Cocaine acts on accumbens monoamines and locomotor behavior via a 5-HT2A/2C receptor mechanism as shown by ketanserin: 24-h follow-up studies.

It is well known that cocaine's psychomotor stimulant properties derive from enhanced monoamines via synaptic transporter/reuptake inhibition and release mechanisms. However, to further understand mechanisms of action for cocaine, which may be receptor-related, ketanserin, a selective 5-HT(2A/2C) antagonist was used to ascertain a possible mediation for 5-HT(2A//2C) receptors in the monoamine and behavioral responses to cocaine. The studies were performed in the freely moving and behaving animal with In Vivo Microvoltammetry. Miniature carbon sensors, BRODERICK PROBE microelectrodes detected dopamine (DA) and serotonin (5-HT) concentrations in Nucleus Accumbens (NAcc) of male, Sprague-Dawley laboratory rats in separate signals and within seconds while at the same time, locomotor behavior was monitored with infrared photobeams. Synaptic release of each monoamine was detected because separate studies showed that the depolarization blocker, gamma-butyrolactone (gamma BL), decreased steady-state values [Pharmacol. Biochem. Behav. 40 (1991) 969]. Acute studies (Day 1) were performed; the animals received single injection of drug(s) in the faradaic behavioral chamber after a stable baseline during habituation behavior was achieved. After completion of the study, the animals were returned to their home cages. Subacute studies (Day 2) were also performed; these took place 24 h later in the faradaic behavioral chamber; same animal control was used and no further drug was administered. Day 2 data were compared to baseline (habituation data) on Day 1. Results showed that (1) Acute administration of Cocaine (10 mg/kg, i.p.) (N=5) increased DA and 5-HT release above baseline (p<0.001) while locomotion was also increased above baseline (p<0.001). (2) In Subacute studies in the cocaine group, when no further drug was administered, DA release decreased (p<0.001) and decreases in 5-HT release also occurred throughout the time course (p<0.05). Locomotor behavior increased above baseline and showed a trend toward statistical significance (p<0.07). (3) Acute administration of Ketanserin/Cocaine (3 mg/kg s.c. and 10 mg/kg i.p., respectively) (N=6) showed that ketanserin antagonized DA and 5-HT release (p<0.001), while locomotion was antagonized as well (p<0.001). (4) In Subacute studies, in the ketanserin/cocaine group, when no further drug was administered, DA decreased (p<0.001), but 5-HT increased (p<0.001), while locomotor activity increased above baseline and a trend toward statistical significance was seen (p<0.07). Additional saline controls were without effect (p>0.05). In summary, Acute studies showed that cocaine produced its psychostimulant responses on monoamines and behavior and ketanserin antagonized these responses, likely via a 5-HT(2A/2C) receptor mediation. Presynaptic and postsynaptic responses were not distinguished, suggesting, in addition, a role for 5-HT-ergic modulation of DA, likely DA(2) postsynaptic modulation Subacute cocaine studies showed that on Day 2, deficiencies in monoamines occurred, reflecting cocaine withdrawal mechanisms neurochemically, while locomotor behavior did not show such dramatic deficiencies. Indeed, behavior increased above baseline. Moreover, ketanserin reversed 5-HT-related and not DA-related cocaine monoamine responses, while locomotion continued to be insignificantly increased above baseline as was seen in the Subacute cocaine group. The data suggest that presynaptic 5-HT(2A/2C) receptor mechanisms may be important during withdrawal from single injection of cocaine.

Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal.

There is an increasing awareness that a psychosis, similar to that of schizophrenic psychosis, can be derived from cocaine addiction. Thus, the prototypical atypical antipsychotic medication, clozapine, a 5-HT(2)/DA(2) antagonist, was studied for its effects on cocaine-induced dopamine (DA) and serotonin (5-HT) release in nucleus accumbens (NAcc) of behaving male Sprague-Dawley laboratory rats with In Vivo Microvoltammetry, while animals' locomotor (forward ambulations), an A(10) behavior, was monitored at the same time with infrared photobeams. Release mechanisms for monoamines were determined by using a depolarization blocker, gamma-butyrolactone (gammaBL). BRODERICK PROBE microelectrodes selectively detected release of DA and 5-HT within seconds and sequentially in A(10) nerve terminals, NAcc. Acute and subacute studies were performed for each treatment group. Acute studies are defined as single injection of drug(s) after a stable baseline of each monoamine and locomotor behavior has been achieved. Subacute studies are defined as 24-h follow-up studies on each monoamine and locomotor behavior, in the same animal at which time, no further drug was administered. Results showed that (1) acute administration of cocaine (10 mg/kg ip) (n=5) significantly increased both DA and 5-HT release above baseline (P<.001) while locomotion was also significantly increased above baseline (P<.001). In subacute studies, DA release decreased significantly below baseline (P<.001) and significant decreases in 5-HT release occurred at the 15-min mark and at each time point during the second part of the hour (P<.05); the maximum decrease in 5-HT was 40% below baseline. Locomotor behavior, on the other hand, increased significantly above baseline (P<.05). (2) Acute administration of clozapine/cocaine (20 and 10 mg/kg ip, respectively; n=6) produced a significant block of the cocaine-induced increase in DA (P<.001) and 5-HT release (P<.001). Cocaine-induced locomotion was blocked simultaneously with each monoamine by clozapine as well (P<.001). In subacute studies, DA release continued to be blocked presumably via clozapine by exhibiting a statistically significant decrease (P<.001), but 5-HT release increased significantly (P<.001), while cocaine-induced locomotor activity also continued to be antagonized by clozapine, i.e., locomotor activity exhibited no difference from baseline (P>.05). In summary, acute studies (a) support previous data from this laboratory and others that cocaine acts as a stimulant on the monoamines, DA and 5-HT and on locomotor behavior as well and (b) show that clozapine, 5-HT(2)/DA(2) antagonist, blocked enhanced DA, 5-HT and psychomotor stimulant behavior induced by cocaine. Subacute studies (a) suggest that withdrawal responses occurred in the cocaine group, based on recorded deficiencies in monoamine neurotransmitters (b) show that withdrawal effects in the cocaine group likely presynaptic, were distinguished from locomotor behavior, classically known to be mediated postsynaptically, and finally, (c) suggest that clozapine, with longer lived pharmacokinetic properties, reversed 5-HT cocaine-related withdrawal effects, but was unable to reverse DA cocaine-related withdrawal responses. Taken together with data from this laboratory, in which the 5-HT(2A/2C) antagonist, ketanserin, affected cocaine neurochemistry in much the same way as did clozapine, a mediation by either separate or combined 5-HT(2A/2C) receptors for these clozapine/cocaine interactions, is suggested. Further studies, designed to tease out the responses of selective 5-HT(2A) and 5-HT(2C) receptor compounds to cocaine and clozapine/cocaine, are underway.

Acute and subacute effects of risperidone and cocaine on accumbens dopamine and serotonin release using in vivo microvoltammetry on line with open-field behavior.

In vivo microvoltammetry was used to detect dopamine (DA) and serotonin (5-HT) release from nucleus accumbens (NAcc) of freely moving, male, Sprague-Dawley laboratory rats, while animals' locomotor (forward ambulations) and stereotypic behavior (fine movements of sniffing and grooming) were monitored at the same time with infrared photobeams. Monoamine release mechanisms were determined by using a depolarization blocker (gamma-butyrolactone, gamma BL). Miniature carbon sensors (BRODERICK PROBES microelectrodes) smaller than a human hair were used in conjunction with a semidifferential electrochemical circuit to detect release of each monoamine in separate signals and within seconds. The purpose was to evaluate the neuropharmacology of the 5-HT(2)/DA(2) antagonist risperidone in its current therapeutic role as an atypical antipsychotic medication as well as in its potential role as pharmacotherapy for cocaine psychosis and withdrawal symptoms. Acute (single drug dose) and subacute (24-h follow-up studies in the same animal, no drug administration) studies were performed for each treatment group. The hypothesis for the present studies is derived from a growing body of evidence that cocaine-induced psychosis and schizophrenic psychosis share similar neurochemical and behavioral manifestations. Results showed that (1) Acute administration of risperidone (2 mg/kg sc) significantly increased DA and 5-HT release in NAcc above baseline (habituation) values (P<.001) while locomotion and stereotypy were virtually unaffected. In subacute studies, DA release did not differ from baseline (P>.05), whereas 5-HT release was significantly increased above baseline (P<.001). Locomotion increased over baseline but not to a significant degree, while stereotypy was significantly increased above baseline (P<.05). (2) Acute administration of cocaine (10 mg/kg ip) significantly increased both DA and 5-HT release above baseline (P<.001), while locomotion and stereotypy were significantly increased over baseline (P<.001). In subacute studies, DA decreased significantly below baseline (P<.001) and significant decreases in 5-HT release occurred at 15, 20, 50 and 55 min (P<.05). Behavior increased above baseline but did not reach a statistically significant degree. (3) Acute administration of risperidone/cocaine (2 mg/kg sc and 10 mg/kg ip, respectively) showed a significant block of the cocaine-induced increase in DA release in the first hour (P<.001) and 5-HT release in both hours of study (P<.001). Cocaine-induced locomotion and stereotypy were blocked simultaneously with the monoamines (P<.001). In subacute studies, DA and 5-HT release returned to baseline while locomotion and stereotypy increased insignificantly above baseline. Thus, (a) these studies were able to tease out pharmacologically the critical differences between presynaptic and postsynaptic responses to drug treatment(s) and these differences may lead to more effective therapies for schizophrenic and/or cocaine psychosis. (b) Taken together with other data, these acute studies suggest that risperidone may possibly act via inhibition of presynaptic autoreceptors to produce the observed increases in accumbens DA and 5-HT release, whereas cocaine may be acting at least in part via serotoninergic modulation of DA postsynaptically. The subacute data suggest that pharmacokinetics may play a role in risperidone's action and that neuroadaptation may play a role in the mechanism of action of cocaine. Finally, the ability of risperidone to block cocaine-induced psychostimulant neurochemistry and behavior during acute studies while diminishing the withdrawal symptoms of cocaine during subacute studies suggests that risperidone may be a viable pharmacotherapy for cocaine psychosis and withdrawal.