ABSTRACT
The major aim of this work was to compare sensitized responses to amphetamine with those of apomorphine. This was done using both a univariant analysis of locomotor activity and a multivariant neural network analysis of five different behaviors. The neural network analysis compares the pattern of behaviors from a treated group to a set of patterns from control conditions and estimates the dose of drug in control conditions that best matches the pattern of behaviors of the treated group. Both methods indicated that repeated administration of 2.0 mg/kg amphetamine but not 0.5 mg/kg amphetamine resulted in sensitization to the administration of a 0.5 mg/kg amphetamine challenge given 10 days following the end of the sensitizing regimen. Both analyses indicated sensitization following repeated administration of 5 mg/kg apomorphine. Studies of cross sensitization were done using a neural network analysis that could distinguish patterns of behavior elicited by amphetamine from those elicited by apomorphine. Such studies indicated that apomorphine elicits an apomorphine-like response in animals sensitized to either apomorphine or amphetamine. In contrast, amphetamine produces an amphetamine-like response in animals sensitized to amphetamine and an apomorphine-like response in animals sensitized to apomorphine. The results indicate that neural network analysis may be a useful tool for analyzing drug effects on patterns of behavior.
Subject(s)
Amphetamine/pharmacology , Apomorphine/pharmacology , Dopamine Agonists/pharmacology , Neural Networks, Computer , Animals , Male , Motor Activity/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
At doses that elicit behavioral activation, apomorphine does not induce Fos-protein in the nucleus accumbens of control animals but does under conditions of denervation supersensitivity. The purpose of this study was to determine whether apomorphine induces Fos-protein in animals sensitized by repeated treatment with apomorphine and whether the magnitude of such induction parallels the magnitude of behavioral response observed after different sensitizing paradigms. Apomorphine did induce Fos-protein expression in animals pretreated with apomorphine; however, the rats showing highest levels of induction were not those showing the largest behavioral responses.
Subject(s)
Apomorphine/pharmacology , Dopamine Agonists/pharmacology , Locomotion/drug effects , Proto-Oncogene Proteins c-fos/drug effects , Animals , Male , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Proto-Oncogene Proteins c-fos/biosynthesis , Rats , Rats, Sprague-Dawley , Sensitivity and SpecificityABSTRACT
Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. Impairment of GABAergic neurotransmission may be involved in the pathogenesis of epileptic phenomena. We have previously characterized biochemical and histological changes following unilateral intrahippocampal infusion of a phosphorothioate antisense oligodeoxynucleotide to the GABA(A) receptor gamma2 subunit in rats in vivo. The aim of the present study was to investigate the behavioral changes of rats following unilateral hippocampal antisense 'knockdown' of the GABA(A) receptor gamma2 subunit. Antisense, but not mismatch control oligodeoxynucleotide treated rats had a significant weight loss (10%) during 6 d of treatment. Antisense treated rats exhibited no changes in spontaneous behavior, including anxiety-like behavior as measured in the social interaction test, compared to mismatch oligodeoxynucleotide treated rats. However, antisense treated rats developed pronounced changes in induced seizure activity. Seizures induced by subcutaneously injected pentylenetetrazol were markedly accentuated in antisense treated rats compared to treatment naive rats, whereas mismatch treated rats showed a lower seizure score than that of naive rats. Antisense treated rats had a significantly elevated threshold for seizures induced by electrical stimulation in the maximal electroshock seizure threshold test. The results suggest that intrahippocampal infusion of antisense oligodeoxynucleotide to the GABA(A) receptor gamma2 subunit leads to specific alterations in the sensitivity to induced seizures. The results are viewed as consequences of selective down-regulation of GABA(A) receptors and diminished inhibitory neurotransmission in the hippocampus.
Subject(s)
Hippocampus/metabolism , Oligonucleotides, Antisense/pharmacology , Receptors, GABA-A/genetics , Seizures/metabolism , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Convulsants , Electroshock , Handling, Psychological , Hippocampus/drug effects , Interpersonal Relations , Male , Motor Activity/drug effects , Motor Activity/physiology , Pentylenetetrazole , Rats , Rats, Wistar , Receptors, GABA-A/drug effects , Seizures/chemically induced , Seizures/physiopathologyABSTRACT
The behavioral consequences of co-activation of metabotropic and ionotropic excitatory amino acid receptors were studied in mice using intracerebroventricular (i.c.v.) co-infusion of the metabotropic receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) with the subtype-specific ionotropic receptor agonists N-methyl-D-aspartate (NMDA), kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). I.c.v. co-infusion of ionotropic receptor agonists (0.3-3 nmol/min) with a fixed dose of 1S,3R-ACPD (144 nmol/min) decreased time to onset of clonic convulsions (P < 0.05). Pretreatment with i.c.v. infusion of 72 nmol of 1S,3R-ACPD reduced time to onset of convulsions induced by an intravenous (i.v.) infusion of NMDA (P < 0.05) but had no effect on convulsions induced by pentylenetetrazol. These results reveal that activation of the metabotropic excitatory amino acid receptor selectively potentiates the behavioral response following activation of the ionotropic excitatory amino acid receptors.
Subject(s)
Behavior, Animal/drug effects , Cycloleucine/analogs & derivatives , Receptors, Glutamate/drug effects , Seizures/chemically induced , Animals , Cycloleucine/pharmacology , Drug Synergism , Injections, Intraventricular , Kainic Acid/pharmacology , Male , Mice , N-Methylaspartate/pharmacology , Neurotoxins/pharmacology , Pentylenetetrazole/pharmacology , Receptors, Glutamate/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacologyABSTRACT
Intracerebroventricular (i.c.v.) infusion in mice of the selective metabotropic excitatory amino acid receptor agonist 1S,3R-1- aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) (0.6-575 nmol/min) dose dependently induced face washing and scratching. In contrast, the subtype-specific ionotropic excitatory amino acid receptor agonists N-methyl-D-aspartate (NMDA), kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) (0.3-3.0 nmol/min) dose dependently induced clonic convulsions. I.c.v. infusion of the non-selective metabotropic receptor agonists ibotenate (6 nmol/min) or quisqualate (30 nmol/min) induced clonic convulsions. However, when ionotropic receptors were blocked with (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801, dizoclipine) (3 nmol/min) or 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(f)-quinoxaline (NBQX) (9 nmol/min), respectively, face washing and scratching behavior emerged. Neither MK-801 or NBQX (ED50 value > 100 nmol/min), nor the putative metabotropic receptor antagonist L-amino-3-phosphoro-propionic acid (L-AP3) (> 176 nmol/min); nor the dopamine receptor antagonists SCH 23390 (> 74 nmol/min), metoclopramide (> 89 nmol/min) and haloperidol (> 27 nmol/min) antagonized 1S,3R-ACPD-induced scratching (144 nmol/min). These results suggest that the behavioral consequences of i.c.v. infusion of 1S,3R-ACPD in mice reflect a selective activation of metabotropic receptors that differs from the behavioral changes observed with i.c.v. infusion of ionotropic receptor agonists.
