W.H. Lyness

Destruction of dopaminergic nerve terminals in nucleus accumbens: Effect on d-amphetamine self-administration ☆

Control rats initiate self-administration of d-amphetamine and achieve stable injection rates within 7-10 days. Rats in which dopamine nerve terminals in nucleus accumbens were destroyed by bilateral microinjections of 6-hydroxydopamine (6-OHDA) did not initiate self-administration of d-amphetamine when tested for as long as 19 days. In rats previously trained to self-administer d-amphetamine, 6-OHDA injections into nucleus accumbens abolished d-amphetamine self-administration. These results suggest that dopaminergic nerve terminals in nucleus accumbens are necessary for both the acquisition and maintenance of d-amphetamine self-administration.

Increased self-administration of d-amphetamine after destruction of 5-hydroxytryptaminergic neurons ☆

Rats will initiate self-administration of d-amphetamine and achieve a stable injection rate within 7-10 days. Animals injected intraventricularly with 5,7-dihydroxytryptamine, which selectively destroys 5-hydroxytryptamine-containing neurons, consistently self-injected larger amounts of d-amphetamine from the first day of training, but the acquisition of a stable rate of drug self-administration was not altered. Bilateral microinjection of 5,7-dihydroxytryptamine into nucleus accumbens failed to alter either the acquisition of d-amphetamine self-administration or the maintenance of a stable rate of injection.

II. Measurement of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in discrete brain nuclei using reverse phase liquid chromatography with electrochemical detection

Abstract A rapid and sensitive method has been outlined for the measurement of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) utilizing a weak cation-exchange resin and liquid chromatography with electrochemical detection. The sensitivity of the procedure allows measurement of the amine in punches of rat substantia nigra even after local injection of the neurotoxin 5,7-dihydroxytryptamine. Increases in 5-HT and decreases in 5-HIAA concentrations after pargyline, and selective increases in 5-HIAA concentrations after probenecid were detected in selected brain regions (nucleus accumbens, anterior striatum, substantia nigra). Thus, this procedure is sensitive enough to estimate 5-HT turnover in discrete nuclei of the rat brain.

The effects of d-lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), pentobarbital and methaqualone on punished responding in control and 5,7-dihydroxytryptamine-treated rats

The purpose of the present study was to determine the role of central 5-hydroxytryptamine (5-HT) neuronal systems in the effects of d-lysergic acid diethylamide (LSD), 2,5-methoxy-4-methylamphetamine (DOM), pentobarbital (PB) and methaqualone (MQ) on punished responding in rats. Water-deprived rats were trained to drink from a tube that was electrified at intervals (variable interval 21 sec; 0.03 mA current intensity), electrification being signalled by a tone. In daily 10-min control sessions, these animals accepted a relatively constant number of shocks; water consumption was also quite stable. At maximally effective doses PB, and to a lesser extent MQ, produced large (400-600 percent of control) increases in punished responding with little decrease in water intake. Higher doses of these agents produced a significant depression of unpunished responding (water intake). The hallucinogens, on the other hand, produced only moderate (125-175 percent of control) increases in the number of shock received, yet a similar depression of unpunished responding. Selective destruction of 5-HT neurons by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine per se produced little change in the number of shocks received or water consumed in controls sessions. This destruction of 5-HT neurons failed to alter the effects of PB or MQ on punished or unpunished responding. The increase in punished responding produced by the hallucinogens, however, was blocked by this destruction of 5-HT neurons. Furthermore, the capacity of the hallucinogens to decrease water intake was significantly potentiated by the neurotoxin pretreatment. These data demonstrate that the effects of the hallucinogens LSD and DOM on conditioned suppression are quite different from those of PB and MQ, and that this difference may be due to the extent of 5-HT involvement in the effects of these agents.

Increased self-administration of d-amphetamine by rats pretreated with metergoline ☆

Rats trained to self-administer d-amphetamine were pretreated with metergoline, a long-acting 5-hydroxytryptaminergic antagonist, and immediately placed in self-administration cages for 8 hours. During the first 3 hours after metergoline the normal pattern of d-amphetamine self-administration was unaltered, but thereafter the rate of self-injections was increased. Between 4 and 6 hr the self-injections in metergoline-treated rats were increased in a regular fashion and subsequently (7-8 hr) in a stereotyped manner, i.e., rapid bursts of lever presses with little space between injections. In amphetamine-naive rats the levels of striatal and nucleus accumbens dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, rose with time after metergoline injection. Levels of 5-hydroxyindoleacetic acid remained unchanged in these brain areas. The neurochemical results suggest a correlation between the dopaminergic actions of metergoline and d-amphetamine self-administration.

Enhancement of the behavioral effects of 2,5-dimethoxy-4-methyl-amphetamine (DOM) by pretreatment with p-chlorophenylalanine

Seven food deprived male rats were trained to press a bar on a fixed ratio-40 (FR-40) schedule of food reinforcement. Administration of 0.5 mg/kg 2,5-dimethoxy-4-methyl amphetamine (DOM) immediately before the start of the session resulted in cessation of responding for some portion of the 40-min test session. Three successive days of p-chlorophenylalanine (PCPA) administration (100 mg/kg) 30 min after each session reduced 5-hydroxytryptamine (5-HT) to 15-26% of control concentrations in various brain regions but did not alter control rates of responding under the FR-40 schedule. Administration of 0.5 mg/kg DOM following this PCPA pretreatment resulted in a greater amount of nonresponding than observed earlier. These data suggest that the effects of the phenethylamine hallucinogen DOM are enhanced by disruption of 5-HT neuronal activity.