strychnine and Substance-Withdrawal-Syndrome

Pentylenetetrazol (PTZ), a GABA(A) receptor antagonist and prototypical anxiogenic drug, has been extensively utilized in animal models of anxiety. PTZ produces a reliable discriminative stimulus which is largely mediated by the GABA(A) receptor. Several classes of compounds can modulate the PTZ discriminative stimulus including 5-HT(1A), 5-HT(3), NMDA, glycine, and L-type calcium channel ligands. Spontaneous PTZ-lever responding is seen in trained rats during withdrawal from GABA(A) receptor compounds such as chlordiazepoxide and diazepam, and also ethanol, morphine, nicotine, cocaine, haloperidol, and phencyclidine. This effect is largely mediated by the GABA(A) receptor, which suggests that anxiety may be part of a generalized withdrawal syndrome mediated by the GABA(A) receptor. There are also important hormonal influences on PTZ. Corticosterone plays some role in mediation of its anxiogenic effects. There is a marked sex difference in response to the discriminative stimulus effects of PTZ, and estrogens appear to protect against its anxiogenic effects. Further work with the PTZ drug discrimination is warranted for characterization of anxiety during withdrawal, and the hormonal mechanisms of anxiety.

Topics: Animals; Anxiety Disorders; Calcium Channels, L-Type; Discrimination, Psychological; Drug Interactions; GABA Antagonists; GABA-A Receptor Antagonists; Glycine Agents; Models, Animal; Nicotine; Pentylenetetrazole; Pituitary-Adrenal System; Receptors, GABA-A; Receptors, Glycine; Receptors, Nicotinic; Receptors, Serotonin; Serotonin; Sex Factors; Strychnine; Substance Withdrawal Syndrome

The lateral habenula (LHb) is activated by a range of aversive states including those related to alcohol withdrawal and has glycine receptors (GlyRs), a sensitive target of alcohol. However, whether GlyRs in the LHb contribute to alcohol-related behaviors is unknown. Here, we report that rats experiencing withdrawal from chronic alcohol consumption showed higher anxiety and sensitivity to stress compared to their alcohol-naïve counterparts. Intra-LHb injection of glycine attenuated these aberrant behaviors and reduced alcohol intake upon alcohol re-access. Glycine's effect was blocked by strychnine, a GlyR antagonist, indicating that it was mediated by strychnine-sensitive GlyRs. Conversely, intra-LHb strychnine elicited anxiety- and depression-like behaviors in Naïve rats but not in withdrawal rats. Additionally, both the frequency and the amplitude of the spontaneous IPSCs were lower in LHb neurons in slices of withdrawal rats compared to naïve rats. Also, there were sporadic strychnine-sensitive synaptic events in some LHb neurons. Bath perfusion of strychnine induced a depolarizing inward current and increased action potential firings in LHb neurons. By contrast, bath perfusion of glycine or sarcosine, a glycine transporter subtype 1 inhibitor, inhibited LHb activity. Collectively, these data reveal that LHb neurons are under the tonic glycine inhibition both in physiological and pathological conditions. Activation of GlyRs reverses LHb hyperactivity, alleviates aberrant behaviors, and reduces alcohol intake, thus highlighting the GlyRs in the LHb as a potential therapeutic target for alcohol-use disorders.

Topics: Action Potentials; Alcohol Drinking; Animals; Anxiety; Behavior, Animal; Depression; Glycine; Habenula; Inhibitory Postsynaptic Potentials; Male; Microinjections; Neural Inhibition; Neurons; Rats; Receptors, Glycine; Sarcosine; Strychnine; Substance Withdrawal Syndrome

A novel series of N-substituted 4-ureido-5,7-dichloro-quinolines were synthesized to contain pharmacophores directed at voltage-sensitive sodium channels (VSNaCs) and N-methyl-D-aspartate (NMDA) receptors. These compounds were shown to act in a use-dependent manner as antagonists of VSNaCs and to act as selective competitive antagonists at the strychnine-insensitive glycine recognition site of NMDA receptors. These agents had little or no effect on alpha-adrenergic receptors, other glutamate receptors, or sites other than the glycine site on the NMDA receptor, and did not block voltage-sensitive calcium channels in vitro. In vivo, the compounds were active in preventing or reducing the signs and symptoms of neurohyperexcitability and had anxiolytic properties. Unlike benzodiazepines, N-substituted 4-ureido-5, 7-dichloro-quinolines showed little interaction with the sedative effects of ethanol, but were effective in controlling ethanol withdrawal seizures. The combined actions of these compounds on VSNaCs and NMDA receptors also impart properties to these compounds that are important for preventing and reducing excitotoxic neurodegeneration, but these compounds lack the undesirable side effects of other agents used for these purposes.

Topics: Animals; Anti-Anxiety Agents; Ataxia; Behavior, Animal; Binding Sites; Binding, Competitive; Cells, Cultured; Cerebellum; Dose-Response Relationship, Drug; Ethanol; Glycine; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neurons; Oocytes; Phenylurea Compounds; Protein Binding; Quinolines; Rats; Receptors, Adrenergic, alpha; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Seizures; Sodium Channel Blockers; Sodium Channels; Sound; Strychnine; Substance Withdrawal Syndrome; Xenopus

Withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice were selectively bred to have severe (WSP) or mild (WSR) handling-induced convulsions after chronic ethanol inhalation. The purpose of the present experiments was to determine whether seizure susceptibility differences between WSP and WSR mice during ethanol withdrawal were specific to agents acting at gamma-aminobutyric acidA or excitatory amino acid (EAA) receptors. Male WSP and WSR mice were exposed to ethanol vapor or air for 24 or 72 h. During peak withdrawal (i.e., between 6.5 and 8 h after removal from the inhalation chambers), separate groups of animals were administered pentylenetetrazol, (+)bicuculline, N-methyl-D-aspartate, kainic acid, or strychnine via timed tail vein infusion. Withdrawal from ethanol significantly increased sensitivity to pentylenetetrazol and (+)bicuculline versus air-exposed WSP and WSR mice. In contrast, sensitivity to N-methyl-D-aspartate-induced convulsions was significantly decreased in the ethanol-exposed WSR and unchanged in the ethanol-exposed WSP mice. Sensitivity to kainic acid was significantly increased in both ethanol-exposed WSR and WSP mice, although the magnitude of change in sensitivity was greater in the ethanol-withdrawing WSP line. Interestingly, sensitivity to strychnine was decreased similarly in the ethanol-exposed WSP and WSR mice, compared with their respective air-exposed animals. These results suggest that chronic ethanol increased sensitivity to convulsants active at gamma-aminobutyric acidA receptors similarly in WSP and WSR mice, but differentially changed sensitivity to convulsants active at EAA receptors in the lines. This supports a role for EAA systems in determining genetic susceptibility to alcohol withdrawal.

Topics: Administration, Inhalation; Alcoholism; Animals; Central Nervous System Depressants; Convulsants; Drug Administration Schedule; Ethanol; Genetic Predisposition to Disease; Male; Mice; Receptors, GABA-A; Receptors, Glutamate; Seizures; Sensitivity and Specificity; Strychnine; Substance Withdrawal Syndrome

Opioid receptors located on interneurons in the ventral tegmental area (VTA) inhibit GABA(A)-mediated synaptic transmission to dopamine projection neurons. The resulting disinhibition of dopamine cells in the VTA is thought to play a pivotal role in drug abuse; however, little is known about how this GABAA synapse is affected after chronic morphine treatment. The regulation of GABA release during acute withdrawal from morphine was studied in slices from animals treated for 6-7 d with morphine. Slices containing the VTA were prepared and maintained in morphine-free solutions, and GABAA IPSCs were recorded from dopamine cells. The amplitude of evoked IPSCs and the frequency of spontaneous miniature IPSCs measured in slices from morphine-treated guinea pigs were greater than placebo-treated controls. In addition, activation of adenylyl cyclase, with forskolin, and cAMP-dependent protein kinase, with Sp-cAMPS, caused a larger increase in IPSCs in slices from morphine-treated animals. Conversely, the kinase inhibitors staurosporine and Rp-CPT-cAMPS decreased GABA IPSCs to a greater extent after drug treatment. The results indicate that the probability of GABA release was increased during withdrawal from chronic morphine treatment and that this effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during acute withdrawal may be one adaptive mechanism that results from prolonged morphine treatment.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dopamine; Dopamine Antagonists; Enzyme Activation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Guinea Pigs; Interneurons; Morphine; Nerve Tissue Proteins; Organophosphorus Compounds; Patch-Clamp Techniques; Phorbol 12,13-Dibutyrate; Picrotoxin; Receptors, GABA-A; Salicylamides; Serotonin; Signal Transduction; Staurosporine; Strychnine; Substance Withdrawal Syndrome; Tegmentum Mesencephali; Thionucleotides

We are selectively breeding mice prone (WSP) and resistant (WSR) to ethanol withdrawal seizures assessed by handling induced convulsions (HIC). The possibility that differences between the lines in HIC scores are a result of differences in general CNS excitability not specific to ethanol withdrawal was examined. Using treatments which produce generalized seizures (electroconvulsive shock, strychnine, and flurothyl) and gamma amino-butyric acid (GABA) antagonists (picrotoxin, bicuculline, and pentylentetrazol), the ED50 for seizures was determined in the selected lines. In addition, the sensitivity of WSP and WSR mice to the anticonvulsant actions of ethanol against each treatment was determined. Neither the convulsant amperage 50 (CA50) for ECS nor the ED50 for any drug treatment differed for the selected lines. When ethanol (1.5 g/kg) was administered prior to ECS, there was a dramatic differential suppression of ECS in the lines: the CA50 of WSR mice was elevated 5-fold, whereas the CA50 of WSP mice increased only two fold. Ethanol pretreatment also elevated the ED50 for strychnine and flurothyl in WSR mice significantly more than WSP mice, but the line difference was smaller than for the anticonvulsant effect against ECS. The ED50s for the GABA antagonists were not different between the WSR and WSP lines after ethanol pretreatment. We conclude that genetic selection is producing lines of mice that differ specifically in the degree of seizure severity caused by withdrawal from ethanol physical dependence and not in generalized CNS excitability. An increased sensitivity to the anticonvulsant effects of ethanol against some convulsant treatments has appeared as a correlated response to selection in the WSR line.

Topics: Animals; Anticonvulsants; Electroshock; Ethanol; Flurothyl; GABA Antagonists; Humans; Male; Mice; Seizures; Strychnine; Substance Withdrawal Syndrome

Administration of di-n-propylacetate (DPA), an inhibitor of SSA-dehydrogenase, produces in naive rats abstinence behaviour which can be blocked by morphine and bicuculline and may be useful as a behavioural correlate of increased GABA-ergic activity. The usefulness of this model has been demonstrated by studying the effect of bicuculline, picrotoxin, strychnine, morphine, aminooxyacetic acid, 3-mercaptopropionate and thiosemicarbazide on DPA-induced abstinence behaviour. Behaviour was suppressed both by bicuculline or picrotoxin, while the selective glycine antagonist strychnine was ineffective. A comparable syndrome could not be evoked by treatment with aminooxyacetic acid, a GABA-transaminase inhibitor, indicating that the effect of DPA was not caused by inhibition of this enzyme. Instead, aminooxyacetic acid suppressed the DPA-induced abstinence behaviour, suggesting that two GABA-ergic systems with opposite effects on behaviour can be distinguished. The syndrome was also suppressed by convulsant doses of 3-mercaptopropionate, while thiosemicarbazide was ineffective. Abstinence behaviour was further suppressed by morphine with an ED50 of 0.5 mg/kg and this action could be clearly separated from its depressant effect on locomotor activity in non-treated animals. These results suggest that morphine receptors may be involved in DPA-induced abstinence behaviour. Based on these experiments a model has been proposed for GABA-ergic terminals being under the inhibitor influence of GABA-ergic autoreceptors. It is proposed that DPA-induced abstinence behaviour may be useful as a model of increased GABA-ergic activity to aid study of the regulation and properties of the GABA-ergic system in vivo.

Topics: 3-Mercaptopropionic Acid; Aminooxyacetic Acid; Animals; Behavior, Animal; Catalepsy; gamma-Aminobutyric Acid; Humans; Male; Picrotoxin; Rats; Strychnine; Substance Withdrawal Syndrome; Thiosemicarbazones; Valproic Acid

Single doses of serine (250 mg/kg i.p.) failed to elevate central glycine in mice (1 h after injection), or to compensate for losses caused by implantation of morphine base (70 mg/animal), and reduced the jumping response to nalorphine (100 mg/kg i.p.). In contrast, sustained treatment with 250-mg/kg doses of serine at 24-hour intervals produced increases in brain and medullar glycine (1 h after 4th injection: 46-50% in normal, 39-75% in morphine-dependent mice, and enhanced the jumping response (40% over controls).

Topics: Animals; Brain; Drug Tolerance; Glycine; Humans; Male; Mice; Morphine Dependence; Nalorphine; Serine; Strychnine; Substance Withdrawal Syndrome

Topics: Aggression; Animals; Blood-Brain Barrier; Desipramine; Humans; Male; Mice; Morphine; Strychnine; Substance P; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Central Nervous System; Dose-Response Relationship, Drug; Ethanol; Humans; Male; Mice; Pentylenetetrazole; Picrotoxin; Reserpine; Seizures; Strychnine; Substance Withdrawal Syndrome; Time Factors

Topics: Alcoholism; Animals; Auditory Threshold; Behavior, Animal; Electroshock; Ethanol; Female; Humans; Pentylenetetrazole; Rats; Seizures; Strychnine; Substance Withdrawal Syndrome; Substance-Related Disorders