Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors

Summary The partial dopamine receptor agonists SDZ 208-911 {N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamide|, and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (–80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (–32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ 208–912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208–912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (³H-spiperone) receptor site and somewhat lower affinity for the 5-HT_1A (3H-8-OH-DPAT) receptor site. SDZ 208–911 and SDZ 208–912 also showed high affinities for central alpha₂ (³H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208–911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208–911, SDZ 208-912 and terguride reduced the activity to 10–20% of controls with SDZ 208–912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called jerking behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208–911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208–912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses. SDZ 208–912 and SDZ 208–911 completely reversed the inhibition of firing rate produced by d-amphetamine, while SDZ 208–912 partially (81 %) reversed the inhibitory effects of apomorphine. It is concluded that all three amino-ergolines possess partial dopamine receptor agonistic effects with SDZ 208–911 and terguride displaying a similar intrinsic efficacy (in certain models approximately 50% of that of quinpirole or apomorphine). On the other hand, SDZ 208–912 displays a very low intrinsic efficacy, detectable only in the electrophysiological model and in reserpinized rats. The results are discussed in relation to the potential clinical utility of these compounds as antipsychotic agents. Send offprint requests to K. Svensson at the above address     

Effects of chronic administration of the D1 receptor partial agonist SKF 77434 on cocaine self-administration in rhesus monkeys

RATIONALE: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. OBJECTIVE: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. METHODS: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. RESULTS: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. CONCLUSIONS: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.     

Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats

Fluctuations in extracellular dopamine and DOPAC levels in nucleus accumbens septi (NAS) were monitored in 1-min microdialysis samples taken from rats engaged in intravenous cocaine self-administration. For four rats the dose per injection was fixed at 2.0 mg/kg; for four others the dose per injection was varied irregularly, from one response to the next, between three levels (0.5, 1.0 and 2.0 mg/kg). Regardless of the dosing regimen, extracellular dopamine levels were tonically elevated by 200–800% within the cocaine self-administration periods, fluctuating phasically within this range between responses. In the fixed dose condition, the phasic increases following each injection (and the phasic decreases preceding them) averaged approximately 50% of the mean tonic elevation. Phasic fluctuations in dopamine levels remained time-locked to lever-presses even when response rate was irregular, because of the variable dose condition. In the variable dose condition greater increases in dopamine and longer inter-response times followed injections of the higher doses; dopamine fluctuations were consistent with the multiple-infusion pharmacokinetics of cocaine. DOPAC levels showed a slow tonic depression during cocaine self-administration, but individual injections were not associated with discernible phasic fluctuations of DOPAC. These data are consistent with the hypothesis that falling dopamine levels trigger successive responses in the intravenous cocaine self-administration paradigm, but inconsistent with the notion that extracellular dopamine levels are depleted at the times within sessions when the animal initiates drug-seeking responses.     

Effects on cocaine and food self-administration of (+)-HA-966, a partial agonist at the glycine/NMDA modulatory site, in rats

Rationale (+)-HA-966, a partial agonist at the glycine/NMDA modulatory site, significantly reduced IV cocaine self-administration in a fixed-ratio (FR) schedule. Since this effect was observed studying only one dose of cocaine and considering the characteristic bell-shaped curve generated by cocaine in self-administration studies under FR schedules, the precise nature of the effect is not clear.Objective To identify the nature of the effect of (+)-HA-966 on cocaine self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement.Methods Rats were prepared with IV catheters and trained to self-administer cocaine. In the first experiment three doses of (+)-HA-966 (10, 30 and 100 µg/5 µl ICV) were evaluated for their effects on 0.25 mg/0.1 ml per infusion cocaine self-administration on FR1 with 20-s time-out (TO). Next, 30 µg/5 µl ICV (+)-HA-966 was evaluated as pretreatment on a complete dose-response for cocaine self-administration. In a third experiment the effect of the same dose was evaluated on cocaine or food self-administered on the PR schedule.Results (+)-HA-966 at doses of 10 or 30 µg reduced cocaine self-administration in an FR1 schedule during the first hour interval of the 2-h session. This partial agonist at the glycine/NMDA modulatory site also reduced the number of injections of cocaine earned during the first hour of the session but not the final ratio reached under a PR schedule. However, under this schedule (+)-HA-966 also reduced operant responding for food reinforcement.Conclusions (+)-HA-966 reduced responding maintained by cocaine or food. Whether (+)-HA-966 induces a general motivational rather than a performance deficit, leading to reduced responding for either cocaine and food, is unclear.     

Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat

The effect of the selective D1 antagonist, SCH 23390, and the selective D2 antagonist, spiperone, was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Both SCH 23390 and spiperone pretreatment increased responding up to doses of 10.0 µg/kg, and decreased responding at higher doses. Since rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy, behavior maintained by cocaine was also investigated under a progressive-ratio schedule. The breaking point obtained under this schedule is used as a measure of the efficacy of the reinforcer and this value is not exclusively determined by response rate. With the progressive-ratio schedule, both SCH 23390 and spiperone produced dose-dependent decreases in the highest ratio completed in rats self-administering cocaine. The results obtained using the FR 5 and progressive-ratio schedules suggest that both D1 and D2 receptors are involved in mediating the reinforcing effects of cocaine.     

Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans

Rationale: Data in laboratory animals suggest that D₁ receptor agonists may have potential utility for the treatment of cocaine abuse. Objective: The effects of ABT-431, a selective agonist at the dopamine D₁ receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. Method: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4 mg IV) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus $5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. Results: ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of “High,”“Stimulated,” dose liking, estimates of dose value, “Quality,” and “Potency.” Furthermore, there was a trend for ABT-431 (4 mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. Conclusions: These data suggest that D₁ agonists may have potential utility for the treatment of cocaine abuse. Received: 18 August 1998/Final version: 16 October 1998     

Effects of gabapentin on cocaine self-administration, cocaine-triggered relapse and cocaine-enhanced nucleus accumbens dopamine in rats

Gabapentin is a gamma-aminobutyric acid (GABA) analogue, with GABAmimetic pharmacological properties. Gabapentin is used for the treatment of seizures, anxiety and neuropathic pain. It has been proposed that gabapentin may be useful in the treatment of cocaine dependence. However, clinical trials with gabapentin have shown conflicting results, while preclinical studies are sparse. In the present study, we investigated the effects of gabapentin on intravenous cocaine self-administration and cocaine-triggered reinstatement of drug-seeking behavior, as well as on cocaine-enhanced dopamine (DA) in the nucleus accumbens (NAc). We found that gabapentin (25-200mg/kg, i.p., 30min or 2h prior to cocaine) failed to inhibit intravenous cocaine (0.5mg/kg/infusion) self-administration under a fixed-ratio reinforcement schedule or cocaine-triggered reinstatement of cocaine-seeking behavior. In vivo microdialysis showed that the same doses of gabapentin produced a modest increase ( approximately 50%, p<0.05) in extracellular NAc GABA levels, but failed to alter either basal or cocaine-enhanced NAc DA. These data suggest that gabapentin is a weak GABA-mimic drug. At the doses tested, it has no effect in the addiction-related animal behavioral models here tested. This is in striking contrast to positive findings in the same animal models shown by another GABAmimetic - gamma-vinyl GABA (see companion piece to present article).     

Ventral pallidal extracellular fluid levels of dopamine, serotonin, gamma amino butyric acid, and glutamate during cocaine self-administration in rats

RATIONALE: Dopamine innervation of the nucleus accumbens is thought to have a major role in the biological processes underlying cocaine self-administration. Recent data suggest that dopamine innervation of the ventral pallidum (VP) may also play an important role. OBJECTIVES: This experiment was initiated to assess extracellular fluid levels of dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), and glutamate (Glu) in the VP of rats self-administering cocaine using in vivo microdialysis. METHODS: Rats were implanted with intravenous jugular catheters and a microdialysis probe guide cannula into the VP and trained to self-administer (SA) three different doses of cocaine during each daily session. Other rats (yoked rats) were surgically prepared in identical fashion and received vehicle infusions during microdialysis sessions when the SA rat to whom they were yoked produced cocaine infusions. When stable baselines of self-administration were obtained, microdialysates were collected during two consecutive daily self-administration sessions. Neurotransmitter levels were measured using HPLC with electrochemical (DA and 5-HT) or fluorescence detection (GABA and Glu). RESULTS: In SA rats, extracellular fluid levels of DA [DA]e and 5-HT [5-HT]e were elevated throughout the session and levels of Glu [Glu]e showed small increases at a few isolated time points during the session. The increases in [DA]e and 15-HT]e were dose-dependent. Extracellular fluid levels of GABA [GABA]e were unchanged, as were levels of all four neurotransmitters in the yoked rats. CONCLUSIONS: These data support a potential role for DA and 5-HT innervations of the VP in intravenous cocaine self-administration.     

Involvement of dopamine in the aversive stimulus properties of cocaine in rats

Previous studies of cocaine self-administration have demonstrated central dopaminergic involvement in cocaine's positive reinforcing properties. The present study reports the ability of pimozide, a dopamine receptor antagonist, to attenuate a conditioned taste aversion induced by repeated injections of cocaine. Rats placed on a daily water deprivation schedule were subsequently presented with a novel saccharin taste in their drinking fluid immediately followed by administration of four 9 mg/kg injections of cocaine spaced at 20 min intervals. These animals exhibited a reduction in saccharin intake on subsequent presentations. Animals pretreated with pimozide 90 min prior to the saccharin-cocaine pairings failed to show this reduction. In a second experiment using an identical procedure, repeated injections of lithium chloride were shown to induce a CTA both in pimozide-pretreated and control animals. The results of these two experiments are consistent with the notion that a functional relationship may exist between neurochemical mechanisms underlying both the aversive (CTA-inducing) and positive reinforcing properties of self-administered drugs such as cocaine.     

Time-dependent recovery from the effects of 6-hydroxydopamine lesions of the rat nucleus accumbens on cocaine self-administration and the levels of dopamine in microdialysates

Rationale Neurotoxin induced lesions of dopamine-releasing neurons that innervate the nucleus accumbens (NAcc) alter cocaine self-administration. In addition, elevated extracellular levels of NAcc dopamine (DA) are thought to be central to the biological mechanisms that underlie this behavior.Objectives This study assessed the long-term effects of 6-hydroxydopamine (6-OHDA) induced lesions of the NAcc on cocaine self-administration and the dialysate levels of dopamine ([DA]_d) in this structure to determine if recovery of drug intake was correlated with the DA response.Methods Rats implanted with jugular catheters and bilateral cannulas were trained to self-administer cocaine and subsequently received bilateral intracranial micro-injections of 6-OHDA or vehicle into the NAcc. The levels of DA and cocaine were determined in microdialysates of the NAcc collected during experimental sessions 6–7, 14–16, 29–30, and 44–46 days post-treatment.Results The 6-OHDA induced lesions significantly reduced cocaine self-administration for 3 weeks while vehicle treatment had a moderate effect for the first several days. Cocaine-induced increases in NAcc [DA]_d did not return to sham/vehicle treated control levels for 6 weeks in the lesioned group and DA content in the NAcc was 46% of control at 44 days post-lesion.Conclusions Although dopaminergic lesions of the NAcc produced profound effects on cocaine self-administration, responding recovered to control levels before cocaine-induced increases in NAcc [DA]_d while content of DA in the NAcc did not recover. These data suggest that the plasticity of neuronal systems in the NAcc related to cocaine self-administration and their response following 6-OHDA lesions is more complex than restoration of DAergic tone.     

Evidence for partial agonist properties of daltroban (BM 13,505) at TP receptors in the anæsthetized open-chest rat

We sought to determine whether the intrinsic pulmonary hypertensive activity of the purported thromboxane A₂/prostanoid (TP) receptor antagonist, daltroban, was mediated by TP receptors, using the high efficacy TP receptor agonist, U-46619, and the silent TP receptor antagonist, SQ 29,548. In pentobarbitone-anæsthetized, open-chest rats (n = 4–10 per group), non-cumulative injections of U-46619, dose-dependently increased mean pulmonary arterial pressure (MPAP) with an ED₅₀ (geometric mean with 95% confidence limits in parentheses) of 1.4 (1.1– 2.3) μg/kg i.v.. Daltroban increased MPAP in a bell-shaped manner, with an apparent ED₅₀ [29 (21–35)μg/kg i.v.] being 21 fold less potent than that of U-46619. The maximal pulmonary hypertensive responses evoked by daltroban represented about half those induced by U-46619 (25.4 ± 1.0 vs. 12.7 ± 2 mmHg; P < 0.05 between groups). The TP receptor antagonist SQ 29,548 fully antagonized increases in MPAP evoked by equihypertensive doses of U-46619 (1.25 μg/kg) or daltroban (80 μg/kg). Further experiments were carried out to determine whether daltroban antagonized the pulmonary hypertensive responses evoked by the high efficacy agonist, U-46619, or by itself as receptor theory would predict for a partial agonist. Daltroban (10–2500 μg/kg) antagonized, although not fully, U-46619 (20 μg/kg)-evoked pulmonary hypertensive responses, since prominent intrinsic pulmonary hypertensive effects of daltroban were observed in the same range of doses. Furthermore, in contrast to U-46619 (1.25 μg/kg), daltroban (80 μg/kg) failed to evoke a second pulmonary hypertensive response following a previous injection, as would be expected for a partial agonist. Collectively, the results strongly suggest that daltroban behaves as a partial agonist at TP receptors in the pulmonary vascular bed of the rat in vivo.     

Psychopharmacological responsiveness to the dopamine agonist quinpirole in normal weanlings and in weanling offspring exposed gestationally to cocaine

The behavioral responsiveness to challenge doses of the D₂ agonist quinpirole was examined in 21-day-old normal offspring (experiment 1) as well as offspring exposed gestationally to cocaine (experiment 2). In both experiments weanling rats received a subcutaneous injection of 0 (0.9% saline), 0.04, 0.08, 0.5, or 1.0 mg/kg/3 cc of the D₂ agonist quinpirole and were placed in a divided glass testing apparatus containing either a dish of wet mash plus a food pellet or wood block (experiment 1) or both a food pellet and a wood block (experiment 2). Behaviors were recorded for 5 min via time-sampling at 30 and 60 min post-injection. In experiment 1 the three highest doses of quinpirole increased the amount of forward locomotion, rearing, sniffing and probing, as well as increasing directed oral movements at both the wood block and food pellet; in general these findings are reminiscent of those reported previously in adult animals. In experiment 2, cocaine-exposed weanlings exhibited an increased sensitivity to the stimulating effects of a low dose of the D₂ agonist for forward locomotion and rearing as well as an increase in the overall incidence of sniffing behavior and chewing on food pellets. These data provide psychopharmacological evidence that the increase in striatal D₂ binding previously observed in weanling offspring exposed gestationally to cocaine (Scalzo et al. 1990) may be associated with an increased behavioral sensitivity to the D₂ agonist quinpirole.     

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.     

Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats

Rationale  Dopamine D2-like partial agonists such as aripiprazole have received some attention as potential pharmacotherapies for the treatment of psychostimulant addiction. However, the preclinical evaluations so far have focused on acute effects of aripiprazole. Objectives  We tested the hypothesis that aripiprazole, both as acute and as chronic treatment, would preferentially decrease cocaine self-administration while sparing behavior maintained by a natural reinforcer, resulting in a shift in the allocation of behavior from cocaine-taking towards the alternative reinforcer. Materials and methods  Rats were trained to self-administer intravenous cocaine in a concurrent choice procedure, with a palatable food as the competing reinforcer, under a fixed ratio (FR) 1 FR 5 chain schedule. Aripiprazole was then administered as continuous infusion by osmotic minipumps for 5 days, during which performance in the choice procedure was assessed daily. Results  An intermediate dose of aripiprazole decreased cocaine self-administration and shifted the cocaine choice curve to the right as an acute treatment. However, as a chronic treatment, aripiprazole failed to decrease cocaine self-administration or cocaine choice, despite a dose-dependent decrease in overall response rates and food-maintained behavior. Conclusions  Our results confirm and extend earlier findings and indicate that acute administration of aripiprazole can decrease cocaine self-administration. However, based on the present data, chronic treatment with aripiprazole does not show much promise as a potential pharmacotherapy for cocaine addiction. Both acute and chronic treatment data are in agreement with published clinical findings, suggesting that the concurrent choice procedure in rats has predictive validity of efficacy in humans.     

The purported dopamine agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) acts as a nonselective α-adrenoceptor agonist in inducing hypertension,hypomotility and hypothermia in the rat

Following peripheral administration the purpoted dopamine (DA) agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) was shown to increase the diastolic blood pressure of pithed rats and to decrease rat motility and rectal temperature. Dose-effect relationships were established and half-maximal effective doses for the hypertensive and hypothermic response to DPI were calculated to be 4·4 nmol/kg i.v. and 2.0 μmol/kg i.p., respectively. Pretreatment with various antagonists revealed that both α₁- and α₂-adrenergic mechanisms were responsible for the DPI-induced hypertension, hypomotility and hypothermia, indicating that DPI acts as a non-selective α-adrenoceptor agonist. Qualitatively the DPI-induced effects were found to correlate well with those reported for its structural analogue clonidine, thus suggesting a similar mechanism of action for these agents. DA receptor antagonists appeared to lack inhibitory potency towards any of DPI-elicited responses. The results do not therefore support the designation of DPI as a DA receptor agonist.     

Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats

The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural subtrates are responsible for the reinforcing actions of these two drugs.     

Effects of the calcium antagonist isradipine on cocaine intravenous self-administration in rats

The effect of isradipine, a dihydropyridine calcium antagonist, on cocaine intravenous self-administration in rats was investigated. Administration of (±)isradipine (1.25–5 mg/kg SC) 2 h before the cocaine self-administration session induced a significant and dose-dependent increase in the number of coacine injections with respect to basal values. This effect was sterospecific, with the (+) form of isradipine being active, while the (–) stereoisomer was ineffective. These results suggest that isradipine antagonizes the rewarding properties of cocaine, possibly by inhibiting those dopaminergic systems related to reward mechanisms. These results further indicate a possible use of isradipine, or structurally similar compounds, in the treatment of cocaine related disorders.     

On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine.

The role of ascending noradrenergic (NA) and dopaminergic (DA) systems in intravenous self-administration of cocaine in rats was investigated by examining the effects of 6-hydroxydopamine-induced lesions of these systems on responding for the drug on a FR-1 schedule of reinforcement. Lesions of the dorsal and ventral NA bundles that reduced hippocampal-cortical NA by 96% and hypothalamic NA by 72% failed to have any effects on responding for cocaine. Lesions of the nucleus accumbens that reduced the DA content of this nucleus by 90% resulted in a significant and long-lasting (15 days) reduction in self-administration of cocaine. Apomorphine self-administration was not affected in the same animals. Identical lesions of the n accumbens had only transient (2-3 days) effects on food-reinforced operant responding, suggesting that the prolonged disruption of cocaine self-administration was not the result of motor deficits. The results are discussed with reference to the possibility that DA terminals in the n accumbens may mediate some of the positive reinforcing properties of cocaine.     

Self-administration of the dopamine D3 agonist 7-OH-DPAT in rhesus monkeys is modified by prior cocaine exposure

Cocaine self-administration was compared with responding maintained by the dopamine D₃ agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) in rhesus monkeys. In the first experiment, monkeys (n=3) with an extensive cocaine history responded under a fixed-interval (FI) 5-min schedule of IV cocaine (0.03 mg/kg per injection) presentation, during daily 4-h sessions. When responding was stable, dose-response curves were determined for cocaine (0.01-0.3 mg/kg per injection) and 7-OH-DPAT (0,001–0.1 mg/kg per injection); each dose was available for at least five consecutive sessions. When substituted for the baseline dose of cocaine, other doses of cocaine and 7-OH-DPAT maintained rates higher than responding maintained by saline injections, in all monkeys. 7-OH-DPAT maintained response rates equal to or higher than rates of cocainemaintained responding in all monkeys. In a second experiment, acquisition of 7-OH-DPAT self-administration was evaluated in a group of cocaine-navie monkeys (n=3). Various doses of 7-OH-DPAT (0.003–0.03 mg/kg during daily 4-h sessions. After 10–13 sessions, 7-OH-DPAT self-administration could not be trained in any cocaine-naive monkey. When cocaine was made available to these monkeys, responding was reliably maintained within one to four sessions and the schedule was gradually increased to FI 5-min. After stable responding under an FI 5-min schedule of 0.03 mg/kg per injection cocaine presentation, 7-OH-DPAT (0.01 mg/kg per injection) was again made available to two of the monkeys, and maintained responding at rates higher than saline. To determine better whether a history of responding maintained by another reinforcer would result in high rates of 7-OH-DPAT self-administration, two cocaine-naive monkeys were trained to respond under an FI 5-min schedule of food presentation. Substituting 7-OH-DOAT (0.003–0.03 mg/kg per injection) for food resulted in very low rates of responding. Taken together, these results suggest that despite comparable reinforcing effects in cocaine-substitution studies, 7-OH-DPAT and cocaine differ in their rate of acquisition, perhaps indicating a lower abuse liability for 7-OH-DPAT.     

The dopamine D2 partial agonist and antagonist terguride decreases heroin self-administration on fixed- and progressive-ratio schedules

Dopamine partial agonists have been suggested to be potential therapeutic candidates for pharmacological intervention in drug addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are hypothesized to behave as functional antagonists in conditions of high dopaminergic tone. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the dopamine D₂ receptor, on intravenous heroin self-administration on fixed- and progressive-ratio schedules of reinforcement. The effects of terguride on oral sweet solution (4% sucrose) self-administration on a fixed-ratio schedule were also tested. Terguride dose-dependently decreased heroin self-administration on the fixed-ratio schedule and decreased the maximum number of responses for heroin self-administration on a progressive-ratio schedule. In contrast, terguride did not significantly affect oral sucrose self-administration. These data suggest that terguride may represent a novel pharmacological strategy for the treatment of opiate addiction.