Selective blockade of the discriminative stimulus effects of pentobarbital in pigeons

The ability of CNS stimulants to block the discriminative effects of pentobarbital was studied in pigeons trained to discriminate IM pentobarbital (5 mg/kg) from saline. Pentobarbital, when administered alone, consistently produced greater than 90% pentobarbital-appropriate responding. The concomitant administration of pentobarbital and increasing doses of bemegride or pentylenetetrazol resulted in a dose-related decrease in pentobarbital-appropriate responses. In contrast, picrotoxin, another CNS stimulant, had little or no effect on pentobarbital-appropriate responding produced by pentobarbital.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46426/1/213_2004_Article_BF00432447.pd

Mechanisms of Action of Currently Prescribed and Newly Developed Antiepileptic Drugs

Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, -y-aminobutyric acid A (GABA A ) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABA A -receptor-mediated inhibition. Phenytoin, car-bamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the Af-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65554/1/j.1528-1157.1994.tb05955.x.pd

Anticonvulsant drug actions on neurons in cell culture

Two actions of clinically used antiepileptic drugs have been studied using mouse neurons in primary dissociated cell culture. The antiepileptic drugs phenytoin, carbamazepine and valproic acid were demonstrated to limit sustained high frequency repetitive firing of action potentials at free serum concentratons that are achieved in patients being treated for epilepsy. Furthermore, an active metabolite of carbamazepine also limited sustained high frequency repetitive firing while inactive metabolites of phenytoin and carbamazepine did not limit sustained high frequency repetitive firing. Phenobarbital and clinically used benzodiazepines limited sustained high frequency repetitive firing of action potentials, but only at concentrations achieved during the treatment of generalized tonic-clonic status epilepticus. Ethosuximide did not limit sustained high frequency repetitive firing even at concentrations four times those achieved in the serum of patients treated for generalized absence seizures. Phenobarbital and clinically used benzodiazepines enhanced postsynaptic GABA responses at concentrations achieved free in the serum during treatment of generalized tonic-clonic or generalized absence seizures. However, phenytoin, carbamazepine, valproic acid and ethosuximide did not modify postsynaptic GABA responses at therapeutic free serum concentrations. These results suggest that the ability of antiepileptic drugs to block generalized tonicclonic seizures and generalized tonic-clonic status epilepticus may be related to their ability to block high frequency repetitive firing of neurons. The mechanism underlying blockade of myoclonic seizures may be related to the ability of antiepileptic drugs to enhance GABAergic synaptic transmission. The mechanism underlying management of generalized absence seizures remains unclear.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41657/1/702_2005_Article_BF01243417.pd

Structural, Metabolic, and Functional Brain Abnormalities as a Result of Prenatal Exposure to Drugs of Abuse: Evidence from Neuroimaging

Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in living human subjects. Here we review the neuroimaging literature of prenatal exposure to alcohol, cocaine, and methamphetamine. Neuroimaging studies of prenatal alcohol exposure have reported differences in the structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, as well as in the white matter tracts that connect these brain regions. Functional imaging studies have identified significant differences in brain activation related to various cognitive domains as a result of prenatal alcohol exposure. The published literature of prenatal exposure to cocaine and methamphetamine is much smaller, but evidence is beginning to emerge suggesting that exposure to stimulant drugs in utero may be particularly toxic to dopamine-rich basal ganglia regions. Although the interpretation of such findings is somewhat limited by the problem of polysubstance abuse and by the difficulty of obtaining precise exposure histories in retrospective studies, such investigations provide important insights into the effects of drugs of abuse on the structure, function, and metabolism of the developing human brain. These insights may ultimately help clinicians develop better diagnostic tools and devise appropriate therapeutic interventions to improve the condition of children with prenatal exposure to drugs of abuse

Allopregnanolone and Pentobarbital Infused Into the Nucleus Accumbens Substitute for the Discriminative Stimulus Effects of Ethanol

BACKGROUND: The discriminative stimulus effects of ethanol are mediated in part by the gamma-aminobutyric acid type A (GABA(A)) receptor system. We have previously shown that microinjections of the competitive GABA(A) agonist muscimol in the nucleus accumbens and amygdala fully substitute for the discriminative stimulus effects of systemic ethanol. However, it is not known whether allosteric binding sites on GABA(A) receptors located within specific limbic brain regions contribute to the discriminative stimulus effects of ethanol. METHODS: Male Long-Evans rats were trained to discriminate between intraperitoneal injections of ethanol (1 g/kg) and saline under a fixed-ratio 10 schedule of sucrose (10% w/v) reinforcement. Injector guide cannulae, aimed at both the nucleus accumbens core and the hippocampus area CA1, were then implanted to allow site-specific infusion of GABA(A)-positive modulators. RESULTS: Infusion of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, or 3alpha-5alpha-P) in the nucleus accumbens resulted in dose-dependent full substitution for intraperitoneal ethanol (50% effective dose = 0.38 ng/microl per side). Likewise, injection of the barbiturate pentobarbital into the nucleus accumbens also substituted dose-dependently for ethanol (50% effective dose = 1.55 microg/microl per side). However, infusions of either 3alpha-5alpha-P or pentobarbital in the hippocampus failed to substitute for ethanol and produced inverted U-shaped dose-response curves. CONCLUSIONS: These results demonstrate that allosteric positive modulation of GABA(A) receptors in the nucleus accumbens produces full substitution for the stimulus effects of ethanol. This suggests that GABA(A) receptors in the nucleus accumbens may play a more influential role in the discriminative stimulus effects of ethanol than those in the hippocampus