benzofurans and Cocaine-Related-Disorders

Preclinical studies have demonstrated that kappa-opioid agonists can attenuate the neurochemical and behavioral effects of cocaine that are related to its reinforcing efficacy, suggesting that kappa-agonists may serve as pharmacotherapies for cocaine dependence. This 8-week inpatient study examined the ability of enadoline, a selective and high-efficacy kappa-agonist, and butorphanol, a mixed agonist with intermediate efficacy at both mu- and kappa-receptors, to reduce the direct pharmacodynamic effects and self-administration of intravenous cocaine in humans (n = 8). Acute doses of intramuscular enadoline (20, 40, and 80 microg/kg), butorphanol (1.5, 3, and 6 mg/70 kg) and placebo were examined separately as pretreatments during each of three test sessions with cocaine in a constrained random order. A cocaine dose-effect session (0, 20, and 40 mg cocaine i.v., 1 h apart) examined direct pharmacodynamic interactions on subjective and physiological indices; self-administration sessions examined choice behavior for cocaine (40 mg i.v. for six trials) versus money 1) in the presence of a sample cocaine dose with money choices presented in ascending value, and 2) in the absence of a sample dose with money choices presented in descending values. Enadoline (80 microg/70 kg) significantly (p < 0.05) reduced some of the positive subjective effects of cocaine (e.g., ratings of "high"), while butorphanol failed to modify subjective responses. Both agents were safely tolerated in combination with cocaine without adverse physiological responses. Cocaine self-administration was significantly greater across all pretreatment conditions when the sample dose was given and ascending money choices were used. Enadoline and butorphanol failed to modify cocaine self-administration. These data suggest that these kappa-agonists may be safely administered in the presence of cocaine but do not produce significant attenuation of cocaine's direct effects or self-administration under these acute dosing conditions.

Topics: Adult; Analgesics, Opioid; Benzofurans; Butorphanol; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Injections, Intramuscular; Male; Neuroprotective Agents; Pyrrolidines; Receptors, Opioid, kappa; Reinforcement, Psychology

Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT).. This study investigated the role of kappa opioid receptor and 5-HT mechanisms in kappa agonist-induced attenuation of cocaine priming in monkeys.. Squirrel monkeys were trained to self-administer cocaine (0.18-0.3 mg/kg/injection) under a second-order schedule in which drug seeking was maintained jointly by cocaine injections and a cocaine-paired visual stimulus. In extinction sessions, saline was substituted for cocaine, and the cocaine-paired stimulus was omitted. During test sessions, only saline was available for self-administration, and response-contingent presentations of the cocaine-paired stimulus were restored.. Priming injections of cocaine (0.1-1.0 mg/kg) induced reinstatement of drug seeking. Maximal levels of responding were similar to those maintained by active cocaine self-administration. Pretreatment with the kappa agonists enadoline (0.01 mg/kg) and spiradoline (0.3 mg/kg) or the 5-HT transport inhibitors fluoxetine (5.6 mg/kg) and citalopram (10.0 mg/kg) attenuated the priming effects of cocaine, shifting the cocaine dose-response function rightward and downward. Inhibition of cocaine-induced reinstatement of drug seeking by spiradoline and fluoxetine was reversed by R(+)8-hydroxy-2-(di-n-propylamino)tetralin (0.03 mg/kg), a 5HT(1A) agonist that inhibits 5-HT release. The effects of spiradoline also were reversed by the kappa antagonist nor-binaltorphimine (10.0 mg/kg).. Results suggest that the capacity of kappa opioid agonists to increase extracellular 5-HT levels may at least partially underlie kappa agonist-induced modulation of cocaine seeking.

Topics: Animals; Benzofurans; Citalopram; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Fluoxetine; Ligands; Naltrexone; Pyrrolidines; Receptors, Opioid, kappa; Saimiri; Selective Serotonin Reuptake Inhibitors; Self Administration; Serotonin; Serotonin 5-HT1 Receptor Agonists

The goal of this study was to determine D(1) receptor availability in human cocaine-dependent (CD) subjects and matched healthy controls (HCs). In addition, the CD subjects performed cocaine self-administration sessions in order to explore the association between D(1) receptor availability and cocaine-seeking behavior. Twenty-five CD subjects (40+/-4 years, 19M/6 F) and 23 matched HCs (38+/-4 years, 19M/4F) were scanned with PET and the radiotracer [(11)C]NNC 112. During the cocaine self-administration sessions, CD volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth $5. D(1) receptor availability was measured in the limbic, associative, and sensori-motor striatum in addition to cortical brain regions. No difference in D(1) receptor availability was seen between the two groups. A negative association was seen between D(1) receptor BP(ND) in the limbic striatum and the choice for the 6 mg dose of cocaine (r=-0.47, p=0.02, corrected for age). These results do not support the hypothesis that cocaine dependence is associated with a reduction in D(1) receptor availability in the striatum. However, within the CD subjects, low D(1) receptor availability in the ventral striatum was associated with the choice to self-administer cocaine, suggesting that low D(1) receptor availability may be associated with an increased risk of relapse in cocaine dependence.

Topics: Adult; Benzazepines; Benzofurans; Brain Mapping; Choice Behavior; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Receptors, Dopamine D1; Reinforcement Schedule; Self Administration

There is evidence showing that the opioid systems play an important role in cocaine addiction; fewer studies have examined their roles in cocaine withdrawal. This study was conducted to determine whether cocaine or chronic withdrawal from cocaine alters the receptor component of the kappa-opioid system. Male Fischer rats were injected with saline or cocaine (3x15 mg/kg/day for 4 days, 3x20 mg/kg/day for 4 days, 3x25 mg/kg/day for 4 days, and 3x30 mg/kg/day for 2 days), three times daily at 1-h intervals in an escalating dose paradigm for 14 days. Identically treated rats were withdrawn from cocaine or saline for 14 days. We performed quantitative autoradiographic mapping of kappa-opioid receptors (KOP-r) in the brains of rats treated with this escalating dose "binge" cocaine administration paradigm and of rats withdrawn from cocaine for 14 days. A significant condition (chronic/withdrawal) effect was shown across all regions analyzed. A significant increase in [3H]CI-977 binding to KOP-r was detected in the septum of rats treated with an escalating dose binge cocaine administration paradigm and killed 30 min after the last cocaine injection. In contrast, there was a decrease in KOP-r binding in the septum and the basolateral amygdala of rats withdrawn for 14 days from chronic escalating dose binge cocaine administration, compared to rats at the end of 14 days chronic escalating dose cocaine administration. These results reconfirm and extend that KOP-r undergoes upregulation in response to chronic binge cocaine administration here, with an escalating dose. The observed lowering in KOP-r binding, which was shown in two brain regions of cocaine withdrawn animals, might contribute to the persistent dysphoria reported a long time after the discontinuation of the drug.

Topics: Amygdala; Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Benzofurans; Cocaine; Cocaine-Related Disorders; Dopamine Uptake Inhibitors; Down-Regulation; Drug Administration Schedule; Male; Neuroprotective Agents; Pyrrolidines; Rats; Rats, Inbred F344; Receptors, Opioid, kappa; Septum of Brain; Tritium

Kappa opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that kappa agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the kappa agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the alpha(2)-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of kappa opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by kappa agonists.

Topics: Animals; Behavior, Addictive; Benzofurans; Clonidine; Cocaine-Related Disorders; Corticotropin-Releasing Hormone; Male; Naltrexone; Norepinephrine; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Saimiri; Self Administration; Stress, Psychological

As kappa agonists have been proposed as treatments for cocaine abuse, the cardiovascular effects of the kappa opioid receptor agonists ethylketocyclazocine (EKC) and enadoline were investigated in conscious squirrel monkeys. Both EKC and enadoline increased heart rate with little effect on blood pressure. This effect appeared to be specific for kappa receptors as the mu opioid agonist morphine did not mimic the effects of the kappa agonists. The opioid antagonist naltrexone, at a dose of 1.0 mg/kg, blocked the effect of EKC. An action at both central and peripheral receptors may be responsible for the heart rate increase following kappa agonist treatment. The ganglionic blocker chlorisondamine partially antagonized the effect of EKC on heart rate, suggesting central involvement, while the peripherally-acting agonist ICI 204,448 ((+/-)-1-[2,3- (Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) also increased heart rate, supporting a peripheral site of action. When given in combination with cocaine, EKC produced effects that were sub-additive, suggesting that the kappa agonists may be used safely as cocaine abuse treatments.

Topics: Animals; Benzofurans; Blood Pressure; Cocaine; Cocaine-Related Disorders; Drug Interactions; Ethylketocyclazocine; Heart Rate; Male; Pyrrolidines; Receptors, Opioid, kappa; Saimiri