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Biomedical subjects

J Willetts

Publications and source records attributed to J Willetts.

24 records · Page 2Linked to original sources
PubMed1988

Receptor mediation of the discriminative stimulus properties of phencyclidine and sigma-opioid agonists.

Evidence has accumulated that the discriminative stimulus effects of phencyclidine (PCP) may be transduced by a specific receptor in mammalian brain. Two major lines of evidence support this hypothesis. One is the structure-activity correlation that arylcyclohexylamine analogs of PCP have for PCP-like discriminative effects and displacement of [3H]PCP binding. The other, even stronger, evidence is that representatives of some nonarylcyclohexylamine classes of drugs are both generalized from PCP and have activity at PCP-binding sites. These include the psychotomimetic sigma-agonist opioids such as (+)-N-allylnormetazocine (NANM), the 1,3-substituted dioxolanes dexoxadrol and etoxadrol and some benz(f)isoquinolines. Early evidence suggested that there may be a complete overlap in the discriminative effects and receptor systems for PCP and sigma-agonists, and there continues to be evidence to support the commonality of these drug groups. On the other hand, binding studies with radiolabeled sigma agonists have revealed a non-PCP site. The role of this site in the behavioral actions of sigma-agonists is at present unknown. PCP analogs and other PCP-like drugs also can function as reinforcers for self-administration behavior, suggesting that the same cellular mechanisms may be responsible for both discriminative and reinforcing stimulus effects of these drugs. PCP has been shown to block many of the in vitro and in vivo effects of N-methyl-D-aspartate (NMDA), a putative specific agonist for a subtype of excitatory amino acid receptor. Recent evidence that NMDA antagonists are generalized from PCP in rats and pigeons provides evidence that modification of excitatory amino neurotransmission may be a physiological function of the PCP receptor and that this receptor complex may be involved in PCP's discriminative stimulus effects.

Analgesics, Opioid↗
PubMed1988

The discriminative stimulus effects of N-methyl-D-aspartate antagonists in phencyclidine-trained rats.

The discriminative stimulus effects of two competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-7-phosphonoheptanoate (APH) and 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonate (CPP), were assessed in rats trained to discriminate phencyclidine from saline. Systemically administered APH (10-60 mg/kg i.p.) failed to elicit phencyclidine-lever responding; however, partial generalization from phencyclidine occurred following intracerebroventricular (i.c.v.) administration of APH (1.5-30 micrograms). Systemic and central administration of CPP (3-30 mg/kg i.p.; 0.1-10 micrograms i.c.v.) also resulted in partial generalization from phencyclidine. Partial generalization was also obtained with methohexital (5-30 mg/kg i.p.). However, generalization to APH, CPP and methohexital was usually accompanied by decreased response rates, and response rate decreases frequently occurred without appreciable phencyclidine-lever selection, indicating that these drugs also had no phencyclidine-like behavioral effects. The drug di-ortho-tolyl guanidine (DTG) which binds with high-affinity to sigma receptors failed to elicit phencyclidine-lever responding, even at doses which reduced response rates. These findings suggest that although competitive NMDA antagonists share some discriminative stimulus properties with phencyclidine, there is not a complete overlap in the discriminative stimulus properties of competitive and non-competitive NMDA antagonists. Furthermore, the discriminative stimulus effects of APH and CPP were no more similar to phencyclidine than those of methohexital.

2-Amino-5-phosphonovalerate↗
PubMed1985

The acute and chronic effects of capsaicin on slow excitatory transmission in rat dorsal horn.

The acute and chronic effects of capsaicin on rat spinal dorsal horn neurons and the excitatory transmission in the dorsal horn were investigated by means of intracellular recording techniques in the spinal cord slice preparation. Bath application of capsaicin (1-2 X 10(-5) M) produced in a majority of cells a prolonged depolarization associated with an increase in synaptic activity and intense neuronal discharges. During and immediately following the capsaicin depolarization, repetitive stimulation of a dorsal root failed to elicit the slow depolarization. After neonatal capsaicin treatment the proportion of dorsal horn neurons exhibiting the slow excitatory transmission was markedly reduced, however, the fast excitatory postsynaptic potentials were present in all examined cells. In addition, the proportion and sensitivity of the cells responding with a slow depolarization to substance P increased.

Animals↗
PubMed1983

Fine structural changes in cat L7 ventral horn neurones after chronic sub LD50 DFP.

The fine structural changes in the ventral anterior horn of spinal segment L7, have been studied in adult cats after single and chronic sub LD50 (0.1 to 0.75 mg/kg SC with a cumulative range of 1.3 mg/kg to 10.5 mg/kg) low dose exposure to diisopropylfluorophosphate (DFP). Only the motoneurons of the chronically treated animals show an increase in the number of lysosomes, neurofilaments and vesicle-like structures. A large number of coated vesicles is observed within axons and axon terminals of both acute and chronically treated animals. Morphological evidence of axon and terminal degeneration is seen only in chronically treated animals. The present study shows that chronic sub LD50 low dose administration of DFP over periods from 5 to 21 days results in degenerative changes of presynaptic terminals and axons, with the severity of the changes being dependent on dose and duration of treatment. The data are interpreted by comparison with single high dose exposure reported in the literature with a discussion of acute and delayed neurotoxic effects of DFP, on the central nervous system.

Animals↗