Response of nicotine self-administration in the rat to manipulations of mu-opioid and γ-aminobutyric acid receptors in the ventral tegmental area

Rationale: The mesolimbic dopamine system has been implicated in the reinforcing effects of nicotine, a drug which appears to act at least in part through the ventral tegmental area (VTA). Other neuronal elements in the VTA are important in drug reward. In particular, mu opioid receptors in the VTA have been shown to influence cocaine reinforcement. Objective: The aim of this study was to test whether the mu opioid receptors in the VTA also regulate the intake of nicotine. Methods: This research was carried out with animals trained to self-administer nicotine or cocaine, or to respond for food. Mu receptors were targeted with the selective agonist [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) and γ-aminobutyric acid (GABA) receptors with the selective agonists baclofen and muscimol; each of these compounds was delivered by microinfusion into the VTA. Results: The mu-selective agonist DAMGO, tested over a dose range of 0.005–0.05 μg, had an effect at the highest dose only, where it produced a reduction in self-administration maintained by doses of either 10 μg/kg or 30 μg/kg per infusion of nicotine. Intra-VTA microinfusions of DAMGO did not reinstate extinguished responding previously established for nicotine, nor did they have prominent effects on operant behavior maintained by food. In contrast to the overall limited effects of DAMGO on nicotine self-administration, the GABA agonists muscimol and baclofen each reduced nicotine self-administration substantially when delivered into the VTA, whereas they were less effective against cocaine self-administration. Conclusions: The lesser effect of DAMGO microinfusions in the VTA on nicotine than cocaine self-administration is associated with the opposite efficacy of GABA agonists. These findings suggest that nicotine and cocaine differentially activate circuitry in which mu receptors are situated, especially GABAergic elements. Received: 20 October 1998 / Final version: 24 November 1999     

Manipulations of mu-opioid and nicotinic cholinergic receptors in the pontine tegmental region alter cocaine self-administration in rats

Rationale: The pedunculopontine tegmental nucleus (PPTg) has been implicated in drug reward, particularly in the development of dependence. However, little is known of the receptor systems within this nucleus which might be involved. Furthermore, some research suggests that the PPTg may also be part of the neuronal circuitry involved in established drug-taking behavior. Objective: The objective of these experiments was to examine the role of mu-opioid and nicotinic cholinergic mechanisms in the PPTg in cocaine self-administration. Methods: Microinfusions of mu-opioid and nicotinic receptor selective compounds were made into the PPTg of rats trained to self-administer cocaine intravenously, in the vicinity of cholinergic cells which are known to project to the midbrain dopamine neurons of the ventral tegmental area (VTA). Results: The mu-opioid selective agonist DAMGO, tested at doses of 0, 0.05 and 0.5 μg, produced a dose-related reduction in the number of cocaine infusions obtained during the 1-h self-administration sessions. The mu-selective antagonist CTOP (0–2 μg) and nicotine (0–10 μg) did not produce significant changes in cocaine self-administration. Microinfusions of the nicotinic antagonist dihydro-β-erythroidine (0–30 μg) produced a small but significant increase in cocaine-maintained responding. Conclusions: These data show that mu-opioid mechanisms in the PPTg can influence cocaine self-administration markedly. Moreover, the data demonstrate that PPTg circuitry can influence drug reward in already-established drug-reinforced behavior, as well as during the development of dependence (as shown by previous research). Received: 30 November 1998 / Final version: 25 March 1999     

Effects of drugs on food- and cocaine-maintained responding III: Dopaminergic antagonists

 The effects of three dopamine (DA) antagonists (SCH23390, pimozide, and chlorpromazine), with various degrees of selectivity for D₁ and D₂ receptors, and an agonist (the cocaine analog, CFT) were studied on responding maintained under a multiple fixed-ratio (FR) 30 food, FR30 cocaine (1–100 μg/kg per injection) delivery, with an interposed 10-min time-out (TO), schedule in rhesus monkeys. The effects of each drug depended upon the unit dose of cocaine. With an intermediate (10 μg/kg per injection) unit dose of cocaine, each antagonist decreased rates of responding maintained by either event in a dose-related manner. At higher (56–100 μg/kg per injection) unit doses of cocaine, antagonists generally increased and then decreased both food- and cocaine-maintained responding in a dose-related manner. These increases appeared to result from the blockade of non-specific rate-decreasing effects of self-administered cocaine, questioning their relevance to the reinforcing effects of cocaine. The results failed to support a role for pharmacological selectivity in this rate-decreasing effect of cocaine, as both D₁ and D₂ antagonists were able to reverse the effect. In contrast, CFT decreased cocaine-maintained responding at doses less than those that decreased food-maintained responding, and failed to shift the cocaine dose-effect function to the left. These results, together with previous work, suggest that agonists can selectively decrease drug-seeking behavior. Received: 5 January 1996 / Final version: 5 August 1996     

Cocaine effects in the ventral tegmental area: Evidence for an indirect dopaminergic mechanism of action

Summary Behavioral studies have implicated central dopaminergic systems, especially the ventral tegmental area of Tsai (VTA), in the mediation of the reinforcing effects of drugs of abuse such as cocaine. A brain slice preparation of the VTA was used to assess the direct effects of cocaine on the spontaneous activity of dopamine-type neurons. When superfused with 1–10 μM cocaine the firing rate of spontaneously active VTA neurons was decreased, with no corresponding change in spike height. While there was a considerable variability in the response to a given concentration of cocaine among the individual units, every cell inhibited by dopamine was also inhibited by cocaine. The local anesthetic lidocaine had variable effects on firing rate, but never potentiated the inhibitory effects of dopamine. Inhibitory responses to either dopamine or cocaine were blocked by the specific D2 dopamine receptor antagonist sulpiride. Small concentrations of cocaine (0.1–0.5 μM), which by themselves had little or no effect on spontaneous activity, potentiated the inhibitory effect of exogenously applied dopamine. Furthermore, the inhibitory action of apomorphine on spontaneous activity in the VTA was not potentiated by cocaine. These observations suggest that in low concentrations, cocaine can act as a dopamine reuptake inhibitor in the VTA, and that the resultant increase in extracellular dopamine acts upon dopamine autoreceptors to inhibit cellular activity. Send offprint requests to T. V. Dunwiddie     

Prejunctional α2A-autoreceptors in the human gastric and ileocolic arteries

This study was undertaken to determine the subtype of prejunctional α₂-autoreceptors in human blood vessels. Segments of gastric and ileocolic arteries were incubated with [³H]noradrenaline and subsequently perifused with modified Krebs-Henseleit solution containing cocaine (12 μM). Five periods of electrical stimulation (S₁–S₅) were applied (1 Hz, 1 ms, 50 V for 1 min). Concentration-response curves for the facilitatory effect of eight α-adrenoceptor antagonists [rauwolscine, 2-[2-(2-methoxy-1,4-benzodioxanyl)] imidazoline (RX821002), yohimbine, phentolamine, idazoxan, 2-(2’,6’-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxan (WB4101), spiroxatrine and prazosin] were determined. All antagonists enhanced the stimulation-evoked overflow of tritium, indicating the existence of α₂-autoreceptors. The EC _30% values of the antagonists (concentrations that increased the evoked overflow of tritium by 30%) were taken as a measure of affinity to the autoreceptors. Correlations between the pEC _30% values obtained in the present study and the pK _i values of the same antagonists at cloned human α_2A-, α_2B-, α_2C-adrenoceptors expressed in Chinese hamster lung cells and at α_2D-adrenoceptors in the rat submaxillary gland or the bovine pineal gland showed that the α₂-autoreceptors in the human gastric and ileocolic arteries resemble most closely the α_2A-subtype. Received: 6 April 1998 / Accepted: 4 May 1998     

Characterization of the discriminative stimulus effects of buprenorphine in pigeons

Rationale: The pedunculopontine tegmental nucleus (PPTg) has been implicated in the self-administration of drugs, particularly nicotine, which acts directly through the PPTg in addition to targeting midbrain dopamine neurons. The direct action of nicotine in PPTg may be through GABAergic mechanisms that have been shown to influence nicotine self-administration preferentially compared to cocaine. Objective: The purpose of these experiments was to examine several pharmacological manipulations that alter neuronal activity in the PPTg for their specificity or generality in nicotine versus cocaine reinforcement. Methods and results: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the muscarinic agonist carbachol (0.1–1.0 μg), the μ opioid agonist DAMGO (0.005 and 0.05 μg), tetrodotoxin (5 ng) and neostigmine (0.5 nmol) each reduced the self-administration of nicotine and cocaine maintained on an FR5 schedule of reinforcement. The muscarinic antagonist scopolamine (0.1–1.0 μg) and the opioid antagonist CTOP (1 μg) did not affect self-administration, but reversed the effects of the respective agonist when co-administered with it. Carbachol and DAMGO were also tested in self-administration maintained on a progressive-ratio schedule; each agonist again reduced both nicotine and cocaine self-administration. Conclusions: PPTg manipulations are able to alter established self-administration of nicotine, which acts at the level of the ventral tegmental area and the PPTg itself, and cocaine, which acts through the mesolimbic dopamine system. These data suggest that the PPTg is an important substrate in drug dependence. Electronic Publication     

Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats

Abstract Rationale. Previous work from our laboratory indicated that Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA) and that 5-HT₃ antagonists will inhibit EtOH-stimulated somatodendritic release of dopamine within the VTA. Objectives. The objective of this study was to use the intracranial self-administration procedure to determine the involvement of 5-HT₃ receptors in mediating the reinforcing effects of EtOH within the VTA, and to increase our understanding of central nervous system mechanisms involved in the rewarding effects of EtOH. Methods. Adult female Wistar rats were stereotaxically implanted with guide cannulae aimed at the posterior VTA. After 1 week, rats were placed into standard two-lever experimental chambers for a total of seven sessions (4-h sessions separated by 48 h) and allowed to self-administer vehicle alone, a 5-HT₃ antagonist alone, 200 mg% EtOH alone, or combinations of 200 mg% EtOH with different concentrations of a 5-HT₃ antagonist (n=6–9 per group). Results. Throughout all seven sessions, Wistar rats self-infused more 200 mg% ETOH (25±5 infusions) than vehicle (5±4 infusions) or 5-HT₃ antagonist (6±4 infusions) (P<0.05), and responded significantly more (P<0.05) on the active than inactive lever (e.g., 50±12 vs 12±8 responses in session 1). Co-administration of 50 μM or 100 μM ICS 205,930 with 200 mg% EtOH completely prevented the acquisition and maintenance of EtOH self-infusion into the posterior VTA. Similarly, co-administration of either 25–100 μM LY-278–584 or 10–100 μM zacopride with 200 mg% EtOH completely blocked EtOH-maintained intracranial self-administration behavior. Conclusions. The results of this study suggest that the reinforcing effects of EtOH within the posterior VTA of Wistar rats require activation of local 5-HT₃ receptors. Electronic Publication     

Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule

 The present study examined the reinforcing effects of cocaine and heroin, alone and combined, in rhesus monkeys (n=4) responding under a progressive-ratio (PR) schedule. The PR schedule consisted of five components, each made up of four trials (i.e., 20 trials total), with each trial in a component having the same response requirement. The initial response requirement was fixed-ratio (FR) 120, which doubled across components to a maximum of FR1920. A trial ended with an injection or the expiration of a 15-min limited hold and the inter-trial interval was 30 min. Cocaine dose-response functions (13–400 μg/kg per injection) for injections/session were monophasic, i.e., increased with dose until responding reached an asymptote or a peak. Heroin dose-response functions (1.6–100 μg/kg per injection) for injections/session were biphasic functions, i.e., increased to a peak and then decreased, whereas heroin dose-response functions for response rate were monophasic and reached an asymptote. When cocaine (1.6–200 μg/kg per injection) was combined with heroin (0.4–6.4 μg/kg per injection), low doses of cocaine (3.2–25 μg/kg per injection) and heroin (0.4–1.6 μg/kg per injection) that did not maintain behavior when tested alone did so when tested in combination. Combination with heroin resulted in a leftward shift in the cocaine dose-response functions, indicating that heroin increased the potency of cocaine as a reinforcer. This heroin-induced increase in cocaine′s reinforcing potency may be a contributing factor to abuse of cocaine and heroin combinations (i.e., ”speedballs”) in humans. However, maximum injections/session for cocaine combined with heroin were not different from cocaine alone, suggesting that the reinforcing efficacy of combinations of cocaine and heroin were not higher than that of cocaine alone. Received: 14 January 1997 / Final version: 25 March 1997     

Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine

Rationale: The growing abuse of cocaine combined with morphine-like opiates (”speedballs”) in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in subjects trained to discriminate a relatively high dose of cocaine from vehicle. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, training rats to discriminate a relatively low dose of cocaine may influence its interactions with opioid agonists. Objectives: The objectives of this study were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the interactions between cocaine and either the μ opioid agonist morphine or the κ opioid agonist U50,488. Methods: Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which selected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine. Results: In substitution tests, cocaine was 2.9 times more potent under the low- than the high-dose training condition. Morphine substituted fully for cocaine in the majority of subjects trained to discriminate the low, but not the high, dose of cocaine. U50,488 engendered mainly saline-lever responses under both training conditions. In pretreatment studies, morphine enhanced and U50,488 attenuated the discriminative stimulus effects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments. Conclusions: The results demonstrate that cocaine–opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of μ and κ opioid receptors in modifying the discriminative stimulus effects of cocaine. Received: 9 December 1998 / Final version: 24 June 1999     

Contrasting effects of clonidine and diazepam on tests of working memory and planning

Theα ₂ adrenoceptor has recently been implicated in working memory (WM), a function dependent on the integrity of the prefrontal cortex. Using a double-blind, placebo-controlled design, the present investigation examines the effects of two doses (1.5 μg/kg and 2.5 μg/kg) of the mixedα ₁/α ₂ adrenoceptor agonist clonidine (CLO) on performance of various computerised tests of WM and planning in healthy, young volunteers. These are compared to the effects produced by two doses (5 mg and 10 mg) of diazepam (DZP) on largely the same set of neuropsychological tests in a comparable set of subjects. Administration of CLO resulted in impulsivity of responding in a planning task, as well as differential dose-dependent effects on two analogous tests of spatial and visual WM. The nature of these effects were suggestive of mnemonic, rather than executive, dysfunction. Conversely, DZP produced specific deficits on tests of spatial WM and planning very similar to those seen following lesions to the frontal lobes. Therefore, these two sedative drugs produce doubly dissociable, dose-dependent effects on different aspects of cognitive function.     

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules

Rationale: Recent reports have indicated that the γ-aminobutyric acid (GABA)_B agonist baclofen attenuates the reinforcing effects of cocaine. Objectives: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. Methods: In the first series of experiments, three dose–response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FR1 schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 μg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. Results: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine- reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. Conclusion: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. Received: 22 July 1999 / Final version: 23 September 1999     

Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents

Rationale: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. Objectives: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3′-, 4′-, 3′,4′′- and 4′,4′′-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. Methods: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. Results: All of the compounds displaced [³H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([³H]nisoxetine) and serotonin ([³H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [³H]pirenzepine binding to muscarinic M₁ receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2–3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate IP saline from 29 μmol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4′-Cl-BZT, the cocaine discriminative-stimulus effects were shifted leftward by co-administration of the present BZT analogs. Conclusions: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers. Electronic Publication     

Celiprolol: agonist and antagonist effects at cardiac β1- and vascular β2-adrenoceptors determined under in vivo conditions in the rat

Celiprolol is a β-adrenoceptor antagonist which has desirable ancillary properties since it is relatively cardioselective and can exert direct vasodilator and bronchodilator effects. Here agonist and antagonist effects of celiprolol at cardiac β₁- and vascular β₂-adrenoceptors were determined under in vivo conditions in the rat. All experiments were carried out in catecholamine-depleted, pentobarbital anesthetized and vagotomized rats, placed under artificial respiration. I.v. administrations were madevia the femoral vein. Blood pressure was measured from the cannulated right carotid artery and heart rate was recorded with a cardiotachometer. Celiprolol (10 μg/kg to 1 mg/kg i.v.) produced dose-related increases in heart rate and decreases in mean carotid artery blood pressure which were of longer duration than those mediated by standard agonists of β₁-(isoprenaline) or β₂-(salbutamol) adrenoceptors respectively. Although the maximal increase in heart rate by celiprolol (110±4 beats/min, n=7) was approximately half that of isoprenaline (198±1 beats/min, n=5), isoprenaline acted at doses 200-fold lower than celiprolol. Betaxolol (0.03-0.3 mg/kg i.v.), a β₁-adrenoceptor antagonist, inhibited strongly and with similar potency the tachycardic effects of celiprolol (DR₁₀ = 45 μg/kg i.v.) as well as isoprenaline (DR₁₀ = 45 μg/kg i.v.). On the other hand, the hypotensive effects of celiprolol and salbutamol were antagonized markedly and with similar potency by ICI118,551, a relatively selective β₂-adrenoceptor antagonist (DR₁₀ = 15 and 25 μg/kg i.v. respectively). In rats pretreated with celiprolol (0.03 to 0.3 mg/kg i.v.), the heart rate dose-response curves to isoprenaline were shifted to the right of those determined in matched groups of vehicle-pretreated animals. In this respect, celiprolol was half as potent as betaxolol in blocking cardiac β₁-adrenoceptors. Furthermore, celiprolol also antagonized the hypotensive effects of salbutamol, but, in this respect, celiprolol was 90-fold less potent than ICI 118,551. In conclusion, these results clearly indicate that celiprolol has the ability of stimulating and blocking not only cardiac β₁- but also vascular β₂-adrenoceptors. The effects on cardiac β₁-adrenoceptors as well as the agonism of β₂-adrenoceptors are produced by similar doses of celiprolol. These doses are notably lower than those necessary to block β₂-adrenoceptors. Thus, this pharmacological profile, which has also been demonstrated in humans, indicates that celiprolol is a modulator of cardiac β₁-adrenoceptors with vascular β₂-adrenoceptor agonist properties. Received: 26 June 1996 / Accepted: 3 March 1997     

Blocking GABAA receptors in the anterior ventral tegmental area attenuates ethanol intake of the alcohol-preferring P rat

 The effect of blocking the A subtype of γ-aminobutyric acid (GABA_A)receptors in the anterior ventral tegmental area (VTA) on ethanol (EtOH; 10% v/v) and saccharin (SACC; 0.0125%) consumption was investigated in alcohol-preferring P rats. Picrotoxin (0.005, 0.01, 0.05 and 0.10 μg/0.5 μl) was injected into the VTA, and consumption of EtOH and SACC was assessed in two 2-h limited-access drinking paradigms (concurrent EtOH/ SACC access, and alternate-day-access to EtOH and SACC). Under concurrent-access conditions, the picrotoxin microinjections resulted in a 55 and 84% decrease in EtOH consumption at the 0.05 and 0.10 μg doses, respectively, compared with consumption following microinjections of vehicle solution (P<0.05). Saccharin intake was not significantly altered by picrotoxin. Under alternate-day-access drinking conditions, the picrotoxin microinjections resulted in dose-dependent decreases in EtOH consumption of 37–68%, with significant decreases following the 0.005, 0.05 and 0.10 μg doses (P<0.04). Saccharin intake was significantly reduced only at the 0.05 μg dose. The decrease in EtOH consumption after 0.10 μg picrotoxin was attenuated by co-administration of 0.01 μg muscimol. This dose of muscimol had no effect on EtOH consumption when injected alone. Intra-VTA injections of bicuculline (0.04 μg), another GABA_A antagonist, reduced EtOH intake, comparable to the reduction following 0.10 μg picrotoxin. Microinjections of 0.10 μg picrotoxin in regions outside the VTA failed to decrease EtOH intake. These results suggest that anterior VTA mechanisms regulating alcohol drinking behavior are under tonic GABA inhibition, mediated by GABA_A receptors. The results also suggest that different neural mechanisms are regulating voluntary EtOH and SACC drinking behaviors. Received: 25 November 1997 / Final version: 4 March 1998     

Adenosinergic modulation of 3α-hydroxy-5α-pregnan-20-one induced catalepsy in mice

  Rationale: Neurosteroid 3α, 5α THP, a positive allosteric modulator of the GABA_A receptor Cl^– ionophore complex, induces catalepsy-like dopamine antagonists, adenosine agonists or GABA agonists. Adenosine and dopamine receptors are co-localized on GABAergic neurons in the striatum and regulate GABA-mediated neurotransmission. Moreover, the antagonistic interactions between specific subtypes of adenosine and dopamine receptors are involved in motor depressant or motor stimulant effects of adenosine receptor agonists or antagonists, respectively. Such interaction may modulate neurosteroid-induced catalepsy. Objective: This study examined the modulation of 3α, 5α THP-induced catalepsy by adenosinergic agents. Methods: Catalepsy induced by 3α, 5α THP (2–8 μg, ICV) was assessed by bar test periodically up to 3 h in mice. Adenosine A₁, A_2A or A₃ receptor agonists or antagonists were given IP or ICV prior to 3α, 5α THP. Some animals received IP dopamine D₂ receptor agonist or antagonist 30 min prior to above combination treatment. Results: Adenosine A₁, A_2A, and A₃ receptor agonists potentiated, whereas adenosine A_2A receptor antagonists, but not A₁ antagonists, reversed 3α, 5α THP-induced catalepsy. These effects of adenosine agonists and antagonists were abolished by prior administration of bromocriptine, the dopamine D₂ receptor agonist and spiperone, the dopamine D₂ receptor antagonist, respectively. Conclusions: These findings suggest specific adenosine-dopamine receptor interaction in the striatum to modulate 3α, 5α THP-induced catalepsy. Received: 1 November 1998 / Final version: 5 January 1999     

Long-term effects of olanzapine,risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions

Rationale: D₁ dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). Objectives: The present study investigated the effects of a D₁ antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. Methods: Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0–10.0 μg/kg), SKF-38393 (0–3.0 mg/kg), and SKF-81297 (0–3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D₁ agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. Results: SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. Conclusions: While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs. Electronic Publication     

Histaprodifen, methylhistaprodifen, and dimethylhistaprodifen are potent H1-receptor agonists in the pithed and in the anaesthetized rat

Selective H₂- and H₃-receptor agonists, exhibiting an at least tenfold higher potency than histamine itself at the respective receptors, have been known for several years. Selective H₁-receptor agonists with a potency exceeding that of histamine have become available only recently; the most potent are methylhistaprodifen and dimethylhistaprodifen [N ^α-methyl- and N ^α,N ^α-dimethyl-2-(3,3-diphenylpropyl)histamine, respectively] with 3.4- and 2.4-fold higher potencies than histamine in vitro (in the guinea-pig ileum). The aim of the present study was to examine whether these compounds and the parent compound histaprodifen are potent H₁-receptor agonists in the pithed and in the anaesthetized rat. In pithed, vagotomized rats diastolic blood pressure was decreased by 2-(2-thiazolyl)ethanamine i.v. (which was used as a reference H₁-receptor agonist) and by histaprodifen, methylhistaprodifen, and dimethylhistaprodifen; the maximum decrease was about 45 mmHg for each compound, and the potencies, expressed as pED₅₀, the negative logarithm of the dose (in mole per kilogram body weight) eliciting a half-maximal response, were 7.23, 7.55, 8.43 and 8.12, respectively. The dose/response curves of the four compounds were shifted to the right to about the same extent by the H₁-receptor antagonist dimetindene (1 μmol/kg i.v.). The vasodepressor response was not affected by combined i.v. administration of the H₂- and H₃-receptor antagonists ranitidine and thioperamide, by combined i.v. administration of the α₁- and α₂-adrenoceptor antagonists prazosin and rauwolscine, and by the β-adrenoceptor antagonist propranolol i.v. but was attenuated by the inhibitor of NO synthase, N ^ω-nitro-l-arginine methyl ester i.v. In anaesthetized rats 2-(2-thiazolyl)ethanamine, histaprodifen, methylhistaprodifen and dimethylhistaprodifen i.v. also decreased diastolic blood pressure in a manner sensitive to dimetindene i.v. Our data show that histaprodifen and, in particular, methyl- and dimethylhistaprodifen are highly potent H₁-receptor agonists in vivo. Received: 3 September 1998 / Accepted: 23 October 1998     

Clonidine and diazepam have differential effects on tests of attention and learning

The noradrenergic system has repeatedly been implicated in the mediation of attentional processes. Using a double-blind, placebo-controlled design, the present investigation examines the effects of two doses (1.5 μg/kg and 2.5 μg/kg) of theα ₂ adreno ceptor agonist clonidine (CLO) on performance of various computerised tests of attention and learning in healthy, young volunteers. These are compared to the effects produced by two doses (5 mg and 10 mg) of diazepam (DZP) on largely the same set of neuropsychological tests in a comparable set of subjects. Both doses of CLO were found to impair performance of the RVIP test of sustained attention, while the higher dose alone improved visuo-spatial learning. Conversely, the higher dose of DZP produced profound deficits on visuo-spatial learning, and impaired attentional set-shifting. This study suggests a role for theα ₂ adrenoceptor in selective attention, and for the benzodiazepine receptor in specific cognitive processes mediated by discrete cortical regions.     

Effects of training dose and two- versus three-choice testing procedure on nicotine discrimination responding in humans

Rationale: Discrimination of a drug’s interoceptive stimulus effects often depends substantially on training and testing conditions. Objectives: We examined changes in nicotine discrimination behavior in humans as a function of lowering the training dose and of varying the discrimination testing procedure. Methods: Smokers and never-smokers (n=10 each) were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) and tested on generalization of discrimination responding across a range of doses from 0 to 20 μg/kg. Each subsequently learned to reliably discriminate progressively smaller doses of nicotine from placebo until his or her threshold dose for discrimination was identified (mean=2.7 μg/kg). A repeat testing of generalization responding across 0–20 μg/kg was then conducted, using placebo and the subject’s threshold dose as training doses. Generalization testing involved both two-choice and three-choice (novel response option) quantitative procedures. Results: A significant shift to the left was seen in nicotine-appropriate responding in the two-choice procedure when the nicotine training dose was lowered (i.e. from the first to the second test of generalization). In the three-choice procedure, however, there was no such leftward shift. Instead, in never-smokers, a flattening of nicotine-appropriate responding occurred with a lowering of the training dose, while novel-appropriate responding significantly increased. The subjective effects of ”head rush” and, in never-smokers only, ”jittery” also showed a shift to the left in their relationship with nicotine generalization dose when the training dose was lowered. Conclusions: These results confirm the importance of training and testing conditions on discrimination behavior and subjective drug responses within subjects and demonstrate the utility of the novel-response, three-choice procedure for assessing qualitatively different stimulus effects of novel drug doses. Received: 21 December 1998 / Final version: 11 March 1999     

Opioid enhancement of the discriminative stimulus effects of cocaine: evidence for involvement of μ and δ opioid receptors

 Previous research in squirrel monkeys has shown enhancement of the discriminative stimulus effects of cocaine by μ-opioid agonists, but not by the δ agonist BW373U86. To examine further the role of μ and δ receptor stimulation in the ability of opioid drugs to modulate the discriminative stimulus effects of cocaine, the present study assessed the effects of cocaine alone and combined with SNC 80, a selective high-efficacy δ agonist, and fentanyl, a selective high-efficacy μ agonist. Five adult male squirrel monkeys were trained to discriminate IM injections of 0.3 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. Cumulative doses of cocaine (0.03–1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%, with a decrease in response rate observed at 1.0 mg/kg. Cumulative doses of SNC 80 (0.03–1.0 mg/kg) or fentanyl (0.001–0.01 mg/kg) resulted in a maximum of 22% and 48% drug-lever responding, respectively, accompanied by pronounced decreases in response rate. Administration of either SNC 80 (0.1–1.0 mg/kg) or fentanyl (0.001–0.01 mg/kg) prior to cumulative doses of cocaine produced dose-dependent leftward shifts in the cocaine dose-response function. When the selective δ antagonist naltrindole (1.0 mg/kg) was combined with SNC 80 (1.0 mg/kg) or fentanyl (0.01 mg/kg) prior to cumulative doses of cocaine, the leftward shift of the cocaine dose-response function produced by SNC 80 was blocked, whereas the leftward shift produced by fentanyl was not. By contrast, the μ antagonist naltrexone (0.3 mg/kg) blocked the cocaine-enhancing effects of fentanyl, but not of SNC 80. Combinations of SNC 80 (0.03–0.3 mg/kg) with fentanyl (0.001–0.003 mg/kg) resulted in leftward shifts in the cocaine dose-response function that were comparable in magnitude to the shifts in the cocaine dose-response function produced by either drug alone. These results suggest that opioid enhancement of the discriminative stimulus effects of cocaine is mediated independently by δ- and μ-receptor mechanisms. Received: 5 January 1998 / Final version: 20 March 1998