Phenytoin Blocks the Reversal of a Classically Conditioned Discriminative Eyeblink Response in Rabbits
James D. Churchill
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorSteven E. Voss
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorDaniel P. Miller
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorJoseph E. Steinmetz
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorCorresponding Author
Preston E. Garraghty
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Address correspondence and reprint requests to Dr. P. E. Garraghty at Department of Psychology, Indiana University, Bloomington: IN 47405, U.S.A.Search for more papers by this authorJames D. Churchill
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorSteven E. Voss
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorDaniel P. Miller
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorJoseph E. Steinmetz
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Search for more papers by this authorCorresponding Author
Preston E. Garraghty
Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana, U.S.A.
Address correspondence and reprint requests to Dr. P. E. Garraghty at Department of Psychology, Indiana University, Bloomington: IN 47405, U.S.A.Search for more papers by this authorAbstract
Summary: Purpose: Cognitive deficits associated with chronic treatment with phenytoin (PHT) have been reported. PHT blocks transfer from a signaled appetitive bar press to an active avoidance response in rats. We investigated the effects of PHT and the prodrug fosphenytoin in rabbits required to learn a discrimination and reversal of a classical eyeblink conditioning paradigm.
Methods: Before drug treatment was started, rabbits were trained to produce a discriminated eyeblink response. PHT (n = 7) was administered centrally or the prodrug fosphenytoin (n = 2) was given systemically. Control animals were similarly treated centrally with either saline (n = 3) or no drug treatment (n = 13). Rabbits were then challenged with a stimulus reversal while being maintained on the respective drug.
Results: On the first day of reversal training, control animals typically displayed high response rates to both tones, followed by a reduction in responsiveness to the new conditioned stimulus (CS-) in the ensuing days. In contrast, PHT-treated animals failed to suppress responsiveness to the new CS-.
Conclusions: The response patterns observed are similar to those observed in rabbits with hippocampal ablations, leading us to suggest that the adverse effects of phenytoin may be due to actions in the hippocampus.
REFERENCES
- 1 Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in treatment of convulsive disorders. JAMA 1938; 111: 1068–73.
- 2 Aldenkamp AP, Alpherts WCJ, Diepman L, van't Slot B, Overweg J, Vermeulen J. Cognitive side-effects of phenytoin compared with carbamazepine in patients with localization-related epilepsy. Epilepsy Res 1994; 19: 3743.
- 3 Pullianen V, Jokelainen M. Effects of phenytoin and carbamazepine on cognitive functions in newly diagnosed epileptic patients. Acta Neurol Scand 1994; 89: 814.
- 4 Wilder BJ, McLean JR, Uthman BM. Phenytoin. In: E Wyllie, ed. The treatment of epilepsy: principles and practices. Philadelphia : Lea & Febiger, 1993: 887–99.
- 5 Mohr NL, Steinmetz JE, Garraghty PE. Effects of phenytoin on learned appetitive responses and the subsequent acquisition of escape and avoidance responses. SOC Neurosci Abstr 1994; 20: 1020.
- 6 Renfrey G, Schlinger H, Jakubow J, Poling A. Effects of phenytoin and phenobarbital on schedule-controlled responding and seizure activity in the amygdala-kindled rat. J Pharmacol Exp Ther 1989; 248: 967–74.
- 7 Gabriel M. An extended laboratory for behavioral neuroscience: a review of Classical Conditioning (third edition). Psychobiology 1988; 16: 79–81.
- 8 Gormezano I, Harvey JA. Sensory and associative effects of LSD in classical conditioning of rabbit (Oryctolagus cuniculus) nictitating membrane response. J Comp Physiol Psychol 1980; 94: 64–9.
- 9 Gormezano I, Kehoe EJ, Marshall BS. Twenty years of classical conditioning research with the rabbit. In: JM Sprague, AN Epstein, eds. Progress in psychobiology and physiological psychology. New York : Academic Press, 1983: 197–275.
- 10 Berger TW, Orr WB. Hippocampectomy selectively disrupts discrimination reversal conditioning of the rabbit nictitating membrane response. Behav Brain Res 1983; 8: 49–68.
- 11 Churchill JD, Steinmetz JE, Garraghty PE. Phenytoin blocks the reversal discrimination of a classically conditioned eyeblink in rabbits. SOC Neurosci Abstr 1995; 21: 204.
- 12 Thompson LT, Moyer JR, Akase E, Disterhoft JF. A system for quantitative analysis of associative learning. Part 1. Hardware interfaces with cross-species applications. J Neurosci Methods 1994; 54: 109–17.
- 13 Gould TJ, Steinmetz JE. Multiple-unit activity from rabbit cerebellar cortex and interpositus nucleus during classical discrimination/reversal eyelid conditioning. Brain Res 1994; 652: 98–106.
- 14 Gonzalez-Darder J, Garcia-Teno M. Anticonvulsant effect of intraventricular antiepileptic drugs. Experimental study. Neurol Res 1995; 17: 190–2.
- 15 Leppik IE, Boucher BA, Wilder BJ, et al. Pharmacokinetics and safety of a phenytoin prodrug given IV or IM in patients. Neurology 1990; 40: 456–60.
- 16 Walton NY, Treiman DM. Efficacy of ACC-9653 (a phenytoin prodrug) in experimental status epilepticus in the rat. Epilepsy Res 1990; 5: 165–8.
- 17 Bebin M, Bleck TP. New anticonvulsant drugs. Drugs 1994; 48: 153–71.
- 18 Smith RD, Brown BS, Maher RW, Matier WL. Pharmacology of ACC-9653 (phenytoin prodrug). Epilepsia 1989; 30(suppl): S15–21.
- 19 Knapp LE, Kugler AR, Eldon MA. Fosphenytoin: pharmacokinetics and administration. Emerg Med 1996; 28(suppl): 9–16.
- 20 Lincoln JS, McCormick DA, Thompson RF. Ipsilateral cerebellar lesions prevent learning of the classically conditioned nictitating membrane/eyelid response. Brain Res 1982; 242: 190–3.
- 21 McCormick DA, Thompson RF. Cerebellum: essential involvement in the classically conditioned eyelid response. Science 1984; 223: 2969.
- 22 Steinmetz JS, Logue SF, Steinmetz SS. Rabbit classically conditioned eyelid responses do not reappear after interpositus nucleus lesion and extensive postlesion training. Behav Brain Res 1992; 51: 103–14.
- 23 Rambeck B, Schnabel R, May T, Jurgens U, Villagran R. Postmortem concentrations of phenytoin in different regions of the brain and in the serum: analysis of autopsy specimens from 24 epileptic patients. Ther Drug Monit 1992; 14: 27–35.
- 24 Yan GM, Irwin RP, Lin SZ, Weller M, Wood KA, Paul SM. Diphenylhydantoin induces apoptotic cell death of cultured cerebellar granule neurons. J Pharmacol Exp Ther 1995; 274: 983–90.
- 25 Logan CG. Cerebellar cortical involvement in excitatory and inhibitory classical conditioning. Doctoral dissertation, 1991, Stanford University, Stanford, California.
- 26 Esplin DW. Effects of diphenylhydantoin on synaptic transmission in cat spinal cord and stellate ganglion. J Pharmacol Exp Ther 1957; 120: 301–23.
- 27 Yaari Y, Selzer ME, Pincus JH. Phenytoin: mechanisms of its anticonvulsant action. Ann Neurol 1986; 20: 171–84.
- 28 Greenberg DA, Cooper EC, Carpenter CL. Phenytoin interacts with calcium channels in brain membranes. Ann Neurol 1984; 16: 616–7.
- 29 Woodbury DM. Phenytoin. Mechanisms of action. In: DM Woodbury, JK Penry, CE Pippenger, eds. Antiepileptic drugs. New York Raven Press, 1982: 269–81.
- 30 Wamil AW, McLean MJ. Phenytoin blocks N-methyl-d-aspartate responses of mouse central neurons. J Pharmacol Exp Ther 1993; 267: 218–27.
- 31 Brown LM, Lee Y, Teyler TJ. Antiepileptics inhibit cortical N-methyl-d-aspartate-evoked [3H]norepinephrine efflux. Eur J Pharmacol 1994; 254: 307–9.
- 32 Leung LS, Shen B. Long-term potentiation in hippocampal CA1: effects of afterdischarges, NMDA antagonists, and anticonvulsants. Exp Neurol 1993; 119: 205–14.
- 33 Banks MK, Mohr NL, Bernard EA, Logue SF, Steinmetz JE, Garraghty PE. A comparison of the effects of CPP and phenytoin on transfer from appetitive to aversive contexts in adult rats. Soc Neurosci Abstr 1995; 21: 204.
- 34 Davies J, Evans RH, Herding PL, Olverman AW, Pook P, Watkins JC. CPP, a new potent and selective NMDA antagonist. Depression of central neuron responses, affinity for [3H]D-AP5 binding sites on brain membranes and anticonvulsant activity. Brain Res 1986; 382: 169–73.
- 35 Harris EW, Gariong AH, Monaghan DT, Watkins JC, Cotman CW. Actions of 3–((+/-)-2–carboxypiperazin-4-yl)propyl-1 -phosphonic acid (CPP), a new highly potent antagonist of N-methyl-D-aspartate receptors in the hippocampus. Brain Res 1986; 389: 174–7.
- 36 Olverman HJ, Monaghan DT, Cotman CW, Watkins JC. [3H]CPP, a new competitive ligand for NMDA receptors. Eur J Phannacol 1986; 131: 161–2.
- 37 Churchill JD, Upton MN, Voss SE, Steinmetz JE, Garraghty PE. A comparison of the effects of CPP and phenytoin on a discrimination reversal eyeblink task in rabbits. SOC Neurosci Abstr 1996; 22: 2109.
- 38 Buller AL, Larson HC, Schneider BE, Beaton JA, Morrisett RA, Monaghan DT. The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition. J Neurosci 1994; 14: 5471–84.
Citing Literature
