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K A Cunningham

Publications and source records attributed to K A Cunningham.

At least 37 records · Page 2Linked to original sources
PubMed1996

The role of serotonin in the actions of psychostimulants: molecular and pharmacological analyses.

Cocaine is a highly abused psychostimulant which is a local anesthetic and inhibitor of the reuptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE). This manuscript details a brief summary and the primary conclusions of several presentations geared to present recent pharmacological analyses of the interaction of cocaine with 5-HT systems. These data illustrate the complexity of actions for cocaine in the brain and emphasize that, to fully understand the mechanisms which underlie its potent behavioural effects, the impact of this drug on 5-HT function as well as the interactions between 5-HT and the function of DA mesolimbic pathways must be considered.

Animals↗
PubMed1995

Discriminative stimulus effects of cocaine: antagonism by dopamine D1 receptor blockade in the amygdala.

Mesolimbic dopamine (DA) D1 and D2 receptors appear to be involved in mediating the discriminative stimulus effects of cocaine. The purpose of the present study was to investigate the role of the amygdala DA D1 receptors, in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625-20 mg/kg) produced a dose-related increase in cocaine-lever responding. Intracranial bilateral injections of cocaine (20-200 micrograms, total dose) into the central amygdala engendered, at best, a partial substitution (< 60% drug-lever responding) for the systemic cocaine cue. Central amygdala microinjections of artificial cerebrospinal fluid (ACSF; 1 microliter/side) or SCH 23390 (0.5-2 microgram, total dose) resulted in primarily saline-appropriate responding. In antagonism tests, bilateral injections of the DA D1 receptor antagonist SCH 23390 (0.5-2 microgram, total dose) into the central amygdala produced a dose-related blockade of a systemic dose of cocaine (5 mg/kg) that engendered > 85% cocaine-lever responding when given alone. Additionally, bilateral injection of a fixed dose of SCH 23390 (2 micrograms) into the central amygdala resulted in a rightward shift in the cocaine dose-response curve (2.5-20 mg/kg). Although administration of cocaine into the central amygdala does not mimic the systemic cocaine cue, the present results demonstrate that DA D1 receptors located within the central amygdala appear to have a modulatory role upon the discriminative stimulus properties of cocaine.

Amygdala↗
PubMed1995

Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors.

The present study assessed compounds displaying affinity for 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors for their ability to substitute for, enhance or antagonize the discriminative stimulus effects of cocaine (10 mg/kg) in rats. In substitution tests, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 0.2-1.6 mg/kg), the 5-HT1A/B receptor agonists RU 24969 (0.25-2 mg/kg) and CGS 12066B (2-16 mg/kg), the 5-HT1B/2C receptor agonists m-chlorophenylpiperazine (mCPP; 0.25-2 mg/kg) and m-trifluoromethylphenylpiperazine (TFMPP; 0.125-2 mg/kg), the 5-HT2A/2C receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane ([+/-]-DOB; 0.0625-0.5 mg/kg), the 5-HT2C receptor agonist MK 212 (0.25-1 mg/kg) and the nonselective 5-HT receptor agonist quipazine (1-8 mg/kg) engendered 30% to 70% cocaine-appropriate responding. The DA receptor antagonists SCH 23390 (0.025 or 0.05 mg/kg) and haloperidol (0.125 or 0.25 mg/kg) failed to block the partial substitution of RU 24969 (1 mg/kg) for cocaine. In combination tests, a fixed dose of either quipazine (4 mg/kg), RU 24969 (0.25, 0.5 or 1 mg/kg) or TFMPP (0.5 mg/kg) but not 8-OH-DPAT (0.4 mg/kg) or CGS 12066B (16 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.625-5 mg/kg). In contrast, coadministration of either mCPP (0.25-2 mg/kg) or MK 212 (0.125-2 mg/kg) plus a dose of cocaine (5 mg/kg) that produced > 85% cocaine-appropriate responding when given alone partially antagonized cocaine; mCPP (1 mg/kg) also produced a rightward shift in the cocaine dose-response curve. Neither 8-OH-DPAT (0.2-1.6 mg/kg), (+/-)-DOB (0.125-0.5 mg/kg) nor quipazine (2-8 mg/kg) blocked the cocaine stimulus. The 5-HT1A receptor antagonist NAN 190 (0.2-0.8 mg/kg), the 5-HT2A/2C receptor antagonist LY 53857 (0.5-4 mg/kg) and the 5-HT/DA receptor antagonist pirenperone (0.5-4 mg/kg) neither substituted for nor enhanced cocaine; however, pirenperone but not NAN 190 or LY 53857 partially blocked the cocaine (10 mg/kg) response. Although 5-HT receptor compounds do not substitute for cocaine, several 5-HT receptor agonists (i.e., the indole derivative RU 24969 and the arylpiperazines mCPP, MK 212, TFMPP and quipazine), but not antagonists, differentially modulate the stimulus effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Involvement of 5-HT2C receptors in mediating the discriminative stimulus properties of m-chlorophenylpiperazine (mCPP).

Rats were trained to discriminate the 5-HT receptor agonist m-chlorophenylpiperazine (mCPP; 1 mg/kg) from saline using a two-lever, water-reinforced drug discrimination task. The antidepressant trazodone (1-8 mg/kg), the 5-HT1B/2C receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP; 0.25-1 mg/kg) and MK 212 (0.125-1 mg/kg), and the mixed 5-HT1A/B receptor agonist RU 24969 (0.25-2 mg/kg) substituted fully for mCPP. The 5-HT2A/2C receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.25-1 mg/kg) and d-lysergic acid diethylamide (LSD; 0.02-0.08 mg/kg) and the 5-HT releaser fenfluramine (0.5-2 mg/kg) also mimicked mCPP. Agonists selective for the 5-HT1A or 5-HT3 receptor or the 5-HT reuptake site produced saline-lever responding. The ergoline derivative mesulergine (0.5-4 mg/kg) produced a partial agonist/antagonist profile. The 5-HT1/2 receptor antagonist metergoline (0.125-1 mg/kg) completely blocked the mCPP cue whereas the 5-HT2A/2C receptor antagonists ketanserin and LY 53857 as well as all other 5-HT receptor antagonists failed to block the mCPP cue. The dopamine receptor antagonists SCH 23390 and haloperidol were also ineffective mCPP antagonists. Following pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (pCPA; 100 mg/kg/day) for 3 consecutive days, the discriminability of low doses of mCPP increased, whereas the effects of fenfluramine decreased. The present results suggest that the discriminative stimulus effects of mCPP in rats are mediated primarily by postsynaptic 5-HT2C receptors.

Animals↗
PubMed1994

Discriminative stimulus properties of cocaine: modulation by dopamine D1 receptors in the nucleus accumbens.

Dopamine (DA) D1 and D2 receptors are involved in mediating the behavioral effects of cocaine, including its discriminative stimulus properties. The purpose of the present study was to investigate the role of the nucleus accumbens and, in particular, accumbens DA D1 receptors in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625-20 mg/kg) produced a dose-related increase in cocaine-appropriate responding. Microinjections of cocaine (2.5-40 micrograms) into the nucleus accumbens also engendered dose-dependent and complete substitutions (> 80% drug-lever responding) for the systemic training dose of cocaine, whereas intra-accumbens artificial cerebrospinal fluid (1 microliter/side) produced primarily saline-appropriate responding. In antagonism tests, pretreatment with the DA D1 antagonist SCH 23390 (3-12 micrograms/kg) completely antagonized (< 20% drug-lever responding) a dose of cocaine (5 mg/kg) that produced greater than 90% cocaine-lever responding when given alone. Additionally, intra-accumbens injections of SCH 23390 (0.025-0.4 microgram) prior to systemic cocaine (5 mg/kg) also significantly blocked the cocaine stimulus. The present results confirm the importance of the nucleus accumbens in mediating the discriminative stimulus properties of cocaine and suggest a primary role of accumbens DA D1 receptors in modulating this behavior.

Animals↗
PubMed1994

Habenula lesions decrease the responsiveness of dorsal raphe serotonin neurons to cocaine.

The median and dorsal (MR and DR) raphe nuclei are the origin of serotonin (5-HT)-containing neurons that innervate the forebrain. Neurons originating in the medial and lateral habenula provide an extensive afferent input to the midbrain that could serve as a negative feedback circuit. The present study was undertaken to establish whether intact habenula nuclei are required to observe the depressant effects of cocaine on the neural activity of 5-HT somata in the DR. To this end, the spontaneous activity of DR 5-HT neurons was assessed in male rats that had previously received bilateral radiofrequency lesions of the habenula complex either 1-4 h (short term) or 7 days (long term) prior to extracellular recordings of single 5-HT neurons of the DR. In rats with short-term lesions, the inhibitory response to cocaine was significantly attenuated. The mean dose to inhibit activity by 50% (ID50) was increased from 0.68 mg/kg in controls to 2.5 mg/kg in lesioned rats. Short-term habenula lesions also significantly decreased the numbers (but not the firing rates) of 5-HT neurons encountered in the DR. In contrast, the dose-response to cocaine as well as the numbers and firing rates of 5-HT neurons found in rats with long-term habenula lesions did not differ from controls. These results suggest that the inhibitory effects of cocaine on DR 5-HT neuronal activity depend in part on the ability of cocaine to affect habenula control of raphe 5-HT function.

Animals↗
PubMed1993

Discriminative stimulus properties of cocaine in relation to dopamine D2 receptor function in rats.

Previous studies indicate that the discriminative stimulus effects of cocaine are mediated predominantly by indirect activation of dopamine (DA) D2 postsynaptic receptors, although DA D1 receptors may also be involved. In the present study, full or partial D2 agonists and D2 antagonists were tested for their ability to substitute for, potentiate or antagonize the stimulus effects of cocaine in rats (n = 15) trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced task. The full D2 agonists bromocriptine (1.25-20 mg/kg) and quinpirole (0.013-0.2 mg/kg) engendered substantial cocaine-lever responding (> 80% drug-lever responding), whereas the partial D2 agonists preclamol (2.5-10 mg/kg) and terguride (0.313-1.25 mg/kg) produced less than 50% cocaine-lever responding. Co-administration of a threshold dose of cocaine (1.25 mg/kg) with low doses of bromocriptine (1.25-5 mg/kg) or quinpirole (0.025-0.1 mg/kg) induced higher percentages of cocaine-lever responding as compared with occasions when these D2 agonists were given alone. However, co-administration of this dose of cocaine with preclamol (2.5-10 mg/kg) or terguride (0.313-1.25 mg/kg) did not alter the percentage of cocaine-lever responding observed when these partial D2 agonists were administered alone. Pretreatment with the D2 antagonists bromuride (0.25-1 mg/kg) and haloperidol (0.125-0.5 mg/kg) significantly reduced the percentage of cocaine-lever responding. Preclamol (0.625-10 mg/kg) and terguride (0.019-5 mg/kg), but not bromocriptine (2.5-20 mg/kg) or quinpirole (0.01-0.08 mg/kg), significantly reduced the percentage of cocaine-lever responding. These results suggest that full D2 agonists substitute completely for cocaine, whereas partial D2 agonists do not produce cocaine-like responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding.

Repeated cocaine intoxication can result in the development of behavioral sensitization in animals and psychosis in humans, phenomena that have been associated with alterations in dopamine (DA) function. Using electrophysiologic and autoradiographic techniques, modifications of central serotonin (5-hydroxytryptamine; 5-HT) systems were investigated in rats treated with a regimen of cocaine administration that produced behavioral sensitization. The inhibitory response of single 5-HT neurons in the dorsal raphe (DR) to (-)-cocaine, the 5-HT uptake inhibitor fluoxetine or the 5-HT1A agonist 8-hydroxy-2-[di-N-propylamino]tetralin (8-OHDPAT) was significantly enhanced in cocaine-treated rats. Furthermore, several brain areas that contain either cell bodies (DR) or terminals for 5-HT (medial and sulcal prefrontal cortex, frontal cortex) showed cocaine-induced elevations in [3H]imipramine-labeled 5-HT uptake sites, while [3H]-8-OHDPAT-labeled 5-HT1A receptors were decreased only in the central medial amygdala. These results suggest that modifications of autoregulatory mechanisms secondary to alterations of 5-HT uptake processes may contribute to the development of cocaine sensitization.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Effects of the putative dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 on the discriminative stimulus properties of cocaine.

Recent evidence suggests that the putative dopamine (DA) autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232, share some neurochemical and behavioral effects with both psychostimulants and neuroleptics. The ability of (+)-AJ 76 and (+)-UH 232 to mimic or antagonize the stimulus effects of cocaine was investigated in rats trained to discriminate 5 mg/kg (N = 8) or 10 mg/kg (N = 8) of cocaine from saline in a two-lever, water-reinforced, drug discrimination task. In the cocaine (10 mg/kg) group, administration of (+)-AJ 76 (2.5-20 mg/kg) engendered only a partial substitution for cocaine (maximum 60% cocaine-lever responses). Given in combination with cocaine (10 mg/kg), (+)-AJ 76 (2.5-40 mg/kg) did not significantly attenuate the cocaine cue. A fixed dose of (+)-AJ 76 (2.5 or 10 mg/kg) plus various doses of cocaine (1.25-5 mg/kg) did not alter the cocaine dose-response curve. (+)-UH 232 (2-16 mg/kg) produced primarily saline-appropriate responding in rats trained to discriminate 5 mg/kg of cocaine and was unable to block the interoceptive cocaine state when given in combination with cocaine (5 mg/kg). (+)-UH 232 (2 or 8 mg/kg) also did not alter the cocaine dose-response curve. These results suggest that (+)-AJ 76 and (+)-UH 232 elicit only weak or no cocaine-like stimulus effects and, unlike neuroleptics, do not attenuate the cocaine cue.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Lack of serotonin neurotoxicity after intraraphe microinjection of (+)-3,4-methylenedioxymethamphetamine (MDMA).

Systemic administration of 3,4-methylenedioxymethamphetamine (MDMA) produces depletions of serotonin (5-HT) and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA), decreases 5-HT reuptake sites and diminishes tryptophan hydroxylase activity in various forebrain regions. MDMA has been shown to be neurotoxic to the fine fibers originating from dorsal raphe (DR) 5-HT neurons but not the beaded fibers from the median raphe (MR) nucleus. In the present experiment, MDMA was microinjected directly into the DR or MR to determine whether differential neurotoxicity developed in the DR versus MR fiber systems as measured by 5-HT levels and immunocytochemistry. Two weeks following stereotaxic injection with either vehicle or (+)MDMA (50 micrograms base in 2 microliters) into the DR or MR, rat brains were assayed for 5-HT and catecholamine content or 5-HT immunocytochemistry. HPLC analysis revealed no significant changes in monoamine or metabolite concentrations in the hippocampus and striatum of rats administered intra-DR or -MR (+)MDMA. Raphe sections stained for 5-HT also did not reveal any apparent neurotoxicity. A single cerebral injection of (+)MDMA does not produce neurotoxicity to 5-HT neuronal systems originating in the raphe, although neurotoxicity of multiple MDMA injections into these raphe nuclei cannot be ruled out.

3,4-Methylenedioxyamphetamine↗
PubMed1991

Decrease of GABA-immunoreactive neurons in the amygdala after electrical kindling in the rat.

The present study was designed to investigate the effects of electrical kindling in vivo on GABA immunoreactivity (GABA-IR) of the lateral and basolateral amygdaloid nuclei 2-6 months post-stimulation. Male Sprague-Dawley rats were implanted with bipolar electrodes in the basolateral nucleus and stimulated once per day until 3-5 stage 5 seizures were observed. Coronal sections containing the amygdala were processed for GABA-IR using the contralateral side of the brain. Results indicate that, in comparison to controls, fully kindled animals showed a significant decrease in total number of GABA-IR amygdala neurons. Decreases in GABA-positive punctate structures surrounding unlabeled pyramidal cells were also observed, but not quantified. The present data suggest that epileptogenesis of the amygdala is associated with a significant reduction of GABA-IR in the lateral and basolateral areas throughout the contralateral amygdaloid nucleus.

3,3'-Diaminobenzidine↗
PubMed1991

Cocaine-induced behavioral sensitization is not associated with loss of GABA-immunoreactive neurons in the amygdala.

We investigated whether cocaine-induced behavioral sensitization (15 mg/kg, twice daily for 7 days) is associated with changes in gamma-aminobutyric acid (GABA) neurons in the lateral-basolateral amygdala of male Sprague-Dawley rats. The number of GABA-immunoreactive neurons in the amygdala did not differ between cocaine- and saline-treated rats. Although some aspects of this behavioral phenomenon parallel the kindling model of epilepsy, limbic alterations in GABA neurons do not appear to be associated with behavioral sensitization to cocaine.

Amygdala↗
PubMed1991

Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine.

Evidence suggests that stimulants such as d-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D1 and D2) exist, we investigated the role of both of these receptor subtypes in mediating the internal "state" produced by these stimulants. Two groups of rats (N = 8/group) were trained to discriminate intraperitoneal (IP) injections of either d-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D1 and D2 agonists and antagonists. The D2 agonist quinpirole (0.0313-0.125 mg/kg) mimicked both stimulant cues while the D1 agonist SKF 38393 (5-20 mg/kg) substituted partially for cocaine but not d-amphetamine. Combination tests with DA antagonists indicated that both the D1 antagonist SCH 23390 (0.0063-0.25 mg/kg) and the D2 antagonist haloperidol (0.125-0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) for d-amphetamine was blocked by both DA antagonists. The ability of both D1 and D2 antagonists to attenuate the stimulus effects of d-amphetamine and cocaine raises the possibility that a synergistic ("enabling") interaction between D1 and D2 receptors may modulate stimulant cues.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat.

Cocaine inhibits the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). To investigate the relative role of such reuptake processes in the discriminative stimulus properties of cocaine, male rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination task and were administered neuroactive compounds during substitution or combination tests. The DA reuptake inhibitor GBR 12909 (2-16 mg/kg) completely mimicked cocaine. The reuptake inhibitors for NE (desipramine; 2-8 mg/kg) and 5-HT (fluoxetine; 0.625-5 mg/kg) did not substitute for the training drug. A low dose of either desipramine (3 mg/kg), fluoxetine (1.25 mg/kg), or GBR 12909 (2 mg/kg) coadministered with low doses of cocaine (0.625-2.5 mg/kg) enhanced the discriminative stimulus properties of this psychostimulant. The dose predicted to elicit 50% drug-lever responding is reduced (ED50) in the presence of desipramine (0.38 mg/kg), fluoxetine (0.79 mg/kg) or GBR 12909 (0.84 mg/kg) compared to the ED50 for cocaine (1.57 mg/kg) in the absence of any reuptake inhibitor. The finding that GBR 12909 mimics the cocaine cue corroborates the hypothesis that the stimulus properties of cocaine are mediated predominantly by DA systems. The potentiation of the stimulus effects of cocaine by monoamine reuptake inhibitors in rats suggests that these drugs could also amplify the subjective effects of cocaine in humans, a possibility that should be considered given the current use of antidepressants in the treatment of cocaine abusers.

Animals↗