Bengt E. Hildebrand

Reduced dopamine output in the nucleus accumbens but not in the medial prefrontal cortex in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.

Mesolimbocortical dopamine (DA) neurotransmission is important in the mediation of the dependence-producing actions of nicotine and other drugs of abuse. Withdrawal from chronic treatment with various types of addictive drugs, including amphetamine, cocaine, ethanol and morphine is associated with a decrease in dopaminergic output in the nucleus accumbens (NAC), whereas the effects of withdrawal from these drugs on dopaminergic output in the medial prefrontal cortex (PFC), as yet, remain largely unknown. This study examined putative changes in the extracellular levels of dopamine and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAC and in the PFC of rats displaying behavioral signs of nicotine withdrawal. Rats were infused for 7 days with nicotine via subcutaneously implanted minipumps, whereas control animals carried saline-containing pumps. On the fifth day of infusion a microdialysis probe was implanted in the NAC or the PFC of the rats. Forty-eight hours later the levels of DA and the monoamine metabolites were assessed in the dialysate. The behavioral and biochemical effects of a saline injection and a subsequent challenge with the nicotinic receptor antagonist mecamylamine (1 mg/kg s.c.) were determined. Following mecamylamine challenge in nicotine-treated animals, the levels of DA, DOPAC and HVA in the NAC, but not in the PFC, decreased below pre-injection levels and in relation to control animals. The score of abstinence signs increased in the nicotine-treated rats, as compared both to the score after saline and to that in control animals. The decreased DA output in the NAC in animals displaying nicotine withdrawal signs is similar to that seen after withdrawal of several other drugs of abuse, and may have bearing on motivational deficits associated with the abstinence reactions.

Mode of Action of Atypical Neuroleptics in Relation to the Phencyclidine Model of Schizophrenia: Role of 5-HT2 Receptor and α1-Adrenoreceptor Antagonism

&NA; In experiments in rats, by the use of single‐cell recordings from midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), the systemic administration of the schizophrenomimetic N‐ methyl‐D‐aspartate receptor antagonists phencyclidine (PCP) or dizocilpine (MK‐801) caused an increased firing rate but reduced the variability of firing in VTA DA neurons. Burst firing was increased in cells predominantly located in the paranigral nucleus, a subdivision of the VTA largely projecting to the nucleus accumbens and other limbic regions, but reduced in DA cells predominantly located in the parabrachial pigmented nucleus, another subdivision of the VTA that projects largely to the prefrontal cortex (PFC). Thus, a severely impaired signal‐to‐noise ratio within the PFC DA projection was obtained, concomitant with an overactive mesolimbic DA system. The administration of high doses of ritanserin or atypical neuroleptics with prominent serotonin (5‐hydroxytrypyamine) 5‐HT2 receptor antagonist action, such as clozapine or amperozide, produced preferential activation of the PFC DA projection. In contrast, the selective D2 receptor antagonist raclopride caused a greater activation of the subcortical than cortical DA projections, as assessed by microdialysis experiments in vivo from our laboratory. Adding ritanserin treatment to raclopride markedly enhanced the raclopride‐induced increase in DA levels in the medial PFC, an effect probably mediated by augmentation of the raclopride‐induced increase in the burst firing of mesocortical DA neurons, but failed to affect the action of raclopride on striatal DA levels. In addition, ritanserin alone preferentially increased extracellular concentrations of DA in the shell subdivision of the nucleus accumbens that is closely linked to the limbic system, as assessed by in vivo voltammetry. However, the PCP‐ or MK‐801‐induced increased burst firing within the mesolimbic DA projection, which is probably causally related to the hyperlocomotion induced by these drugs in low doses, was significantly inhibited by the administration of the &agr;1‐adrenoceptor antagonist prazosin. Like high but not low doses of raclopride, prazosin also antagonized the behavioral stimulation induced by the systemic administration of MK‐801 in rats. Thus, atypical antipsychotic drugs such as clozapine and amperozide with high affinity for 5‐HT2 receptors and relatively high affinity for &agr;1‐adrenoceptors can, by 5‐HT2 blockade, preferentially activate and improve DA signaling in the mesocortical DA projection after distortion by drugs such as PCP. At the same time, these drugs may antagonize a hyperactive mesolimbic DA system not only postsynaptically through D2 antagonism, but also presynaptically through their &agr;1‐adrenoceptor‐blocking properties.

Prazosin inhibits MK-801-induced hyperlocomotion and dopamine release in the nucleus accumbens

This study examined the putative inhibitory effect of the alpha 1-adrenoceptor antagonist prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)pip erazine) on changes evoked by the psychotomimetic, non-competitive NMDA receptor antagonist, MK-801((+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclohepten-5, 10-imine), in locomotor activity and extracellular concentrations of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens as assessed by microdialysis in freely moving rats. MK-801 (0.1 and 0.3 mg/kg, s.c.) induced a significant, dose-dependent increase in horizontal locomotor activity but did not affect rearing. Prazosin administration alone (1 mg/kg, s.c.) only slightly reduced horizontal activity during an initial 10 min measurement period, although it consistently reduced rearing. However, pretreatment with prazosin effectively suppressed the locomotor stimulation caused by either dose of MK-801 throughout the whole observation period, i.e. 40 min. Both doses of MK-801 significantly increased extracellular levels of dopamine in the nucleus accumbens up to approximately 90%. In addition, MK-801 dose dependently increased dopamine metabolite concentrations in the nucleus accumbens, but 5-HIAA was significantly increased only by the high dose of MK-801. When given alone, prazosin did not affect either dopamine, DOPAC, HVA or 5-HIAA levels. However, prazosin pretreatment effectively blocked MK-801-evoked increases in dialysate dopamine concentrations. Consequently, the potent and selective alpha 1-adrenoceptor antagonist prazosin was found to specifically suppress MK-801-evoked, but not basal dopamine release in the nucleus accumbens, while effectively blocking MK-801-evoked locomotor stimulation with only negligible effects on basal locomotor activity. Thus, alpha 1-adrenoceptor antagonism may act by reducing the sensitivity of the mesolimbic dopamine system to pharmacological or environmental challenge. Since most antipsychotic drugs exhibit both dopamine D2 receptor and alpha 1-adrenoceptor antagonistic properties, they may alleviate psychosis not only through blockade of postsynaptic dopamine receptors, but also presynaptically on the mesolimbic dopamine system, through their alpha 1-adrenoceptor antagonistic action. This latter action may contribute to reduce evoked dopamine hyperactivity, e.g. in response to stress.

Behavioral manifestations of the nicotine abstinence syndrome in the rat : peripheral versus central mechanisms

Abstract The nicotine abstinence syndrome was studied in the rat utilizing a modified rating scale of the opiate abstinence syndrome. Rats were infused with 10.27 mg/kg per day nicotine hydrogen tartrate for 7 days via subcutaneous minipumps. The behavior of each animal was observed before, during and after termination of the nicotine infusion. The abstinence signs in the withdrawal sessions included gasps, genital licks, ptosis, shakes, teeth chatter, yawns and changes in locomotor activity. Abstinence was induced through surgical removal of the pump or through administration of a nicotinic receptor antagonist, acting either centrally and peripherally (mecamylamine 1 mg/kg SC) or peripherally only (chlorisondamine 1 mg/kg SC). Statistical evaluation revealed a significant increase in overall abstinence signs both at 16 (P < 0.05) and 40 h (P < 0.01) after termination of the nicotine infusion, as compared to the number of signs in the nicotine treated animals’ baseline sessions and to the number of signs in control animals (P < 0.05). There was also a significant reduction in locomotor activity during both withdrawal sessions. Animals injected with mecamylamine or chlorisondamine displayed a larger increase in the abstinence score (P < 0.001) than the spontaneously abstinent animals. Acute administration of different doses of nicotine or of the peripherally acting nicotinic receptor agonist tetramethylammonium (0.8 mg/kg SC) reversed the behavioral nicotine abstinence syndrome. Our results show that a nicotine abstinence syndrome can be elicited in rats on a chronic nicotine regimen either by acute withdrawal of nicotine or by the administration of nicotinic receptor antagonists and that peripheral nicotinic receptors may contribute significantly to the overall withdrawal reaction.

Role of α7 nicotinic receptors in nicotine dependence and implications for psychiatric illness

It has previously been shown that the reinforcing and dependence-producing properties of nicotine depend to a great extent on activation of nicotinic receptors within the ventral tegmental area (VTA), i.e. the site of origin of the mesolimbocortical dopaminergic projection. Based on the data reviewed in the present study, it is suggested that nicotine by stimulating presynaptic alpha7 nicotinic receptors within the VTA, that are probably localized on glutamatergic afferents from the medial prefrontal cortex, produces sequentially an increase in glutamate concentrations, stimulation of NMDA receptors found on dopamine (DA)-containing neurons in the VTA, enhanced firing activity of VTA-DA neurons, augmented DA release in the nerve terminal regions, and enhanced c-fos expression in the dopaminergic projection areas through activation of D1-DA receptors. In addition, it appears that alpha7 nicotinic receptors within the VTA are directly involved in nicotine-related reward and withdrawal responses. These data may be instrumental in understanding how nicotine interacts with the mesolimbocortical dopaminergic system, which is perhaps the most important component of the neural mechanisms underlying nicotine dependence. These results may also contribute to unraveling the cellular basis of nicotines association with neuropsychiatric disorders, thereby offering the prospect of new therapeutic advances for their treatment.

Behavioral and Biochemical Manifestations of Mecamylamine-Precipitated Nicotine Withdrawal in the Rat: Role of Nicotinic Receptors in the Ventral Tegmental Area

Brain mesolimbic dopamine (DA) neurons are considered critical for the dependence-producing action of nicotine, and its stimulatory effect on behavior and DA neurotransmission appears largely mediated via nicotinic receptors (nAChRs) in the ventral tegmental area (VTA). The nAChR antagonist mecamylamine administered systemically in chronically nicotine-treated rats elicits a behavioral withdrawal syndrome concomitant with a reduced DA output in the nucleus accumbens (NAC). Here, we investigated the behavioral and biochemical consequences of intrategmental administration of mecamylamine in rats chronically infused with nicotine by means of minipumps for 14 days (9 mg/kg/day). Bilateral, intrategmental mecamylamine injections (1, 3 or 9 μg/0.5 μl/ side) dose-dependently increased abstinence signs such as gasps, teeth chatter, and reduced locomotor activity in nicotine-treated, but not in control animals. Moreover, a unilateral intrategmental injection of 9 μg mecamylamine reduced DA output in the ipsilateral NAC of chronically nicotine-treated rats, but not in control animals. Consequently, nAChRs in the VTA may be involved not only in the stimulatory effects of acute nicotine administration, but also in the withdrawal reaction following cessation of chronic nicotine treatment.

Selective c-fos Induction and Decreased Dopamine Release in the Central Nucleus of Amygdala in Rats Displaying a Mecamylamine-Precipitated Nicotine Withdrawal Syndrome

In the present study the neuronal expression of Fos, the protein product of c‐fos, was used to study changes in neuronal activity in nerve terminal regions of the ascending dopaminergic system during nicotine withdrawal. Rats were infused for 14 days with nicotine (9 mg/kg/day nicotine hydrogen tartrate) via minipumps, whereas control animals carried empty pumps. Withdrawal was induced by the nicotinic receptor (nAChR) antagonist mecamylamine (1 mg/kg, s.c.). The behavior of each animal was observed after mecamylamine injection and subsequently its brain was processed for Fos‐like immunoreactivity. Following mecamylamine, the score of abstinence signs increased in the nicotine‐treated rats as compared to controls. The number of Fos‐positive nuclei was substantially increased in the central nucleus of amygdala (CNA) in animals undergoing mecamylamine‐precipitated withdrawal, whereas no significant changes in c‐fos expression were observed in the basolateral amygdaloid nucleus, the core and the shell of the nucleus accumbens, the dorsolateral striatum, or the medial prefrontal cortex. Since there are indications of involvement of amygdaloid dopaminergic neurotransmission in anxiety—a core symptom of withdrawal from dependence‐producing drugs—in a second experiment utilizing microdialysis we examined whether nicotine withdrawal affects dopaminergic neurotransmission in the CNA. Following mecamylamine injection, dopamine (DA) significantly decreased in nicotine‐treated animals compared with controls. These results indicate that the mecamylamine‐precipitated nicotine withdrawal reaction is accompanied by a selective induction of c‐fos and a concurrent decrease in DA release in the CNA, which may have a bearing on symptoms such as anxiety and distress, which frequently are associated with the nicotine abstinence reaction in humans. Synapse 35:15–25, 2000.

Nicotine withdrawal in the rat: role of α7 nicotinic receptors in the ventral tegmental area

Previous data show that nicotinic receptors in the ventral tegmental area are of importance for the nicotine withdrawal syndrome. Here we have investigated the specific role of alpha7 nicotinic receptors in the ventral tegmental area for the neurobiological and behavioral consequences of nicotine withdrawal. Rats were exposed to nicotine for 14 days via s.c. osmotic minipumps. Bilateral intrategmental injections of the selective alpha7 nicotinic receptor antagonist methyllycaconitine reduced locomotion in the nicotine-treated rats, but not in control animals. Unilateral intrategmental injection of methyllycaconitine reduced dopamine output in the ipsilateral nucleus accumbens of nicotine-treated rats, but not in controls. Our results indicate that alpha7 nicotinic receptors in the ventral tegmental area are involved in the nicotine withdrawal syndrome.

Intraaccumbal mecamylamine infusion does not affect dopamine output in the nucleus accumbens of chronically nicotine-treated rats

Summary. Recently we have shown that the nicotinic receptor (nAChR) antagonist mecamylamine both when administered systemically and locally into the ventral tegmental area (VTA) to chronically nicotine-treated rats reduces dopamine (DA) output in the nucleus accumbens (NAC) and elicits behavioral withdrawal signs. However, the putative contributory role of nAChRs in the NAC in mediating these effects of systemic mecamylamine has not been clarified. Therefore, we here investigated the effect on extracellular levels of DA in the NAC of local intraaccumbal administration of mecamylamine to chronically nicotine-treated rats and its putative behavioral correlates. In these experiments local application of mecamylamine into the NAC, in a concentration that increased NAC DA levels in control rats, did not affect DA output or behavior in the nicotine-treated animals. These results provide further support for the contention that nAChRs in the VTA, but not in the NAC, are of major importance for the mesolimbic DA reduction and associated behavioral signs in nicotine withdrawal.