Comparison of the electrocortical changes induced by (+)-amphetamine and chlorpromazine when perfused directly into the dorsal raphé nucleus of the cat.

1 (+)-Amphetamine mimicked the intermittent and sustained electrocortical desynchronization produced by (-)-noradrenaline (NA) when perfused directly into the dorsal raphé nucleus of cat encéphale isolé preparations. 2 The effects of amphetamine or NA were abolished or significantly attenuated by prior application of (-)-propranolol. 3 The effect of amphetamine, but not that of NA, was blocked by prior applications of guanethidine or chlorpromazine (CPZ). 4 Desmethylimipramine (DMI) produced dose-related changes in electrocortical activity which were similar to those induced by NA when applied to the same sites within the dorsal raphé nucleus. 5 DMI potentiated the effects of both amphetamine and NA, but guanethidine only abolished the DMI-induced potentiation of the amphetamine response. 6 (-)-Propranolol, guanethidine and CPA produced a short period of electrocortical desynchronization at the beginning of the perfusion period before antagonism of the amphetamine response was apparent. 7 The results suggest that CPZ and amphetamine have an action within the dorsal raphé nucleus possibly related to noradrenergic terminals.     

Muscimol injections in the nucleus raphé dorsalis block the antinociceptive effect of morphine in rats: apparent lack of 5-hydroxytryptamine involvement in muscimol''s effect.

The effect of morphine (3 mg kg-1 subcutaneously) on tail flick in the tail immersion test was studied in rats which had received a muscimol (100 ng) injection either in the nucleus raphé dorsalis (DR) or medianus (MR). The levels of 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and striatum of muscimol-injected animals. Muscimol injections in the DR reduced 5-HIAA concentrations in the striatum but not in hippocampus, whereas in animals which had received muscimol in the MR a selective decrease in hippocampal 5-HIAA levels was found. Muscimol injections in the DR blocked the effect of morphine while no effect was seen in animals which had received muscimol in the MR. An injection of 5,7-dihydroxytryptamine (6 micrograms in 3 microliter) in the DR did not change the effect of morphine or muscimol. These findings indicate that muscimol-sensitive neurones in the DR, which are probably not 5-hydroxytryptaminergic, are involved in the effect of morphine on tail flick in tail immersion. The muscimol-sensitive neurones involved in this effect of morphine do not seem to exist in the MR.     

Electrocortical changes induced by the perfusion of noradrenaline, acetylcholine and their antagonists directly into the dorsal raphé nucleus of the cat.

1 The electrocortical changes induced by the perfusion of drugs directly into the dorsal raphé nucleus of the cat encéphale isolé preparation have been studied. 2 (-)-Noradrenaline (NA), (-)-adrenaline, or (-)-isoprenaline (Isop) produced intermittent or sustained electrocortical desynchronization during the perfusion period. 3 These changes were markedly attenuated or completely abolished by the prior perfusion of (+/-)-sotalol or (-)-propranolol, but not by equimolecular concentrations of (+)-propranolol. 4 The effects of NA or Isop were also blocked by phentolamine, whereas phenoxybenzamine either potentiated the responses to NA and Isop or mimicked the effects of these catecholamines. 5 The effect of dopamine was similar to that induced by NA, but could not be elicited at all of the perfusion sites where NA was effective. It could be blocked by (+/-)-sotalol or (-)-propranolol and also by the prior perfusion of fusaric acid. 6 Acetylcholine (ACh) increased, or initiated, electrocortical synchronization. These effects could be antagonized by sensory stimulation, the prior perfusion of atropine, or the simultaneous perfusion of NA at the same site. 7 Lignocaine, induced prolonged electrocortical desynchronization, behavioral alerting and an increased responsiveness to sensory stimulation. 8 The results have been discussed in relation to the possible involvement of inhibitory beta-adrenoceptors and facilitatory cholinoceptors (muscarinic) in the functioning of the dorsal raphé nucleus.     

Evidence that 5-hydroxytryptamine release in rat dorsal raphé nucleus is controlled by 5-HT1A, 5-HT1B and 5-HT1D autoreceptors.

Electrically stimulated 5-hydroxytryptamine (5-HT) release was monitored in slices of rat dorsal raphé nucleus (DRN) by fast cyclic voltammetry. Pseudo-single pulse stimulations (5 pulses at 100 Hz) were used to enable the effect of various receptor agonists to be seen without competition from endogenously released transmitter. The selective 5-HT1A receptor agonist, (+)-8-OH-DPAT (1.0 microM) decreased stimulated 5-HT release to 31 +/- 3% of controls. This decrease was inhibited by the 5-HT1A receptor antagonists, (+)-WAY-100135 (1.0 microM) and WAY-100635 (0.1 microM) but not by the 5-HT1D/B antagonist, GR127935 (0.05 microM). The selective 5-HT1B receptor agonist, CP-93129 (0.3 microM) decreased stimulated 5-HT release to 61 +/- 4% of control. This effect was antagonized by the 5-HT1B receptor antagonist, isamoltane (0.5 microM) but not by (+)-WAY-100135. The 5-HT1D agonist, sumatriptan (0.5 microM) decreased stimulated 5-HT release to 52 +/- 2% of controls. This decrease was blocked by GR-127935 but not by WAY-100635. These results suggest that 5-HT release in the rat DRN is under the control of 5-HT1A, 5-HT1B and 5-HT1D autoreceptors.     

Caffeine-phenacetin interaction in the rat: effects on absorption,metabolism and locomotor activity

The interactive effects of caffeine and phenacetin on the locomotor activity of the DA rat involved changes in absorption and metabolism as well as effects possibly exerted at the cns level. Phenacetin initially retarded the absorption of caffeine when coadministered by gavage but not when caffeine was given intraperitoneally and phenacetin orally. Phenacetin also increased the time for the plasma/caffeine concentration to peak, increased its peak concentration and prolonged its presence in the plasma. Urinary excretion patterns, suggested a blockade of the N-demethylation of caffeine by phenacetin. In contrast, caffeine had only a minor influence on the absorption and metabolism of phenacetin. The locomotor effects of the caffeine-phenacetin combination reflected the absorptive and metabolic interactions which occurred. Caffeine-induced hyperactivity was initially masked by phenacetin in a dose-dependent manner but after 2 h, when the plasma phenacetin concentrations were much lower, its retarding influence on caffeine metabolism became apparent and hyperactivity consequent upon an elevated plasma caffeine concentration was seen. Phenacetin also antagonized the hyperactive effects of theophylline and of (+)-amphetamine.     

Antidiuretic effects of dibutyryl-cyclic AMP microinjected into the hypothalamic paraventricular nucleus in a water-loaded and ethanol-anesthetized rat

Effects of dibutyryl-cyclic AMP (db-cAMP) and cyclic AMP (cAMP) when microinjected into the hypothalamic paraventricular nucleus (PVN) in a water-loaded and ethanol-anesthetized rat on the rate of urine outflow, urine osmotic pressure and other visceral functions were investigated. The microinjection of db-cAMP decreased the rate of urine outflow with concomitant increase in the urine osmotic pressure, but did not change mean blood pressure, heart rate, respiration rate and rectal temperature. The antidiuretic effect of db-cAMP was more potent than the effect of cAMP, the median effective doses (ED50) being approx. 40 nmol for db-cAMP and more than 300 nmol for cAMP, respectively. The time-courses for the antidiuretic effects and for the increase in the urine osmotic pressure showed a similar pattern, with the maximal effect at approx. 30 to 40 min and the duration of approx. one hour or longer. The effect of db-cAMP was potentiated by pretreatment with methylxanthines and inhibited by pretreatment with atropine. A second microinjection of db-cAMP induced a less potent antidiuretic effect than the first microinjection (tachyphylaxis). The results indicated the antidiuretic effects of microinjection of db-cAMP and cAMP into the PVN, and a possible mechanism for this was discussed.     

Investigation of the effects of muscimol on different components of [3H]propyl beta-carboline-3-carboxylate binding to rat hippocampal and cerebellar membranes

The binding of [3H]propyl beta-carboline-3-carboxylate [( 3H]PCC) to rat hippocampal and cerebellar membranes was investigated together with the displacement by PCC of [3H]flunitrazepam [( 3H]FNM). Results were consistent with the presence of a single recognition site in cerebellum and two sites in hippocampys, but the affinity of neither of the hippocampal sites correlated with that in the cerebellum. Muscimol did not alter the affinity or capacity of any of these sites under the conditions used, indicating that PCC does not show the benzodiazepine-like property of GABAergic modulation, at any of the subpopulations of its binding sites.     

Inhibition of d-amphetamine-induced locomotor activity by injection of haloperidol into the nucleus accumbens of the rat

The effect of intracerebral administration of antagonists of dopamine and noradrenaline upon the locomotor stimulation induced by intraperitoneal injection of d-amphetamine sulfate in rats was investigated. Injection of low doses of the dopamine antagonist haloperidol (2.5 g and 5 g) bilaterally into the nucleus accumbens antagonized the locomotor stimulation following d-amphetamine. No significant inhibition was observed following administration of the alpha-adrenergic antagonist phentolamine or the beta-adrenergic antagonist propranolol into the nucleus accumbens. Injection of the same doses of haloperidol into the caudate nucleus did not inhibit the d-amphetamine induced locomotor activity, in contrast to the effects seen following injection into the nucleus accumbens.The results confirm the significance of dopaminergic mechanisms for the locomotor stimulant effect of d-amphetamine and indicate that the mesolimbic dopamine system plays an important role in this respect.     

Injections of dopaminergic, cholinergic, serotoninergic and GABAergic drugs into the nucleus accumbens: effects on locomotor activity in the rat

Locomotor activity was elicited by injecting dopamine into the nucleus accumbens of the chronically cannulated rat. Dopamine was also injected together with cholinergic, serotoninergic and GABAergic agonists and antagonists to investigate the possible contribution to locomotor activity of these putative neurotransmitters. Carbachol elicited a transient enhancement of dopamine-stimulated activity. Atropine attenuated carbachol-stimulated enhancement but did not attenuate dopamine-stimulated activity. Serotonin attenuated dopamine-stimulated activity. The peripheral serotonin antagonist, methysergide, also attenuated locomotion. The administration of GABA elicited a bimodal response in locomotion, the lower dose eliciting a small increase in locomotion and the larger dose eliciting a reduction. The GABA antagonist, picrotoxin, elicited only increases in locomotion at all doses. These results suggest that there is not a cholinergic interneuron on the dopamine-stimulated pathway subserving locomotion but that both cholinergic and serotoninergic projections may modulate locomotor activity. Further they suggest that such modulation must be at least one inhibitory interneuron away from the dopamine synapse on the locomotor pathway. In addition, these results suggest a direct influence of GABAergic interneurons on the pathway subserving locomotor activity within the nucleus accumbens.     

Acute effects of nicotine injection into the nucleus accumbens on locomotor activity in nicotine-naive and nicotine-tolerant rats

To assess the role of nicotine receptors in the nucleus accumbens on locomotor activity we bilaterally implanted guide cannulae for later injection of (-)-nicotine into the nucleus accumbens of Wistar rats. Motor activity was tested in a complex tunnel maze equipped with photocells for automatic recording. This system of dark tunnels elicits spontaneous exploration even after repeated exposure. Half of the rats were made nicotine-tolerant by daily systemic injections of (-)-nicotine for 15 days (nicotine pretreatment); the other half remained nicotine-naive (saline pretreatment). Whereas (-)-nicotine (40 nmol/0.3 microliter) bilaterally injected into the nucleus accumbens of nicotine-naive animals suppressed locomotor activity, the same amount injected into the nucleus accumbens of nicotine-tolerant rats had no effect on locomotor activity. Systemic injections of nicotine (0.4 mg/kg) induced a depression and stimulation of locomotor activity in saline-pretreated and nicotine-pretreated rats, respectively. Our results support a dual role for nicotine in locomotor activity with the initial depressant effect in nicotine-naive animals due to stimulation of the nucleus accumbens and perhaps other structures.     

The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity.

1. The effects of acute and subchronic nicotine and (+)-amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely-moving rats by use of in vivo microdialysis. 2. In rats which had been habituated to the test apparatus for approximately 80 min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4 mg kg-1) caused a dose-dependent increase (P less than 0.01) in spontaneous activity and evoked significant increases (P less than 0.05) in the extracellular levels of DOPAC and HVA. 3. Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg-1) resulted in increased basal levels of dopamine (P less than 0.01) and decreased basal levels of DOPAC (P less than 0.05) in the NAc dialysates. 4. Pretreatment with nicotine (0.1 or 0.4 mg kg-1 daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant (P less than 0.05). 5. If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg-1) resulted in significant increases (P less than 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged (P less than 0.05) the dopamine response to a challenge dose of nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antidiuretic effects of alpha- and beta-adrenoceptor agonists microinjected into the hypothalamic paraventricular nucleus in a water-loaded and ethanol-anesthetized rat

Effects of catecholamines microinjected into the paraventricular nucleus in the hypothalamus on urine outflow in a rat which was loaded with water and anesthetized with ethanol were studied. L-Norepinephrine, L-epinephrine and L-isoproterenol induced potent antidiuresis with similar time courses to each other. The ED50 values for L-norepinephrine, L-epinephrine and L-isoproterenol were approximately 5, 10 and 5 nmol, respectively. The D-isomer of isoproterenol demonstrated no significant antidiuretic activity. The effect of L-norepinephrine was inhibited strongly by premicroinjection of alpha- and beta-adrenoceptor antagonists. The effect of DL-isoproterenol was inhibited strongly by beta-adrenoceptor antagonists, but not affected by alpha-adrenoceptor antagonist. Premicroinjection of a muscarinic antagonist, atropine, partially inhibited anti-diuretic effects induced by L-norepinephrine and DL-isoproterenol. Visceral functions other than urine outflow such as mean blood pressure, respiration rate, heart rate and rectal temperature were not significantly altered when the urine outflow decreased down to 20-30% of the control by microinjection of L-norepinephrine and DL-isoproterenol. The results demonstrated that stimulation of alpha- and beta-adrenoceptor in the paraventricular nucleus induced potent antidiuretic effects, partial inhibition of which by atropine suggested a possible presynaptic facilitation of the release of ACh by the stimulation of the adrenoceptors.     

Antidiuretic effects of alpha- and beta-adrenoceptor agonists microinjected into the hypothalamic supraoptic nucleus in a water-loaded and ethanol-anesthetized rat

Effects of catecholamines microinjected into the supraoptic nucleus in the hypothalamus on urine outflow in rats which were loaded with water and anesthetized with ethanol were studied. L-Norepinephrine, L-epinephrine and L-isoproterenol induced potent antidiuresis, showing similar time courses to each other. The ED50 values for L-norepinephrine, L-epinephrine and L-isoproterenol were approx. 25, 20 and 5 nmol, respectively. The D-isomer of isoproterenol demonstrated no significant antidiuretic activity. The effect of L-norepinephrine was inhibited strongly by preinjection of alpha- and beta-adrenoceptor antagonists. The effect of DL-isoproterenol was inhibited strongly by beta-adrenoceptor antagonists, but not affected by alpha-adrenoceptor antagonist. Among the three catecholamines, only L-epinephrine induced a tachyphylaxis in the antidiuretic effect. Visceral functions other than urine outflow such as blood pressure, respiration rate, heart rate and rectal temperature were not significantly changed by microinjecting antidiuretic doses of the catecholamines. The results demonstrated that stimulation of alpha- and beta-adrenoceptors in the supraoptic nucleus induced a potent antidiuretic effect.     

The effects of MDMA and other methylenedioxy-substituted phenylalkylamines on the structure of rat locomotor activity.

The effects of acute subcutaneous injections of methylenedioxy-substituted phenylalkylamines in rats were tested in an unconditioned motor behavior paradigm using the Behavioral Pattern Monitor (BPM). Based on a previously developed scaling hypothesis and the associated temporal and spatial scaling exponents (alpha and d), the effects of racemic and S(+) 3,4-methylenedioxyamphetamine (MDA), racemic, S(+) and R(-) 3,4-methylenedioxymethamphetamine (MDMA), racemic N-methyl-1-(1,3-benzodioxol-5yl)-2-butanamine (MBDB), racemic N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 2,5-dimethoxy-4-iodoamphetamine, and methamphetamine were characterized using the d-alpha plane. Three distinct dose-response patterns were observed. 1) S(+) and (+/-)MDA had pronounced dose-dependent effects on the structure of motor behavior, which were characterized by long-straight path movements and minimal changes in the amount of motor behavior. 2) (+/-)MDMA and (+/-)MBDB dose-dependently changed patterns of movements towards long-straight paths together with dose-dependent increases in the amount of motor activity. 3) S(+)MDMA and (+/-)MDEA produced dose-related increases in the amount of motor activity with minimal changes of the movement patterns in the BPM. Comparisons with the existing drug discrimination, operant, and biochemical literature on these compounds lead to the conclusion that the observed effects in the d-alpha plane do not simply reflect the different effects of these compounds as dopamine or serotonin (5-HT) releasers or reuptake inhibitors and do not parallel their different abilities to exhibit hallucinogen-like effects. Instead, indirect 5-HT1 effects appear to contribute substantially to the differential changes in the amount and structure of motor behavior induced by the phenylalkylamines. This conclusion may provide an encouraging rationale to develop postsynaptically effective "entactogens," a potential new drug category as adjunctive psychotherapeutics.     

Combined effects of ethanol and MK 801 on locomotor activity in the rat.

The present study examined the effects of ethanol (0.75 g/kg IP) alone and in combination with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK 801 (0.1 mg/kg SC) on the locomotor activity of rats. Sixteen rats were treated with vehicle plus saline, MK 801 plus saline, vehicle plus ethanol, and MK 801 plus ethanol. Locomotor activity was quantified for a period of 12 hours following drug administration. Ethanol was found to significantly decrease locomotor activity whereas MK 801 significantly increased locomotion during the first 2 hours postdrug. In addition, there was a significant additive interaction between ethanol and MK 801 during this time period. Two to four hours postdrug, MK 801 was observed to significantly decrease locomotion. Four to six hours postdrug, ethanol-treated rats had significantly increased locomotor activity whereas MK 801-treated rats displayed significantly decreased locomotion. No significant interaction was found between ethanol and MK 801 4 to 6 hours postdrug. No significant effects of any of the drugs on locomotor activity were observed from 6 to 12 hours postdrug. These results suggest that ethanol and MK 801 produce a pattern of effects on locomotor activity which depend on the time elapsed following drug administration.