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Aims: Buprenorphine is a mu-opioid partial agonist that is marketed in a sublingual formulation as a treatment for opioid dependence. A microcapsule depot sustained-release formulation has been developed which may offer effective treatment of opioid dependence while also minimizing risks of illicit diversion or patient non-compliance. The present study examined the efficacy of depot buprenorphine in suppressing the opioid withdrawal syndrome and in attenuating the effects of exogenous opioid challenge., Design: A placebo-controlled, double-blind, randomized trial., Setting: A closed residential research facility., Participants: A total of 15 opioid-dependent participants were enrolled into the 6-week study., Intervention: Fifteen participants were randomized to receive a single subcutaneous depot injection containing buprenorphine (58 mg) or placebo. Two participants, both of whom received placebo, terminated participation after depot administration. Thirteen participants (six buprenorphine, seven placebo) completed the 6-week study and were assessed throughout the study for signs and symptoms of opioid withdrawal and for response to weekly subcutaneous challenges with 3 mg hydromorphone., Measurement: Subjective, physiological and observer-rated indices of opioid withdrawal and opioid agonist effects., Findings: Depot buprenorphine provided more effective relief from opioid withdrawal than placebo, as evidenced by significantly fewer buprenorphine participants requiring supplemental medications for withdrawal suppression after depot administration compared to participants receiving placebo. In the weekly hydromorphone challenge sessions, depot buprenorphine significantly reduced opioid response on measures of subjective effects and pupillary diameter., Conclusions: Results from this double-blind, placebo-controlled study indicate that depot buprenorphine is effective in providing both withdrawal suppression and opioid blockade. Future studies examining additional doses and repeated dosing regimens with depot buprenorphine are warranted.

Rationale: Previous studies have found a role for dopamine D(2)-like receptors in many of the behavioral effects of cocaine, including its stimulation of locomotor activity and interoceptive discriminative-stimulus effects. However, given the lack of selectivity of most of the available pharmacological tools among D(2), D(3) and D(4) dopamine receptors, the roles of these specific receptors remain unclear., Objectives: The roles of specific dopamine D(4) receptors in the behavioral effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects were investigated using dopamine D(4) receptor knockout (DA D(4)R KO) and wild-type (WT) mice., Methods: The mice were trained in daily sessions to discriminate IP injections of saline from cocaine (10 mg/kg). Responses on one of two response keys intermittently produced a food pellet; one response was reinforced in sessions following cocaine injection (10 mg/kg), and the other response was reinforced in sessions following saline injection. Each 20th response produced a food pellet (fixed-ratio, or FR20 schedule of reinforcement). The dose-effects of cocaine and its interaction with the D(2)-like antagonist, raclopride, were assessed. Horizontal locomotor activity was also assessed in each genotype., Results: As previously shown), cocaine was a more potent stimulant of locomotor activity in the DA D(4)R KO mice compared to WT littermate mice. In addition, cocaine was more potent in producing discriminative-stimulus effects in DA D(4)R KO mice (ED(50) value=0.50 mg/kg) compared to their WT littermates (ED(50) value=2.6 mg/kg). Raclopride shifted the cocaine dose-effect curve in both DA D(4)R KO and WT mice, though the shift was greater for the DA D(4)R KO mice., Conclusions: The present results on the stimulation of activity and interoceptive/subjective effects of cocaine are consistent with the previously reported disregulation of dopamine synthesis in DA D(4)R KO mice, and further suggest a role of the DA D(4)R in vulnerability to stimulant abuse.

The effects of ecopipam (a D(1) selective antagonist) or triazolam pretreatment on the subjective and physiological effects of intravenously administered nicotine were examined in 10 cigarette-smoking cocaine abusers. Under double-blind, randomized conditions, subjects received oral capsule pretreatment (0, 30 or 100 mg ecopipam, or 0.25 mg/70 kg triazolam), followed 120 min later by an intravenous injection of 2 mg/70 kg nicotine or saline. Subjective ratings, heart rate and blood pressure were assessed before and repeatedly after each intravenous injection. Compared to oral placebo pretreatment, both ecopipam and triazolam pretreatment produced significant elevations in subject-reported capsule effect and observer ratings of sleepiness/sedation. Nicotine increased ratings of 'drug effect', 'rush', 'high', 'stimulated', 'liking', 'good effects' and 'bad effects', and produced modest increases in heart rate and blood pressure. Following both intra-venous saline and nicotine injection, ecopipam tended to reduce heart rate and blood pressure. Although both ecopipam and triazolam lowered several subjective ratings following intravenous saline injection, neither ecopipam nor triazolam affected nicotine subjective effects. In contrast to Romach et al. (Arch Gen Psychiatry 56: 1101-1106, 1999), who showed that pretreatment with ecopipam blocked cocaine subjective effects, the current study found no attenuation of the subjective effects of nicotine, and thus, provides no support for the hypothesis that D(1) receptors mediate the cocaine-like subjective effects of nicotine.

Rationale: Dopamine (DA) D2-like antagonists block several effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects. Because these compounds generally lack selectivity among the D2-like DA receptors, the specific roles of the subtypes remain unclear., Objectives: DA D2 receptor knockout (DA D2R KO), heterozygous (HET), and wild-type (WT) mice were used to study the role of D2 DA receptors in the effects of cocaine. Some effects of the relatively selective DA D2-like antagonist raclopride were also studied to further assess the role of D2 receptors., Methods: DA D2R KO, HET, and WT mice were treated with cocaine (1-10 mg/kg) or vehicle, and their horizontal locomotor activity was assessed. The mice were also trained to discriminate i.p. injections of saline from cocaine (10 mg/kg) using a two-response key, fixed-ratio-20 response, food-reinforcement procedure. A range of doses of cocaine (1.0-17 mg/kg) was administered before 15-min test sessions., Results: Both DA D2R KO and HET mice showed reduced levels of horizontal activity relative to WT mice. Cocaine dose dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D2R WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; tested doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. Raclopride, at inactive to fully active doses (0.1-1.0 mg/kg), did not fully substitute for cocaine. Raclopride dose dependently shifted the cocaine dose-effect curve to the right in DA D2R WT and HET mice. However, in DA D2R KO mice, raclopride was inactive as an antagonist., Conclusions: The present data indicate an involvement of D2 DA receptors in the locomotor-stimulating effects and the interoceptive discriminative-stimulus effects of cocaine in WT subjects. However, the D2 receptor is not necessary for the effects, suggesting redundant dopaminergic mechanisms for the discriminative-stimulus interoceptive effects of cocaine.

Rationale: Recent data suggest that dopamine (DA) D1-like receptor full agonists may be potential pharmacotherapeutic agents for treating cocaine abuse. The structurally novel isochroman D1-like agonist, A-77636, has not been well characterized and may prove to be useful as such an agent., Objectives: The interactions of cocaine and A-77636 were compared to those obtained with the better investigated benzazepine D1-like dopamine agonists, SKF 82958 and SKF 81297. The alterations in the locomotor stimulant and discriminative-stimulus effects of cocaine by the full D1-like dopamine receptor agonists were investigated across a full range of doses in order to characterize their interactions., Methods: Drug-naive Swiss-Webster mice were pretreated with SKF 81297, SKF 82958 or A-77636 (1-10 mg/kg) and cocaine (5-56 mg/kg) prior to a 30-min period in which locomotor activity was assessed. Rats were trained on a fixed ratio 20 (FR20) schedule to discriminate IP saline from cocaine (10 mg/kg) injections. Cocaine alone (1-10 mg/kg) and with either A-77636 (0.56-1.7 mg/kg), SKF 82958 (0.01-0.1 mg/kg) or SKF 81297 (0.1-0.56) were injected IP 5 min prior to a 15-min test session., Results: Cocaine maximally stimulated activity at 20-40 mg/kg with higher and lower doses stimulating activity less. Each D1-like agonist produced a dose-related decrease in cocaine-induced locomotor activity and lowered its maximal rate. Each of the D1-like agonists partially substituted for cocaine, with maximal substitution approximating 49, 35, and 24% for SKF 81297, SKF 82958, and A-77636, respectively. SKF 82958 significantly shifted the cocaine dose-effect curve approximately 3-fold to the left. With SKF 81297, there was a trend towards a leftward shift of cocaine dose effects, however the change was not statistically significant. In contrast to the other two D1-like agonists, A-77636 either did not affect the cocaine dose-effect curve or shifted it to the right., Conclusions: All three agonists produced similar effects on cocaine-induced locomotor activity, however the discriminative-stimulus effects of cocaine were affected differently by the D1 agonists. These results suggest fundamental differences in the actions of these D1 agonists. Because A-77636 consistently attenuated the present effects of cocaine, it may prove more useful than the others as a pharmacotherapy to treat cocaine abuse.

Rationale: Previous studies indicate antagonism of cocaine-stimulated locomotor activity by dopamine D2-like receptor antagonists, but only at doses of the antagonists, that by themselves attenuate locomotor activity, raising questions of the specificity of the interaction and whether it might be due solely to a summation of opposing effects., Objectives: The interactions of cocaine and several D2-like dopamine antagonists and non-dopamine "physiological antagonists" were compared across a full range of doses in order to fully characterize the interaction and assess the specificity of the effects of dopamine antagonists and cocaine., Methods: Swiss-Webster mice were treated with either vehicle, a D2-like antagonist (haloperidol, spiperone, raclopride, spiperone, (+) or (-) eticlopride), or a "physiological" antagonist (chlordiazepoxide, clonidine, or R(-) N6-(2-phenylisopropyl)adenosine) and cocaine (5-80 mg/kg) prior to a 30-min locomotor activity test., Results: All test drugs decreased locomotor activity when given alone. All test drugs attenuated cocaine-induced locomotion and decreased peak responding to cocaine. In general, the D2-like antagonists also decreased maximal responding to cocaine and decreased the slope of the ascending limb of the cocaine dose-effect curve, effects not obtained with physiological antagonists., Conclusions: Blockade of D2-like receptors resulted in an interaction with cocaine that was fundamentally different from that produced through non-dopaminergic mechanisms and appears to be more than a summation of opposing effects. The present data suggest that D2-like receptors are involved in the mechanisms underlying the induction of locomotor activity by cocaine.

Caffeine is an excellent model compound for understanding drugs of abuse/dependence. The results of self-administration and choice studies in humans clearly demonstrate the reinforcing effects of low and moderate doses of caffeine. Caffeine reinforcement has been demonstrated in about 45% of normal subjects with histories of moderate and heavy caffeine use. Recent studies provide compelling evidence that caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Tolerance to the subjective and sleep-disrupting effects of caffeine in humans has been demonstrated. Physical dependence as reflected in a withdrawal syndrome in humans has been repeatedly demonstrated in adults and recently demonstrated in children. Withdrawal severity is an increasing function of caffeine maintenance dose, with withdrawal occurring at doses as low as 100 mg per day. Increased cerebral blood flow may be the physiological mechanism for caffeine withdrawal headache. Case studies in adults and adolescents clearly demonstrate that some individuals meet DSM-IV diagnostic criteria for a substance dependence syndrome on caffeine, including feeling compelled to continue caffeine use despite desires and recommendations to the contrary. Survey data suggest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria.

Although the reinforcing properties of food are reduced in the presence of dopamine antagonist drugs, controversy exists about the relative roles of D1 vs D2 receptor subtypes in the actions of these drugs. The current experiment compared the effects of raclopride (a selective D2 receptor antagonist) and SCH 39166 (a selective D1 receptor antagonist) in the response-reinstating effects of food reinforcement. Hungry rats were trained to run a straight-alley for food reinforcement during single daily trials. The operant was then extinguished during consecutive daily non-reinforced trials. Subjects were then injected with one of four doses of raclopride (0.0, 1.0, 0.5, and 0.25 mg/kg, i.p.) or SCH 39166 (0.0, 1.0, 0.5, and 0.1 mg/kg i.p.) 30 min prior to a single reinforced treatment trial. Twenty-four h later, a test trial was conducted in an unbaited runway. The single reinforced trial in the midst of extinction was observed to reinstate operant runway performance. Raclopride, but not SCH 39166, dose-dependently attenuated this reinstatement. Motor control groups ruled out the possibility that these results were due to differential residual motor effects of the drugs. Results suggest that D2, but not D1, dopamine receptors, are involved in the response-reinstating properties of food reinforcement.

Human mixed lymphocyte cultures (hMLC) were used to examine the relationship between mitogenic stimuli (MITO), synthetic human calcitonin (hCT), and human insulin (hINS) on zinc (Zn) transport kinetics. Lymphocytes were isolated using a Ficoll density gradient. The hMLCs were labeled by incubation with 65Zn in either control or MITO-containing media. 65Zn release to equilibrium was then measured in unstimulated and mitogen-stimulated cells treated with hCT and hINS. hCT and hINS were added only during this final incubation due to the rapid response to peptide hormones. Bidirectional transmembrane flux coefficients were calculated using a closed two-compartment model. The hMLCs subjected to MITO stimulation demonstrated a 25% decrease in the fractional efflux coefficient (Kcm) and a 69% increase in the fractional influx coefficient (Kmc) compared with controls. Acute exposure to hINS resulted in a marked increase in Kmc with no significant change in Kcm. Acute exposure to hCT had effects qualitatively similar to those of MITO alone. Neither hormone significantly altered the transport of 65Zn when compared with stimulation with MITO alone.