Svetlana Semenova

κ-Opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice

Abstract Modulation of the reinforcing effects of cocaine and morphine by the κ-opioid receptor agonist U50,488H ( trans -3,4-dichloro- N -methyl- N -(2-1-pyrrolidinyl)-cyclohexyl-benzeacetamide) was studied by using the method of intravenous (i.v.) self-administration in drug-naive Wistar rats and DBA/2 mice. Self-administration of cocaine (by rats) and morphine (by mice) was readily initiated and showed an inverted U-shaped unit dose–response curve. Treatment with the κ-opioid receptor agonist U50,488H dose dependently decreased the intake of both cocaine and morphine when offered in doses that readily initiated and sustained self-administration behavior. Interestingly, treatment with U50,488H induced self-administration behavior with lower sub-threshold doses of cocaine and morphine. With regard to the inverted U-shaped relation between the dose of the drug and the number of self-infusions, it seems that activation of the κ-opioid receptor with U50,488H procuced an almost parallel shift to the left, indicating an increased sensitivity of the animals for the reinforcing effects of cocaine and morphine. These data demonstrate an involvement of κ-opioid systems in the neurobiological mechanisms underlying drug addiction in general, and sensitivity for drug reward in particular. Furthermore, the dual effect of κ-opioid receptor agonists on drug self-administration may prompt further research into the mechanisms underlying the role of endogenous opioids in drug self-administration.

Strain differences in the analgesic and reinforcing action of morphine in mice

The analgesic and reinforcing effects of morphine were compared in four strains of mice (C57BL/6, BALB/c, DBA, CBA). The analgesic action of morphine was measured in tail immersion (49 degrees C), hot plate (60 degrees C), and tail clip (four-point scale of nociceptive response) tests. The reinforcing action of morphine was studied in i.v. self-administration and conditioned place preference techniques. The results demonstrate strain differences in the analgesic and reinforcing action of morphine in mice. The relative rank order of the strains varied for the several tests as well as for the morphine effects. The lack of correlation between analgesic and reinforcing action of morphine in inbred strains supports the conclusion that analgesia and reinforcement are separate processes with different genetic control.

The mGluR2 Positive Allosteric Modulator BINA Decreases Cocaine Self-Administration and Cue-Induced Cocaine-Seeking and Counteracts Cocaine-Induced Enhancement of Brain Reward Function in Rats

Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists were shown previously to nonselectively decrease both cocaine- and food-maintained responding in rats. mGluR2 positive allosteric modulators (PAMs) may represent improved therapeutic compounds because of their modulatory properties and higher selectivity for mGluR2. We analyzed the effects of the selective, brain penetrant, and systemically active mGluR2 PAM potassium 3′-([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl)biphenyl l-4-carboxylate (BINA) and the mGluR2/3 agonist LY379268 on intravenous cocaine self-administration and cocaine-seeking behavior in rats that had short (1 h, ShA) or long (6 h, LgA) access to cocaine. The effects of BINA on food responding and food-seeking behavior were also analyzed. Finally, we examined the effects of BINA on brain reward function and cocaine-induced reward enhancement using the intracranial self-stimulation procedure. BINA decreased cocaine self-administration in both ShA and LgA rats, with no effect on food self-administration. Alternatively, LY379268 nonselectively decreased both cocaine and food self-administration. BINA decreased cue-induced reinstatement of cocaine seeking with no effect on food seeking. The cocaine-induced enhancement of brain reward function was blocked by BINA, although the highest doses of BINA decreased brain reward function when administered alone, suggesting additive, rather than interactive, effects of BINA and cocaine. In conclusion, BINA attenuated the reinforcing and counteracted the reward-enhancing effects of cocaine and decreased cue-induced cocaine-seeking behavior, without affecting behaviors motivated by food reinforcement. The higher selectivity of BINA compared with an mGluR2/3 agonist for drug- vs food-motivated behaviors suggests a therapeutic role for mGluR2 PAMs for the treatment of cocaine addiction and possibly other drugs of abuse.

Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice.

The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-beta-erythroidine (DHbetaE). A rate-independent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10-40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHbetaE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.

Role of γ‐Aminobutyric Acid (GABA) and Metabotropic Glutamate Receptors in Nicotine Reinforcement: Potential Pharmacotherapies for Smoking Cessation

Abstract: Previous work indicated a role for GABA and glutamate in the reinforcing effects of drugs of abuse. The present studies assessed the effects of GABAergic and glutamatergic manipulations on the reinforcing effects of nicotine as assessed by intravenous nicotine self‐administration. Male Wistar rats were allowed to self‐administer either of two nicotine doses under a fixed ratio or a progressive ratio schedule of reinforcement. The effects of a glutamatergic compound on nicotine self‐administration in male DBA/2J mice were also explored. Finally, to assess for nonspecific effects of the drug manipulations, the effects of all test compounds on responding maintained by a food reinforcer were investigated. The pharmacological manipulations used were: γ‐vinyl‐GABA (vigabatrin or GVG), an irreversible inhibitor of GABA transaminase, the GABAB receptor agonists (−)baclofen and CGP44532, and the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP. GVG, CGP44532, and (−)baclofen dose‐dependently decreased nicotine self‐administration on the fixed‐ratio schedule, but also decreased food‐maintained responding. Furthermore, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive‐ratio schedule. MPEP dose‐dependently decreased nicotine self‐administration with no effect on food‐maintained responding in rats. MPEP also decreased nicotine self‐administration in the mice. These results demonstrate that activation of GABAB receptors or blockade of mGluR5 decreased nicotine self‐administration. Although there was some selectivity for the effects of the GABAergic manipulations, there was clear selectivity of the effects of MPEP on nicotine‐ versus food‐maintained responding. Thus, compounds that increase GABAergic neurotransmission and antagonists at mGluR5 have potential as anti‐smoking medications for humans.

Low-affinity NMDA receptor channel blockers inhibit acquisition of intravenous morphine self-administration in naive mice.

Experimental evidence suggests that NMDA receptor antagonists modulate behavioral effects of morphine in models assessing abuse potential of drugs. The present study sought to evaluate the ability of NMDA receptor channel blockers to affect the acquisition of morphine i.v. self-administration in drug- and experimentally naive mice. DBA/2 mice were allowed to self-administer morphine (0.125-4.0 mg/ml) or saline during the 30-min test. Each nose-poke of the active mouse resulted in a 1.6-microl infusion to both the active mouse and the passive (yoked control) mouse. In vehicle-treated mice, differences between operant activity of active and passive mice were most obvious when active mice were allowed to self-inject morphine at the concentration of 0.5 mg/ml (the optimum concentration). Pretreatment with MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexan hydrochloride; 1, 3.2 and 10 mg/kg) shifted the optimum concentration to 0.75 mg/ml. Memantine (1-amino-3,5-dimethyladamantane hydrochloride; 0.3, 1, 3.2 and 10 mg/kg) suppressed both the morphine intake and the difference in nose-poke activity of active vs. passive mice across all tested concentrations of morphine. Dizocilpine ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate; 0.1 mg/kg) was ineffective. Taken together with earlier reports, the present results suggest that low-affinity NMDA receptor channel blockers--in contrast to dizocilpine--attenuate the rewarding potential of morphine.

Decreased prepulse inhibition during nicotine withdrawal in DBA/2J mice is reversed by nicotine self-administration

We characterized spontaneous and mecamylamine-precipitated nicotine withdrawal using intravenous nicotine self-administration, the acoustic startle response, prepulse inhibition and somatic signs of withdrawal in DBA/2J mice. Nicotine dependence was induced by continuous nicotine infusion through osmotic minipumps. Nicotine self-administration was studied before and after the induction of dependence. The initial test revealed significant nicotine self-administration at the 0.048 microg/infusion dose. During the second self-administration test, saline-treated mice exhibited increased aversiveness of response-contingent infusions of high nicotine doses; these changes were not seen in the nicotine-treated animals reflecting tolerance to nicotines effects. Neither mecamylamine administration nor spontaneous withdrawal affected the expression of somatic signs, except that increases in jumping were observed during spontaneous withdrawal. Finally, nicotine withdrawal increased general activity in the startle chambers when no stimuli were presented, possibly reflecting increased body tremor and/or agitation, and decreased prepulse inhibition reflecting a sensorimotor gating deficit; the last two effects were reversed by nicotine self-administration. Thus, nicotine withdrawal results in modest, but yet detectable, changes in the behavior of mice.

Inactivation of the 5-HT7 Receptor Partially Blocks Phencyclidine-Induced Disruption of Prepulse Inhibition

BACKGROUND Studies have implicated the serotonin (5-HT)(7) receptor in physiological and pathophysiological phenomena, including thermoregulation, central control of micturition and locomotion, regulation of circadian rhythm, sleep, and depression. Further, several antidepressant and antipsychotic drugs have high affinity for the 5-HT(7) receptor. METHODS We examined the role of 5-HT(7) receptors in a rodent analogue of sensorimotor gating deficits in schizophrenia: phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI) of acoustic startle. We used mice lacking the 5-HT(7) receptor due to a targeted inactivation of this receptor gene and the selective 5-HT(7) receptor antagonist SB-269970. RESULTS SB-269970 did not affect either baseline PPI or PCP-disrupted PPI. There was no difference between 5-HT(7)(+/+) and 5-HT(7)(-/-) mice in startle reactivity or PPI regardless of prepulse intensity (74-82 dB), interstimulus interval (25-500 msec), or pulse intensity (90-120 dB). Nevertheless, disruption of PPI produced by PCP (10 mg/kg) in wild-type mice was reduced in 5-HT(7)(-/-) mice, although it was not affected by the 5-HT(7) antagonist SB-269970. By contrast, the PPI-disruptive effects of apomorphine (5 mg/kg) and amphetamine (7.5 mg/kg) were comparable in both genotypes. CONCLUSIONS The results indicate a partial role for the 5-HT(7) receptor in the glutamatergic PPI model of sensorimotor gating deficits in schizophrenia that is sensitive to atypical antipsychotics and no involvement of this receptor in the dopaminergic PPI model that is sensitive to typical antipsychotics. Thus, the 5-HT(7)(-/-) mice may provide a useful tool to study the role of 5-HT(7) receptor in the action of atypical antipsychotic drugs and schizophrenia.

Enhancement of morphine self-administration in drug naive, inbred strains of mice by acute emotional stress

The primary reinforcing effect of morphine was compared in two genetically inbred strains of mice (C57BL/6 and DBA/2) using the intravenous self-administration procedure in drug naive animals. The morphine self-administration differed between the mouse strains. DBA/2 but not C57BL/6 acquired self-administration of morphine with a bell-shaped unit dose-response curve. Acute physical stress induced by electrical footshocks did not significantly affect the self-administration in both strains. Acute emotional stress induced by forcing mice to witness another mouse being subjected to acute physical stress caused a shift of the bell-shaped unit dose-response curve of morphine self-administration to the left in the DBA/2 mice. The C57BL/6 mice, which initially failed to demonstrate stable self-administration, started to self-administer morphine after emotional but not physical stress. Emotional distress may increase the individual sensitivity to the rewarding effects of morphine and may render an individual more susceptible to development of drug dependence.

Clozapine treatment attenuated somatic and affective signs of nicotine and amphetamine withdrawal in subsets of rats exhibiting hyposensitivity to the initial effects of clozapine

BACKGROUND Based on the phenomenologic similarity between symptoms of drug withdrawal and the negative symptoms of schizophrenia (e.g., anhedonia), we hypothesized that treatment with clozapine may be effective against nicotine and amphetamine withdrawal. METHODS A rate-independent discrete-trial threshold procedure was used to assess brain stimulation reward in rats prepared with electrodes in the lateral hypothalamus. Somatic signs of nicotine withdrawal were also assessed. RESULTS Clozapine administration (.75 or 1.5 mg/kg) during nicotine or amphetamine withdrawal did not affect the threshold elevations associated with drug withdrawal. The.75 mg/kg clozapine dose reversed the increased number of somatic signs of nicotine withdrawal. Ten days of clozapine treatment (3 mg/kg/b.i.d.) before exposure to nicotine prevented the threshold elevations in a subset of rats and the increases in somatic signs in all subjects. Fourteen-day pretreatment with clozapine (6 mg/kg/day) decreased the duration of amphetamine withdrawal. CONCLUSIONS Correlational analyses indicated that the ability of clozapine to prevent the affective aspects of drug withdrawal depended on low sensitivity to acute clozapine under baseline conditions. The results are consistent with the clinical situation where clozapine is partially effective against the negative symptoms of schizophrenia and more effective in some individuals than others. These results indicate that lack of sensitivity to the initial negative effects of clozapine may predict its a subsequent therapeutic response. Finally, the data suggest that there may be commonalities in the neurosubstrates mediating affective aspects of drug withdrawal and the negative symptoms of schizophrenia.