0-4.0 mg/kg) four times daily for 14 consecutive days and sacrificed two weeks after the last injection. The densities of dopamine D1 receptor binding sites, dopamine transporter binding sites and beta adrenergic receptor binding sites were significantly decreased in caudate nucleus to 51%, 17% and 61% of control, respectively, two weeks after repeated cocaine injections. There were no differences in D2 receptor binding site densities in the caudate, nor were there differences in binding sites between groups in the other brain regions examined: prefrontal cortex (D1, D2, dopamine transporter, beta), nucleus accumbens (D1, D2, dopamine transporter) and substantia nigra (D2). Behavioral observation showed that the cocaine-treated monkeys became sensitized to the repeated injections. Early in the regimen, these animals displayed stereotypic grooming, buccal movements and visual checking after each injection that differed significantly from the saline-treated animals. As the regimen progressed, the frequency of grooming decreased while the frequencies of visual tracking and splayed legs increased in a manner consistent with the development of behavioral sensitization. Together, these findings suggest that the caudate nucleus may be more sensitive than other dopamine-containing brain regions to long-lasting pre- and post-synaptic effects of repeated cocaine administration, and that the changes seen in dopaminergic neurons may be related to behavioral sensitization.

Lack of long-term monoamine depletions following repeated or continuous exposure to cocaine

Cocaine was administered to rats for prolonged periods either by repeated injections (10 mg/kg twice daily for 10 days and 12.5 mg/kg 8 times daily for 10 days) or by continuous intravenous infusion (100 mg/kg/day for 21 days). None of the regimens produced long-lasting depletions of dopamine (DA), serotonin (5-HT), or major metabolites in striatum, hippocampus, hypothalamus, or somatosensory cortex. These results suggest that prolonged exposure to cocaine does not produce neurotoxicity like that observed with d-amphetamine or d-methylamphetamine.

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

RationaleThere is increasing interest in antipsychotics intended to manage positive symptoms via D2 receptor blockade and improve negative symptoms and cognitive deficits via 5-HT1A activation. Such a strategy reduces side-effects such as the extrapyramidal syndrome (EPS), weight gain, and autonomic disturbance liability.ObjectiveThis study aims to review pharmacological literature on compounds interacting at both 5-HT1A and D2 receptors (as well as at other receptors), including aripiprazole, perospirone, ziprasidone, bifeprunox, lurasidone and cariprazine, PF-217830, adoprazine, SSR181507, and F15063.MethodsWe examine data on in vitro binding and agonism and in vivo tests related to (1) positive symptoms (e.g., psychostimulant-induced hyperactivity or prepulse inhibition deficit), (2) negative symptoms (e.g., phencyclidine-induced social interaction deficits and cortical dopamine release), and (3) cognitive deficits (e.g., phencyclidine or scopolamine-induced memory deficits). EPS liability is assessed by measuring catalepsy and neuroendocrine impact by determining plasma prolactin, glucose, and corticosterone levels.ResultsCompounds possessing “balanced” 5-HT1A receptor agonism and D2 antagonism (or weak partial agonism) and, in some cases, combined with other beneficial properties, such as 5-HT2A receptor antagonism, are efficacious in a broad range of rodent pharmacological models yet have a lower propensity to elicit EPS or metabolic dysfunction.ConclusionsRecent compounds exhibiting combined 5-HT1A/D2 properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT1A affinity and efficacy, which can markedly influence activity and side-effect profiles.

Antipsychotic-like vs cataleptogenic actions in mice of novel antipsychotics having D2 antagonist and 5-HT1A agonist properties.

A new generation of proven or potential antipsychotics, including aripiprazole, bifeprunox, SSR181507 and SLV313, exhibit agonist actions at serotonin 5-HT1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT1A receptors, such as haloperidol, olanzapine and risperidone. All the drugs dose-dependently reduced apomorphine-induced climbing or sniffing and, with the exception of ziprasidone, produced complete suppression of these responses. In the bar catalepsy test, when administered alone, haloperidol, olanzapine and risperidone produced marked catalepsy, whereas, at doses up to 40 mg/kg, aripiprazole, SLV313, SSR181507, and sarizotan produced little or no catalepsy. The latter compounds, therefore, displayed a large separation between doses with ‘antipsychotic-like’ and those with cataleptogenic actions. When 5-HT1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of SSR181507 and sarizotan were unmasked, and the catalepsy induced by bifeprunox was enhanced. In the case of aripiprazole and SLV313, although WAY100635 produced upward shifts in their dose–response, the magnitude of catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that 5-HT1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D2 and 5-HT1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.

D-, L- and DL-fenfluramine cause long-lasting depletions of serotonin in rat brain ☆

D-Fenfluramine (1.6-12.5 mg/kg), L-fenfluramine (1.6-25 mg/kg), and DL-fenfluramine (1.6-25 mg/kg) injected s.c. twice daily for 4 consecutive days produced dose-related depletions of serotonin (5-HT) levels in somatosensory cortex, striatum, hypothalamus, and hippocampus of rats (n = 5-8/group) sacrificed two weeks after the last injection. While the results indicate that long-lasting effects of racemic fenfluramine are due to both stereoisomers, the magnitude of depletions caused by the isomers varied with dose, suggesting that they have different neurochemical effects.

Effects of three monoamine uptake inhibitors on behavior maintained by cocaine or food presentation in rhesus monkeys

Rhesus monkeys (n = 6) were surgically prepared with double lumen i.v. catheters and the effects of continuous infusion of the monoamine reuptake blockers mazindol, sertraline and fluoxetine were examined on behavior maintained by food presentation or i.v. cocaine injections. Under baseline conditions, lever pressing was maintained under a three-component multiple schedule of reinforcement in which food (1-g banana-flavored pellets) was available for 600 s under a fixed-ratio 30 schedule in the first and third components. In the second component, the dose of cocaine that maintained maximum rates of responding (0.03 or 0.05 mg/kg per injection) was available for 1800 s under a fixed-ratio 30 schedule. There was a brief time-out after each reinforcer. When behavior was stable, mazindol (0.4-3.2 mg/kg per 24 h), sertraline (0.1-8.0 mg/kg per 24 h) or fluoxetine (0.4-3.2 mg/kg per 24 h) was administered continuously via the second lumen of the double lumen catheter. Mazindol was administered for the same number of sessions that were required for responding to decline to low levels when the monkeys were allowed to self-administer saline [5-13] while sertraline and fluoxetine were administered for a minimum of 21 days. Baseline conditions were reinstated between doses of each drug. Each drug decreased cocaine-maintained responding in a dose-related manner. In most cases, food-maintained responding was disrupted at doses equal to or lower than those that decreased cocaine-maintained responding. Additionally, the higher doses of each drug decreased food intake outside the daily sessions. These results suggest that monoamine uptake blockers with prominent effects on either dopamine or serotonin neurotransmission can decrease cocaine self-administration but only at doses that also affect behavior maintained by other reinforcers.

Interactions between neuroleptics and 5-HT(1A) ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects.

Rationale: Combining neuroleptics with 5-HT1A ligands is thought to improve the preclinical profile of neuroleptics and may be of interest in the development of new compounds that have greater therapeutic potential and/or are better tolerated. Objective: To examine 1) the ability of 5-HT1A ligands to alter the effects of neuroleptics in preclinical models for antipsychotic potential (hindlimb retraction time in the paw test) and extrapyramidal side-effects (forelimb retraction time in the paw test; catalepsy tests), 2) the role of intrinsic activity at 5-HT1A receptors in the modulatory effects of 5-HT1A ligands, and 3) the generality of the interactions across neuroleptics. Methods: The effects of different doses of 5-HT1A ligands with intrinsic activity ranging from high (e.g., 8-OH-DPAT) to low (e.g., WAY 100135) administered together with a fixed, high dose of the neuroleptics haloperidol, risperidone, and tropapride were examined in the paw test and on catalepsy. Results: Firstly, the 5-HT1A agonists 8-OH-DPAT and ipsapirone attenuated the extrapyramidal-like effects of haloperidol and risperidone more than their therapeutic-like effects; this was not observed for tropapride, where all of its effects were markedly attenuated. Secondly, neither the weak 5-HT1A agonist WAY 100135 nor the silent antagonist WAY 100635 attenuated the effects of neuroleptics. Thirdly, neuroleptics apparently differed in their sensitivity to interactions with 5-HT1A agonists inasmuch as 8-OH-DPAT and ipsapirone attenuated the effects of tropapride on hindlimb retraction times more than those of haloperidol or risperidone. Conclusions: The present data suggest that 5-HT1A agonists with intermediate or high, but not low, intrinsic activity may abolish the extrapyramidal effects of neuroleptics. Together with results of previous studies, it appears that 5-HT1A agonists alter the antipsychotic-like effects of neuroleptics, although this may depend on the neuroleptic studied.

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ratio (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or FR 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013–0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.

Metabolic mapping of the effects of intravenous methamphetamine administration in freely moving rats

The 2-[14C]deoxyglucose method was used to examine the effects of acute intravenous administration of methamphetamine (0.5–2.5 mg/kg) on rates of local cerebral glucose utilization in freely-moving rats. These effects were correlated with the effects of methamphetamine on locomotor activity assessed simultaneously in the same animals. Methamphetamine administration resulted in widespread dose-dependent increases in glucose utilization within structures of the extrapyramidal motor system. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, entopeduncular nucleus, subthalamic nucleus, and the lateral cerebellar cortex. In contrast, within the limbic system alterations in metabolic activity were smaller and more selective. Glucose utilization was increased in the nucleus accumbens at all doses tested, but alterations in glucose utilization in the ventral tegmental area, amygdala, and anterior cingulate were observed only at the highest doses of methamphetamine tested. Significant increases in rates of glucose metabolism were also found in the substantia nigra compacta and in the median and dorsal raphe nuclei. Dopamine and serotonin are depleted in these regions, as well as in the ventral tegmental area where glucose utilization was also increased, following chronic treatment with high doses of methamphetamine. These changes in glucose utilization may be indicative of disturbances in the biochemical processes involved in the neurotoxic effects of methamphetamine.