d-Amphetamine and gamma-butyrolactone alteration of dopamine synthesis in the terminals of nigrostriatal and mesolimbic neurons. Possible role of various autoreceptor sensitivities

The rate of synthesis of dopamine (DA) was estimated in vivo in terminals of nigrostriatal and mesolimbic neurons by measuring the accumulation of dihydroxyphenylalanine (DOPA_ in the striatum and in the nucleus accumbens and olfactory tubercle of male rats following the administration of an inhibitor of aromatic L-amino acid decarboxylase. Low to moderate doses of d-amphetamine (0.5 to 1.0 mg/kg) increased DA synthesis in the striatum but were without effect in the nucleus accumbens and olfactory tubercle; a higher dose (5.0 mg/kg) did not alter DA synthesis in any of the brain regions. Despite the lack of effect of d-amphetamine per se in the nucleus accumbens and olfactory tubercle, in both of these regions, as well as in the striatum, this drug was effective in reversing the decreased DA synthesis induced by a monoamine oxidase inhibitor (nialamide) or a DA agonist (apomorphine). γ-Butyrolactone (GBL) increased DA synthesis in the striatum, nucleus accumbens and olfactory tubercle, but it was less potent, less effective, and had a shorter duration of action in the latter two regions. d-Amphetamine, like GBL, may exert part of its effect on DA synthesis by reducing impulse flow in ascending DA neurons, since a low dose of d-amphetamine (0.125 mg/kg) potentiated the GBL-induced increase in DA synthesis in striatum, nucleus accumbens and olfactory tubercle. Regional differences in the actions of GBL and d-amphetamine on DA synthesis may be related to differences in receptor-mediated mechanisms that regulate the synthesis of this amine in neurons terminating in the striatum versus those terminating in nucleus accumbens and olfactory tubercle. At least one difference appears to be in the sensitivity of DA autoreceptors in these regions. The dose of apomorphine needed to reverse the GLB-induced increase of DA synthesis in nucleus accumbens and olfactory tubercle was approximately 1/10 that necessary to cause the same effect in the striatum. Pretreatment with a DA antagonist (haloperidol) potentiated the GBL-induced stimulation of DA synthesis in nucleus accumbens and olfactory tubercle, but not in the striatum. These results suggest that the reduced abilities of GBL and amphetamine to increase DA synthesis in nucleus accumbens and olfactory tubercle may result from a greater sensitivity of autoreceptors on mesolimbic DA neurons permitting a tighter regulatory control over DA synthesis in these neurons.     

Effect of antipsychotic drugs on homovanillic acid levels in striatum and olfactory turbercle of the rat

Dose-response curves for the elevation of homovanillic acid levels in corpus striatum and olfactory tubercle of rats were determined by mass fragmentography after treatment with antipsychotic drugs. The order of potency in both regions was: haloperidol > chlorpromazine > thioridazine and clozapine. The relative elevation of the content of homovanillic acid was significantly greater in the striatum than in the olfactory tubercle for all drugs except thioridazine. The antipsychotic effect of the drugs tested may be related to the interference with dopaminergic mechanisms in striatal and/or limbic areas.     

Tolerance to haloperidol-induced increases in dopamine metabolites: fact or artifact?

Haloperidol increased 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations in the striatum, nucleus accumbens and olfactory tubercle of both drug-naive rats and rats pretreated with haloperidol (10 injections). The increases in metabolite concentrations were greater in all brain regions of the naive rats, suggesting that haloperidol pretreatment resulted in a decreased responsiveness to the drug (tolerance). However, subchronic haloperidol injections also resulted in decreased basal metabolite concentrations in rats killed 48 h after the last injection. While the response of drug-experienced rats to haloperidol was attenuated relative to that of drug-naive rats, this difference could be accounted for entirely by the decreased basal metabolite concentrations that occur after repeated haloperidol injections.     

Responses of dopaminergic and serotonergic systems to triethyllead intoxication

Rats treated with triethyllead (TEL) exhibit a behavioral supersensitivity to challenge with dopamine agonists at 7 days following administration of TEL. In the present series of experiments, some neurochemical mechanisms which may affect this behavioral supersensitivity were detected. Administration of a single dose of TEL chloride (7.88 mg/kg, SC) to male Fischer-344 rats decreased the concentrations of dopamine in hippocampus, and of serotonin in olfactory tubercle, at Day 7 posttreatment. The ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine (one estimate of serotonin turnover) was increased in nucleus accumbens (p less than 0.05), with a similar trend in olfactory tubercle and striatum (p less than 0.10). No changes were detected in binding of [3H]spiperone to D2 dopamine receptors in striatum or olfactory tubercle. However, although basal adenylate cyclase activity was unaltered in TEL-treated rats, the Vmax for dopamine-stimulated adenylate cyclase activity was significantly elevated in olfactory tubercle. Conversely, TEL at micromolar concentrations markedly attenuated both basal and dopamine-stimulated adenylate cyclase activity in vitro in striatal homogenates. These data suggest the hypothesis that administration of TEL to rats results in an up-regulation of D1 dopamine receptors in olfactory tubercle, and that the behavioral supersensitivity of TEL-treated animals to dopamine agonists may, in part, be a result of this receptor supersensitivity.     

Effects of alpha-fluoromethylhistidine on locomotor activity, brain histamine and catecholamine contents in rats.

One hour after the intraperitoneal (i.p.) injection of FMH (200 mg/kg), locomotor activity and rearing were statistically reduced, by 3 hours later, only the locomotor activity was reduced in rats. The i.p. injection of FMH (100 and 200 mg/kg) had no effects on motor incoordination, blood pressure, heart rate and tetrabenazine-induced ptosis in rats. One and 3 hours after FMH injection, the histamine levels significantly decreased in the hypothalamus, cortex and thalamus, slightly in the olfactory bulb, amygdala, pons-medulla oblongata and midbrain, but very little in the striatum, hippocampus, cerebellum and pituitary. On the other hand, noradrenaline and dopamine levels were not affected in most of the regional parts, although in the cortex and midbrain, the dopamine levels were slightly reduced 1 hour after FMH (100 and 200 mg/kg). These data showed that central histamine may play an important role in the locomotor activity of rats.     

Short-term and long-term effects of methamphetamine on biogenic amine metabolism in extra-striatal dopaminergic nuclei

The effects of multiple toxic doses of methamphetamine on catecholaminergic, serotonergic and cholinergic metabolism in the neostriatum, nucleus accumbens, olfactory tubercle and median eminence area of the rat brain have been investigated. Methamphetamine (15 mg/kg s.c.) was administered every 6 hr for 5 doses. Thirty-six hours after the first of 5 doses, tyrosine hydroxylase (TH) activity, as well as dopamine and norepinephrine levels, were significantly decreased in the neostriatum and olfactory tubercle but were not altered in the nucleus accumbens or median eminence area. Prior to the 36-hr time point, drug treatment significantly decreased TH activity in the neostriatum and olfactory tubercle, but did not change the enzyme activity in the nucleus accumbens. Neostriatal TH activity in the neostriatum and olfactory tubercle was significantly decreased up to 30 days after methamphetamine. However, only a slight change in TH activity occurred in the nucleus accumbens at 30 days after drug treatment. In contrast, tryptophan hydroxylase (TPH) activity was significantly decreased from 3 hr after the first dose up to 30 days after the fifth dose in all brain regions investigated. Methamphetamine caused a slight decrease in choline acetyltransferase activity only in the olfactory tubercle at the 36-hr time point. This evidence suggests that the serotonergic neurons are more sensitive to the toxic effects of methamphetamine than the dopaminergic neurons, whereas, the cholinergic neurons seem to be essentially unaffected.     

Presynaptic dopamine receptors

Summary An in vivo model for investigating the interaction of drugs with presynaptic receptors was used to study the effect of chronic treatment of rats with fluphenazine decanoate on the presynaptic dopamine receptors in the neostriatum and olfactory tubercle. In this model system dopaminergic impulse flow is inhibited pharmacologically with -butyrolactone (GBL). This results in an increase of apparent tyrosine hydroxylase activity, estimated by the accumulation of a dopa during the 30-min interval following administration of a dopa decarboxylase inhibitor. Dopamine agonists produce a dose-dependent blockade of the effect of GBL on dopa accumulation.On days 12 through 21 after rats were injected with fluphenazine decanoate, 2 dopamine agonists-apomorphine (tested on days 12, 15, 17, and 21) and trivastal (ET 495; piribidel; tested on days 12, 14, and 19)-were more potent in blocking the GBL-induced increase of dopa accumulation in the striata of treated animals than in controls. Thirty days after the fluphenazine injection the effect of the dopamine agonists on dopa accumulation in the neostriatum returned to control levels. On Day 14 after fluphenazine decanoate injection the dose-response curve of apomorphine's inhibitory effect on the GBL-induced increase of dopa accumulation in the neostriatum was shifted to the left.In control animals apomorphine was approximately 10-fold more potent in depressing the GBL-induced increase of dopa accumulation in the olfactory tubercles than in the neostriatum. Apomorphine was even more potent in the olfactory tubercle on day 14 after a single injection of fluphenazine decanoate. These results suggest that following chronic treatment of rats with a phenothiazine, presynaptic receptors on dopamine nerve terminals in the striatum and limbic system become supersensitive to dopamine agonists.A preliminary account of this work was presented at the Seventh Annual Meeting of the American Neurochemical Society held in Vancouver, British Columbia, March 15–19, 1976     

Bilateral neurochemical changes induced by unilateral cerebral haloperidol administration: evidence for cerebral asymmetry in the rat.

Bilateral alterations in dopamine metabolism were determined in the striatum, olfactory tubercle, and frontal cortex of rats pretested for circling behavior. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine, and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography 15 min after right or left intracarotid infusion of haloperidol. Concentrations of DOPAC and HVA were significantly increased in the striatum and frontal cortex ipsilateral to the side of haloperidol infusion, regardless of whether it was right or left. In contrast, the concentrations of these metabolites were unchanged in the olfactory tubercle after a right side infusion, but bilateral increases were evident after a left side infusion. Higher levels of DOPAC and HVA were also apparent in the left striatum and olfactory tubercle after intravenous jugular administration of haloperidol. Dopamine levels were significantly lower in the left striatum and right olfactory tubercle after intravenous haloperidol infusions. 5-HIAA concentrations were higher in the left olfactory tubercle following left side infusions of haloperidol. These data indicate that unilateral cerebral administration of haloperidol induces asymmetric and side-dependent alterations in dopamine and serotonin metabolites. These differences appear to be due to intrinsic variations in the sensitivity to haloperidol, but are not associated with the direction of circling behavior.     

Development of supersensitivity of apomorphine-induced increases in acetylcholine levels and stereotype after chronic fluphenazine treatment

Dopamine agonists administered systemically produce an increase in striatal levels of acetylcholine (ACh). Possible development of postsynaptic dopamine receptor supersensitivity after neuroleptic treatment was studied by measurement of apomorphine (APO)-induced increase in ACh levels in the striatum and olfactory tubercle. Apomorphine-induced Stereotypic behaviour was also measured. Rats received a single subcutaneous injection of either sesame seed oil vehicle or fluphenazine (FLU) decanoate (10mg kg^?1), a long-acting neuroleptic preparation. After 14 days, rats received APO intraperitoneally, in various doses (0.03–1.0 mg kg^?1). Fifteen minutes later, brain tissue was rapidly fixed by microwave irradiation, dissected, and ACh levels determined by means of gas chromatography. Acetylcholine levels were 75nmol g^?1 in olfactory tubercle and 70 nmol g^?1 in striatum. Apomorphine treatment resulted in dose-dependent increases of ACh level in both regions. Apomorphine-induced increases were greater in rats pretreated with FLU than in controls. Using 0.1 mg kg^?1 APO, the higher striatal ACh-elevating effect found 14 days after FLU treatment was also present 21 days, but not 27 days after FLU treatment. At 21 days after subcutaneous injection, 0.25 mg kg^?1 APO induced significantly greater Stereotypic behaviour in FLU-treated rats than in controls. Thus. FLU treatment led to an apparent temporary supersensitivity of APO-induced increases in ACh levels and stereotypic behaviour.     

A comparison of the potencies of various dopamine receptor agonists in models for pre- and postsynaptic receptor activity

Several dopamine (DA) receptor agonists, notably N,N-dipropyl-2-aminotetralin analogues differing in the number and position of phenolic hydroxyl groups, were evaluated in model systems for pre- and postsynaptic dopaminergic activity. Apomorphine, piribedil and pergolide were included for comparison. All compounds inhibited the gamma-butyrolactone (GBL)-induced increase in DA concentrations in the rat striatum and olfactory tubercle, although a dose-dependency could not be demonstrated for one of the compounds, i.e. N,N-dipropyl-2-amino-5,6-dihydroxy-tetralin. In addition to the reversal of the DA-increase all compounds decreased the HVA and DOPAC levels in a dose-dependent manner, in much the same way as in normal, non GBL-pretreated rats. The potencies of the drugs to decrease HVA in normal rats and to inhibit the DA-increase and to decrease HVA in GBL-pretreated rats, both in the striatum and the olfactory tubercle were compared with each other and with the potencies to induce stereotyped behaviour. It may be concluded that (1) N,N-dipropyl-2-amino-7-hydroxytetralin shows the largest difference in activity in the biochemical and the behavioural models, suggesting a selective presynaptic activity. This was corroborated by the appearance of a marked hypomotility after low doses of this compound; (2) The potencies to decrease striatal HVA concentrations are generally somewhat different from the potencies to inhibit GBL-induced DA-increases, but appear to be comparable to the potencies to inhibit GBL-induced dihydroxyphenylalanine (DOPA)-increases; (3) There is no indication that the DA agonists in general are more potent at presynaptic receptors in the tubercle than in the striatum.     

Dopamine concentrations in the rat brain following injections into the substantia nigra of baclofen, γ-aminobutyric acid, γ-hydroxybutyric acid,apomorphine and amphetamine

Systemic administration of dl-baclofen (20–80 mg/kg) and γ-butyrolactone (250–500 mg/kg) increased the concentration of dopamine but not of norepinephrine in the rat forebrain. These drugs caused an equivalent increase in the concentration of dopamine in the striatum and olfactory tubercle, regions containing terminals of nigrostriatal and mesolimbic dopaminergic neurones, respectively. When injected directly into substantia nigra (A9), GABA, γ-hydroxybutyrate and baclofen increased the dopamine concentration in the forebrain; apomorphine and d-amphetamine were without effect. When injected into the medial portion of the ventral tegmentum (A10) baclofen increased the dopamine concentration in the olfactory tubercle and nucleus accumbens. Following intracerebral injections, dl-baclofen was several hundred times more potent than GABA, and most of the activity of baclofen resided in the l-isomer. Intracerebral injections of picrotoxin antagonized the ability of GABA but not of baclofen to increase the striatal concentration of dopamine. After unilateral intranigral injections of GABA, γ-hydroxybutyrate and baclofen rats circled away from the side of the drug injection.     

In vivo binding of N-n-propylnorapomorphine in the rat brain: regional localization, quantification in striatum and lack of correlation with dopamine metabolism

The accumulation and retention of radioactivity in rat brain were studied after intravenous injection of the dopamine (DA) agonist [3H]N-n-propylnorapomorphine ( [3H]NPA). Dose-dependent saturable accumulation of label was found in the striatum, nucleus accumbens and olfactory tubercle. DA agonists (apomorphine, N,N-dipropyl-5,6-ADTN) and antagonists (haloperidol, cis-flupenthixol) prevented this accumulation. Enhanced accumulation of radioactivity in the striatum was found after 6-OHDA lesions and short- and long-term treatment with reserpine. These results are an indication of specific NPA binding to presumably postsynaptically situated DA receptors. One hour after administration of the drug, the effect of NPA on striatal DA metabolism was not correlated with receptor saturation. Maximal numbers of in vivo NPA binding sites (about 30 and 22 pmol . g-1) in striatal tissue were calculated from independent measurements at 15 and 60 min after NPA injection. Regional distribution of radioactivity after a tracer dose of [3H]NPA was assessed in 35 brain areas and parts of the spinal cord. In addition to the already mentioned DA-rich areas receptor-specific NPA binding was also found in several other brain parts.     

Effects of (+-)3,4-methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats

Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidol's effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.     

Intracranial self-administration of MDMA into the ventral striatum of the rat: differential roles of the nucleus accumbens shell, core, and olfactory tubercle

Rationale Behavioral and anatomical data suggest that the ventral striatum, consisting of the nucleus accumbens and olfactory tubercle, is functionally heterogeneous. Cocaine and d-amphetamine appear to be more rewarding when administered into the medial olfactory tubercle or medial accumbens shell than into their lateral counterparts, including the accumbens core. Objectives We sought to determine whether rats self-administer the popular recreational drug (±)-3,4-methylenedioxymethamphetamine (MDMA) into ventrostriatal subregions and whether the medial olfactory tubercle and medial accumbens shell mediate MDMA’s positive reinforcing effects more effectively than their lateral counterparts. Results Rats receiving 30 mM MDMA into the medial olfactory tubercle, medial accumbens shell, or accumbens core, but not the lateral tubercle or lateral shell, showed higher self-administration rates than rats receiving vehicle. The medial shell supported more vigorous self-administration of MDMA at higher concentrations than the core or medial olfactory tubercle. In addition, intra-medial shell MDMA self-administration was disrupted by co-administration of the D1 or D2 receptor antagonists SCH 23390 (1–3 mM) or raclopride (3–10 mM). Conclusions Our data suggest that the ventral striatum is functionally heterogeneous. The medial accumbens shell appears to be more important than other ventrostriatal subregions in mediating the positive reinforcing effects of MDMA via both D1- and D2-type receptors. Together with previous data, our data also suggest that unidentified actions of MDMA interfere with the positive reinforcing effects of dopamine in the medial olfactory tubercle.     

Comparison of two methods for estimating the acetylcholine turnover in discrete rat brain structures

The acetylcholine turnover rate was determined in olfactory tubercle, nucleus accumbens and striatum of rat brain. The calculation of turnover rates was carried out by means of two different methods: a two compartment analysis and the finite differences method. After pulse injection of [3H]choline the radioactivity of both [3H]acetylcholine and [3H]choline was measured in the above mentioned brain areas. The contents of acetylcholine and choline were measured radioenzymatically. By using the two compartment model the following acetylcholine turnover rates were obtained: olfactory tubercle, 0.577; nucleus accumbens, 0.679; striatum, 1.110 (mumoles/g X hr). When using the finite differences method the values were: olfactory tubercle, 0.517; nucleus accumbens, 0.822; striatum, 1.115 (mumoles/g X hr). This demonstrates that the results obtained by applying the two different methods are nearly identical. Advantages and disadvantages of the two methods are discussed.     

Effects of reserpine and antidepressants on dopamine and DOPAC (3,4-dihydroxyphenylacetic) concentrations in the striatum,olfactory tubercle and median eminence of rats

The dopamine, noradrenaline and 3,4-dihydroxyphenylacetic acid (DOPAC) levels of various rat brain areas (median eminence, olfactory tubercle, rostral and caudal part of the striatum) were measured. The effects of reserpine and antidepressants: amitriptyline, nomifensine and EGYT 475 (1-benzyl-4-/2′-piridycarbonyl/piperazine) were investigated. The dopamine content of the median eminence proved to be the most sensitive to the depletory effect of reserpine. Reserpin (1 mg/kr i.p.) caused a decrease of dopamine in the median eminence, in the olfactory tubercle and in the rostral striatum but not in the caudal striatum. Amitriptyline and EGYT 475 antagonized the reserpine-induce dopamine depletion in the olfactory tubercle. In the median eminence amitriptyline attenuated the effect of the depletor while nomifensine augmented it; EGYT 475 was without effect. The antidepressants antagonized the reserpine-induced increase of DOPAC in the rostral part of the striatum.     

Influence of drugs on striatal and limbic homovanillic acid concentration in the rat brain.

Homovanillic acid (HVA) was measured in the corpus striatum aan the limbic structures nucleus accumbens and olfactory tubercle of the rat, under normal conditions and after different drug treatments. Clozapine, thioridazine, morphine and physostigmine induced a similar percentage HVA increase in the three brain structures studied. Haloperidol and pimozide induced a higher percentage increase of HVA in the corpus striatum and nucleus accumbens when compared with the olfactory tubercle. Oxotremorine induced the highest HVA levels in the nucleus accumbens. Probenecid induced a significantly higher percentage accumulation of HVA in the limbic structures, especially in the olfactory tubercle. The HVA rise seen after haloperidol was suppressed by pretreatment with p-chlorophenylalanine or amino-oxyacetic acid in all structures studied. After atropine or trihexylphenidyl treatment the HVA rise induced by haloperidol was slightly suppressed in the limbic structures only. Our results suggest that not only under normal conditions but also after treatment with various types of drugs, dopamine metabolism as reflected by the HVA levels, is closely related in the different rat brain structures.     

Effects of d-amphetamine and disruption of 5-hydroxytryptaminergic neuronal systems on the synthesis of dopamine in selected regions of the rat brain

The rate of accumulation of DOPA following the administration of a decarboxylase inhibitor was employed to estimate the in vivo rate of dopamine (DA) synthesis in rat brain regions containing the cell bodies (substantia nigra) and terminals (striatum) of nigrostriatal nerves, and the terminals of mesolimbic (nucleus accumbens, olfactory tubercle) and tuberoinfundibular (median eminence) nerves. d-Amphetamine (0.5–2 mg/kg, i.p.) caused a marked increase in DA synthesis in striatum, a modest increase in olfactory tubercle, and was without effect in nucleus accumbens and median eminence. At the largest dose, f-amphetamine slightly reduced DA synthesis in substantia nigra. The mechanism of these regional differences is currently unknown.Depletion of 5-hydroxytryptamine (5-HT) with an intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) or a systemic injection of p-chlorophenylalanine (pCPA) enhanced spontaneous and amphetamine-stimulated locomotor activity. Pretreatment with 5,7-DHT did not alter DOPA accumulation in any brain region of animals injected with d-amphetamine or its vehicle. Pretreatment with pCPA reduced DOPA accumulation only in regions containing terminals of mesolimbic DA nerves. Thus, the increased amphetamine-induced hyperactivity in 5-HT-depleted rats is not reflected in a consistent change in the rate of DA synthesis in the brains of these animals.     

Behavioral and biochemical effects of nicotine in an MPTP-induced mouse model of Parkinson's disease

This study examined the effects of nicotine on locomotor activity and on the level of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and olfactory tubercle of mice that had been treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP significantly lowered the spontaneous locomotor activity 1-2 weeks and 2 months after 2 injections of MPTP (30 mg/kg SC, 24 hr apart) in young adult (3 months) and old mice (22-24 months old). The effect of nicotine on locomotion was biphasic; an initial stimulation of locomotor (0-5 min after nicotine) followed by a depressant period lasting from 5 to 20 min after injection. Tolerance to the depressant effect of nicotine developed after the 5th day of daily injections of nicotine (0.4 mg/kg SC, twice daily). Tolerance did not occur by day 8 to the initial stimulatory effect of nicotine. A similar effect of nicotine on locomotor activity was seen in mice treated with MPTP. The levels of DOPAC and HVA in the striatum were reduced by about 20% in the chronic nicotine-treated animals. The levels of DOPAC, DA, and HVA were reduced in the MPTP-treated mice; however, acute and chronic nicotine did not cause an additional change in the amine levels. The results suggest that nicotine has an influence on locomotor activity in MPTP-treated mice and that this effect is not due to changes in DA receptor activity in the striatum caused by chronic nicotine.     

Time course of interictal EEG patterns induced by a penicillin injection into the olfactory cortex.

In awake rats, the time courses of behavioural and cortical interictal hyperactivity patterns were investigated following an injection of the GABA antagonist Na-penicillin (PCN) (125 IU/0.5 microliters) into the olfactory or motor cortex. The cortical EEG was recorded by means of 6 AgAgCl-electrodes, behaviour was videotaped simultaneously. Behavioural hyperactivity developed immediately after PCN injection. It lasted longer than 2.5 to 4 h in the olfactory but less than 30 min in the motor cortex group of rats. The interictal EEG pattern of the olfactory group was characterized by a slow establishing of three centers of high cortical activity. They were located in the ipsilateral central and the contralateral frontal and occipital cortex. In the motor cortex group, however, a cortical center of high activity developed immediately after the PCN injection near the injection site only, or additionally, over the homotopic area of the contralateral hemisphere. The results indicate different susceptibility properties in the underlying neuronal networks. Ongoing epileptiform activity obviously modifies this susceptibility in a site-specific manner. Moreover, the time-correlated occurrence of high activity in the frontal motor and occipital cortex evoked by a PCN injection into the olfactory cortex suggests a close coupling of these three areas. A coupling between the frontal motor, occipital and focal area could not be shown, if PCN was injected into the motor cortex.