Biomedical subjects

Kenneth Grasing

Publications and source records attributed to Kenneth Grasing.

6 recordsLinked to original sources

PubMed2006

L-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats; Insights towards selegiline's mechanism of action.

Selegiline is an inhibitor of type B monoamine oxidase (MAO) with psychostimulant effects that can decrease morphine-reinforced and non-reinforced responding. The present study was undertaken to compare the effects of MAO inhibition and treatment with L-methamphetamine, the major psychostimulant metabolite of selegiline, on these behaviors. After rats acquired a stable pattern of morphine self-administration under a progressive ratio schedule, chronic treatment was initiated with vehicle, L-methamphetamine, clorgyline (a selective inhibitor of MAO-A), or rasagiline (a selective inhibitor of MAO-B); with both MAO inhibitors administered at a dose selective for one MAO isoform and a higher dose that inhibited both isoforms. Rats were evaluated for up to four cycles of opiate dependence maintained by morphine self-administration and withdrawal during which extinction responding was recorded. Most behavioral measures (92.4%) did not differ in animals evaluated during an initial and subsequent cycles of dependence and withdrawal. All active treatments attenuated non-reinforced responding during extinction. Morphine reinforcement was also decreased by each of the three active treatments, but greater and more prolonged effects were observed following inhibition of MAO-B with rasagiline. Responding during either cue- or morphine-induced reinstatement was attenuated by either clorgyline or rasagiline administered at nonselective doses, but not by either compound administered at selective dose levels. Treatment with L-methamphetamine did not produce significant effects on cue-induced reinstatement, but decreased non-reinforced responding during morphine-induced reinstatement. These findings indicate that morphine reinforcement and different non-reinforced behaviors differ greatly in their susceptibility to modification by psychostimulant treatment or MAO inhibition.

Animals↗

PubMed2005

Protein aggregation in retinal cells and approaches to cell protection.

1. Retinal dystrophies (RD) comprise a group of clinically and genetically heterogeneous retinal disorders, which typically result in the degeneration of photoreceptors followed by the impairment or loss of vision. Although age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are among the most common forms of RD, currently, there is no effective treatment for either disorder. 2. Recently, abnormal protein accumulation and aggregation due to protein misfolding and proteasome inhibition have been implicated in the pathogenesis of RD. In this paper we describe effects of several factors on protein aggregation and survival of photoreceptor cells. 3. Expression of rhodopsin carrying P23H mutation causes its accumulation in intracellular inclusion bodies in a perinuclear area of photoreceptor cells. beta- and gamma-synucleins and heat shock protein Hsp-70, but not alpha-synuclein, protect cultured ocular cells from mutant opsin accumulation. This effect might be explained by their chaperonic activity. 4. Knock-out of alpha- and gamma-synucleins does not affect gross retinal morphology, but induces tyrosine hydroxylase in the inner prexiform layer of the retina. Selegiline-a monoamine oxidase inhibitor used for the treatment of Parkinson's disease, reduces apoptosis and increases viability in cultured retinal pigment epithelium cells (APRE-19). 5. These results suggest that chaperones and selegiline may be considered promising candidates for the protection of ocular cells from the accumulation of misfolded and aggregated proteins.

Animals↗

PubMed2005

Selegiline modifies the extinction of responding following morphine self-administration, but does not alter cue-induced reinstatement, reacquisition of morphine reinforcement, or precipitated withdrawal.

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects which can prevent decreases in dopamine efflux that follow opiate withdrawal. The present study evaluated effects of selegiline treatment on morphine-seeking behavior and morphine reinforcement in Wistar rats (n = 26). In additional animals (n = 30), the ability of single doses of selegiline to modify naloxone-precipitated withdrawal was determined. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of intravenous morphine. Daily intravenous treatment with saline or 2.0mg kg(-1) doses of selegiline was then initiated and continued over 14 days during extinction, reinstatement, and reacquisition of morphine self-administration. To reduce the potential for psychostimulant effects, selegiline was administered approximately 1h following self-administration, extinction, or reinstatement sessions. In some animals (n = 23), effects of saline or selegiline administration on locomotor activity were determined following extinction sessions. Daily selegiline treatment decreased the number of ratios completed and increased response latency during extinction, without modifying these measures during reinstatement or reacquisition of morphine self-administration. Chronic selegiline treatment increased locomotor activity recorded between 4 and 7h after selegiline administration on day 7 of extinction, but otherwise did not alter locomotor activity. Pretreatment with single, 2.0mg kg(-1) doses of selegiline did not modify naloxone-precipitated withdrawal. In conclusion, pretreatment with selegiline produced only a small decrease in responding during extinction of morphine self-administration and did not modify cue-induced reinstatement of morphine-seeking behavior, reacquisition or morphine reinforcement, or precipitated withdrawal.

Animals↗

PubMed2004

Chronic opiate treatment enhances both cocaine-reinforced and cocaine-seeking behaviors following opiate withdrawal.

After chronic exposure to psychostimulants or opiates, self-administration or conditioned place preference with either class is increased (sensitized). Cross-sensitization of conditioned place preference, i.e., enhancement of psychostimulant-induced preferences after exposure to opiates, has also been described, but increases in cocaine self-administration after morphine pretreatment have not been reported. The present study evaluated effects of chronic morphine treatment on cocaine reinforcement. Opiate dependence was established in Wistar rats by administration of morphine as a constant infusion that was gradually increased to a dose of 50mg/kg per day over a 1-week period. Immediately after discontinuation of chronic morphine treatment, animals were allowed to acquire cocaine self-administration under a simple fixed-ratio schedule (FR-1), and were subsequently advanced to a progressive ratio schedule. Acquisition of cocaine self-administration under the FR-1 did not differ in saline- and morphine-pretreated animals. For cocaine self-administration under a progressive ratio schedule measured at 5 or more days after the onset of opiate withdrawal, chronic pretreatment with morphine increased the number of ratios completed, augmented final response requirements, and produced a more stable pattern of cocaine self-administration. Responding was also increased in morphine-pretreated animals during an initial extinction session. These results show that chronic opiate treatment can enhance both cocaine-reinforced and cocaine-seeking behaviors following opiate withdrawal. A similar effect may occur in human patients who discontinue methadone or other forms of replacement therapy for opiate abuse, and may contribute to relapse involving use of cocaine or other psychostimulants.

Animals↗

PubMed2004

Long-term opiate effects on amphetamine-induced dopamine release in the nucleus accumbens core and conditioned place preference.

Withdrawal following chronic exposure to opiates or other drugs of abuse, administered as frequent doses, or a chronic infusion can cause reductions in mesolimbic dopamine (DA) transmission. However, mesolimbic DA transmission can be enhanced by opiates or psychostimulants administered intermittently as a single daily injection. Both enhanced and attenuated responsiveness of the mesolimbic DA system may have important implications for substance abuse disorders. Previous studies have shown that procedures that use electrical stimulation or drug treatments to augment neurotransmitter release are more effective for demonstrating declines in mesolimbic DA transmission that persist for extended periods following opiate withdrawal. The present study evaluated the effects of pretreatment with noncontingent morphine on amphetamine-induced DA release in the nucleus accumbens core and conditioned place preference (CPP). Morphine pretreatment was administered as a constant infusion, which was gradually increased to a dose of 50 mg/kg/day over a 1-week period in Wistar rats. At 10 days after cessation of morphine pretreatment, baseline dialysate DA levels in the nucleus accumbens core were unchanged, but amphetamine-induced increases in DA were attenuated by greater than 50% in morphine-pretreated animals. Morphine pretreatment did not modify locomotor activity during conditioning sessions, expressed as absolute values or change in activity counts between saline and morphine injections. Place preference, conditioned by two morphine pairings at 10 and 11 days after the onset of opiate withdrawal, was enhanced by opiate pretreatment between 12 and 33 days after the onset of withdrawal. In conclusion, morphine pretreatment delivered as a constant infusion can have pronounced and long-lasting effects on DA release and CPP, which may have important implications for drug-seeking behavior and treatment of substance abuse disorders.

Amphetamine↗

PubMed2003

A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats.

RATIONALE AND OBJECTIVES: In preliminary studies, we observed that opiate dependent rats self-administered only a small number of morphine injections under a PR (progressive ratio) schedule developed to study psychostimulant self-administration. Therefore, a new schedule was developed to support morphine self-administration by incrementing response requirements in a relatively gradual manner. The present study compared morphine self-administration under a commonly used PR schedule to self-administration maintained by our modified PR schedule. METHODS: After pretreatment with non-contingent morphine, rats acquired self-administration under fixed-ratio (FR) schedules of intravenous morphine delivery. Morphine-maintained behavior was evaluated under a standard PR schedule (termed "PR3-4", because the third response requirement was four lever presses), and our modified PR schedule (termed "PR9-4", because the ninth response requirement was four lever presses). The PR9-4 schedule was also evaluated for self-administration of morphine doses of 0.001-3.2 mg/kg per injection. RESULTS: The number of ratios completed for morphine self-administration on the PR9-4 schedule, but not the PR3-4 schedule, exceeded values obtained during extinction. Dose-related increases in completed ratios occurred for morphine self-administration on the PR9-4 schedule, with stable patterns emerging after three sessions. A relatively flat dose-response relationship was observed, which did not increase monotonically with morphine dose. Morphine self-administration on the PR9-4 schedule decreased mean inter-injection interval and prolonged the duration of responding during 6-h sessions. CONCLUSIONS: In the present study, a schedule that incremented response requirement gradually (PR9-4) supported reliable self-administration across a range of morphine doses.

Animals↗