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There is growing concern that the psychostimulant Methylphenidate (MPD) is being abused for cognitive enhancement and recreation by healthy adults and adolescents seeking to improve their work or academic performance. This study concomitantly recorded the behavioral and prefrontal cortex (PFC) neuronal activity in freely behaving animals exposed to acute and chronic MPD doses (0.6, 2.5, and 10.0 mg/kg MPD) in order to compare MPD effects on adult and adolescent rats. The PFC is one of the primary brain areas affected by MPD and the drug of choice for treating ADHD. Moreover, the PFC is one of the last brain areas to complete development, suggesting that the behavioral and neurophysiological response to MPD may differ in adolescents and adults. In both adult and adolescent animals, it was observed that the same repetitive (chronic) dose of either 0.6, 2.5, or 10.0 mg/kg MPD elicited behavioral sensitization in some animals and tolerance in others, experimental biomarkers indicating drug of abuse symptoms, and the majority of PFC units recorded in animals expressing behavioral sensitization or tolerance to chronic MPD exposure responded by increasing and decreasing their neuronal firing rate, respectively. Further, it was shown that high doses of 10.0 mg/kg MPD significantly modified adolescent behavioral activity but did not impact adults suggesting that adolescents may be more receptive to chronic MPD exposure. These findings raise concerns regarding the use and abuse of MPD in normal, healthy individuals and support the notion that the adolescent PFC is more susceptible than the adult PFC to neuromodulation from chronic MPD use.

The use of methylphenidate (MPD), a commonly prescribed drug to treat attention-deficit hyperactivity disorder (ADHD), has steadily increased over the past 25 years. This trend has been accompanied by more MPD abuse by ordinary individuals for its cognitive enhancing effects. Therefore, understanding the effects of MPD on the prefrontal cortex (PFC), a brain area involved in higher cortical processing such as executive function, language, planning, and attention regulation, is of particular importance. The goal of this study is to investigate the effects of acute and chronic dose-response characteristics following MPD exposure on both the PFC neuronal population and behavioral activity in freely behaving animals implanted previously with permanent electrodes within the PFC. Four groups of animals were used: saline (control), 0.6, 2.5, and 10.0mg/kg MPD. It was observed that the same dose of either 0.6, 2.5, or 10.0mg/kg repetitive (chronic) MPD exposure elicited behavioral sensitization in some animals and behavioral tolerance in others, and that the majority of PFC units recorded from animals expressing behavioral sensitization to chronic MPD exposure responded to MPD by increasing their neuronal firing rate, whereas the majority of PFC neurons recorded from animals expressing behavioral tolerance in response to chronic MPD responded by decreasing their neuronal firing rate. This data suggests that in animals that display behavioral sensitization, chronic MPD exposure causes an increase in the number of post-synaptic D1 dopamine receptors leading to an increase in behavioral and neuronal firing rate, while in animals that display behavioral tolerance, chronic MPD exposure causes an increase in the number of post-synaptic D2 dopamine receptors leading to a decrease in behavioral and neuronal firing rate. This dichotomy needs to be further investigated.

Methylphenidate (MPD) is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Recently, it is being abused for cognitive enhancement and recreation leading to concerns regarding its addictive potential. The prefrontal cortex (PFC) and caudate nucleus (CN) are two of the brain structures involved in the motive/reward circuit most affected by MPD and are also thought to be responsible for ADHD phenomena. This study is unique in that it investigated acute and chronic, dose-response MPD exposure on animals’ behavior activity concomitantly with PFC and CN neuronal circuitry in freely behaving adult animals without the interference of anesthesia. Further, it compared acute and chronic MPD action on over 1,000 subcortical and cortical neurons simultaneously, allowing for a more accurate interpretation of drug action on corticostriatal neuronal circuitry. For this experiment, four groups of animals were used: saline (control), 0.6, 2.5, and 10.0 mg/kg MPD following acute and repetitive exposure. The data shows that the same MPD dose elicits behavioral sensitization in some animals and tolerance in others and that the PFC and CN neuronal activity correlates with the animals' behavioral responses to MPD. The expression of sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. In general, a greater percentage of CN units responded to both acute and chronic MPD exposure as compared to PFC units. Dose response differences between the PFC and the CN units were observed. The dichotomy that some PFC and CN units responded to the same MPD dose by excitation and other units by attenuation in neuronal firing rate is discussed. In conclusion, to understand the mechanism of action of the drug, it is essential to study, simultaneously, on more than one brain site, the electrophysiological and behavioral effects of acute and chronic drug exposure, as sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. The behavioral and neuronal data obtained from this study indicates that chronic MPD exposure results in behavioral and biochemical changes consistent with a substance abuse disorder.

Methylphenidate (MPD) is the most commonly prescribed psychostimulant for the treatment of attention-deficit hyperactivity disorder (ADHD). MPD acts on brain structures of the reward/motivation system, including the caudate nucleus (CN). The objective of this study was to investigate the acute and chronic dose response effects of MPD on CN neurons in freely behaving adolescent rats. Semi-microelectrodes were implanted into the CN of one hundred and sixty-three adolescent male Sprague-Dawley rats. On experimental day one (ED1), each rat was injected with 0.8 ml saline followed by an injection of MPD (0.6, 2.5, or 10.0 mg/kg). Behavioral and neuronal recordings of 60 min followed each injection. Throughout ED2-6, each rat remained in its home cage and received daily injections of a specific dose of MPD. ED7-9 consisted of a three-day washout period during which no injections were given. On the last day (ED10), each rat was returned to the testing chamber in its home cage and an identical protocol was performed as on ED1. The same repetitive (i.e. chronic) dose of MPD elicited behavioral sensitization in some animals and behavioral tolerance in others. After chronic MPD exposure, CN units recorded from rats expressing behavioral sensitization responded mainly with increased neuronal firing rates. Conversely, rats expressing behavioral tolerance responded mainly with decreased neuronal firing rates. These findings suggest a direct correlation between the behavioral and CN neurophysiological response to chronic MPD in adolescent animals.

Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does not exhibit direct actions on the serotonin transporter, however there is evidence suggesting that the therapeutic effects of MPD may be mediated in part by alterations in serotonin transmission. This study aimed to investigate the role of the dorsal raphe (DR) nucleus, one of the major sources of serotonergic innervation in the mammalian brain, in the response to MPD exposure. Freely behaving adolescent rats previously implanted bilaterally with permanent electrodes were used. An open field assay and a wireless neuronal recording system were used to concomitantly record behavioral and DR electrophysiological activity following acute and chronic MPD exposure. Four groups were used: one control (saline) and three experimental groups treated with 0.6, 2.5, and 10.0 mg/kg MPD respectively. Animals received daily MPD or saline injections on experimental days 1–6, followed by 3 washout days and MPD rechallenge dose on experimental day (ED)10. The same chronic dose of MPD resulted in either behavioral sensitization or tolerance, and we found that neuronal activity recorded from the DR neuronal units of rats expressing behavioral sensitization to chronic MPD exposure responded significantly differently to MPD rechallenge on ED10 compared to the DR unit activity recorded from animals that expressed behavioral tolerance. This correlation between behavioral response and DR neuronal activity following chronic MPD exposure provides evidence that the DR is involved in the acute effects as well as the chronic effects of MPD in adolescent rats.

Methylphenidate (MPD) is a psychostimulant that enhances dopaminergic neurotransmission in the central nervous system by using mechanisms similar to cocaine and amphetamine. The mode of action of brain circuitry responsible for an animal’s neuronal response to MPD is not fully understood. The nucleus accumbens (NAc) has been implicated in regulating the rewarding effects of psychostimulants. The present study used permanently implanted microelectrodes to investigate the acute and chronic effects of MPD on the firing rates of NAc neuronal units in freely behaving rats. On experimental day 1 (ED1), following a saline injection (control), a 30 minute baseline neuronal recording was obtained immediately followed by a 2.5 mg/kg i.p. MPD injection and subsequent 60 min neuronal recording. Daily 2.5 mg/kg MPD injections were given on ED2 through ED6 followed by 3 washout days (ED7 to 9). On ED10, neuronal recordings were resumed from the same animal after a saline and MPD (rechallenge) injection exactly as obtained on ED1. Sixty-seven NAc neuronal units exhibited similar wave shape, form and amplitude on ED1 and ED10 and their firing rates were used for analysis. MPD administration on ED1 elicited firing rate increases and decreases in 54% of NAc units when compared to their baselines. Six consecutive MPD administrations altered the neuronal baseline firing rates of 85% of NAc units. MPD rechallenge on ED10 elicited significant changes in 63% of NAc units. These alterations in firing rates are hypothesized to be through mechanisms that include D1 and D2-like DA receptor induced cellular adaptation and homeostatic adaptations/deregulation caused by acute and chronic MPD administration.

The psychostimulant methylphenidate (MPD, Ritalin) is the prescribed drug of choice for treatment of ADHD. In recent years, the diagnosis rate of ADHD has increased dramatically, as have the number of MPD prescriptions. Repeated exposure to psychostimulants produces behavioral sensitization in rats, an experimental indicator of a drug’s potential liability. In studies on cocaine and amphetamine, this effect has been reported to involve the nucleus accumbens (NAc), one of the nuclei belonging to the motive circuit. The aim of this study was to investigate the role of the NAc on the expression of behavioral sensitization as a response to MPD exposure. In the present study, 20 male Sprague-Dawley rats were divided randomly into three groups: an intact control group, a sham operated group, and a NAc bilateral electrical lesion group. Locomotor activity was assessed for the first two hours following 2.5 mg/kg MPD injection, using open field monitoring systems. Recordings were made during six days of continuous MPD administration, and then upon re-challenge with the same dose following three days of washout. Acute MPD exposure elicited an increase in locomotor activity in all three groups. However, the NAc lesion group exhibited significantly increased locomotor activity in comparison to sham and control groups. Chronic MPD did not elicit sensitization in the NAc lesion group, while both sham and control groups did exhibit behavioral sensitization to repetitive MPD administration. These findings suggest that the NAc plays a significant role in eliciting locomotor activity as an acute effect of MPD, and in the expression of sensitization due to chronic MPD exposure.

Acute and chronic methylphenidate (MPD) were given to adults treated with MPD only in adulthood (adult I) and to adults that had been treated repeatedly during adolescence and adulthood (adult II). Two locomotor activity assays, the open field and the running wheel, were used in a dose response experiment to assess whether methylphenidate (MPD) treatment during adolescence would affect responses to MPD in adulthood. Each experiment lasted 11 days as follows: saline control on experimental day 1 (ED 1), followed by a single daily dose of saline, 0.6, 2.5, or 10 mg/kg MPD for 6 days (ED 2 to ED 7), 3 washout days with no drug administration (ED 8 to ED 10), and saline or MPD challenge on ED 11 at a dose identical to that given on ED 2 to ED 7. Acute MPD elicited characteristic dose response increases in locomotion in both experimental assays of adult I and adult II groups. Adult I and adult II rats tested in the open field assay exhibited sensitization to 2.5 mg/kg MPD and tolerance to 10 mg/kg MPD, while in the wheel-running assay all the three MPD doses elicited sensitization in both adult I and adult II rats. MPD treatment in adolescence did not change the baseline activity when animal reached adulthood. However, the responses to MPD in adult II rat groups were significantly different from the adult I group. Similar observations were noted during washout days. At the low and moderate MPD treatment both experimental assay exhibited similar observations while following the high dose of MPD treatment, the open field assay indicated that tolerance to MPD was expressed, while the wheel-running assay indicated that behavioral sensitization was developed. The distinction between the two assays and adult I and II differences are discussed.

Methylphenidate (MPD), commonly known as Ritalin, is the most frequently prescribed drug to treat children and adults with attention deficit hyperactivity disorder (ADHD). Adolescence is a period of development involving numerous neuroplasticities throughout the central nervous system (CNS). Exposure to a psychostimulant such as MPD during this crucial period of neurodevelopment may cause transient or permanent changes in the CNS. Genetic variability may also influence these differences. Thus, the objective of the present study was to determine whether acute and chronic administration of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) elicit effects among adolescent WKY, SHR, and SD rats and to compare whether there were strain differences. An automated, computerized, open-field activity monitoring system was used to study the dose response characteristics of acute and repeated MPD administration throughout the 11-day experimental protocol. Results showed that all three adolescent rat groups exhibited dose-response characteristics following acute and chronic MPD administration, as well as strain differences. These strain differences depended on the MPD dose and locomotor index. Chronic treatment of MPD in these animals did not elicit behavioral sensitization, a phenomenon described in adult rats that is characterized by the progressive augmentation of the locomotor response to repeated administration of the drug. These results suggest that the animal’s age at time of drug treatment and strain/genetic variability play a crucial role in the acute and chronic effect of MPD and in the development of behavioral sensitization.

Children with attention deficit hyperactivity disorder (ADHD) are treated for extended periods of time with the psychostimulant methylphenidate (MPD). The psychostimulants cocaine, amphetamine, and MPD exhibit similar structural configuration and pharmacological profile. The consequence of the long-term use of psychostimulants such as MPD as treatment for ADHD in the developing brain of children is unknown. Repeated treatment with psychostimulants has been shown to elicit adverse effects in behavior, such as dependence, paranoia, schizophrenia, and behavioral sensitization. Behavioral sensitization and cross-sensitization between two drugs are used as experimental markers to determine the potential of a drug to develop dependence/addiction. Although there are many reviews written about behavioral sensitization involving psychostimulants, scarcely any have focused specifically on MPD-elicited behavioral sensitization and cross-sensitization with other psychostimulants. Moreover, the response to MPD and the expression of ADHD vary among females and males and among different populations due to genetic variability. Since the interpretation and synthesis of the data reported are controversial, this review focuses on the adverse effects of MPD and the role of age, sex, and genetic composition on the acute and chronic effects of MPD, such as MPD-elicited behavioral sensitization and cross-sensitization with amphetamine in animal models. Animal models of drug-induced locomotor stimulation, particularly locomotor sensitization, can be used to understand the mechanisms underlying human drug-induced dependence.

Male Sprague-Dawley rats were divided to three groups (each n = 8) and were housed in test cages where motor activity was recorded continuously for 16 days using a computerized motor activity monitoring system to determine whether repeated administration of MK-801 could block the development and/or the expression of sensitization to the locomotor effects of methylphenidate (MPD). One group of rats received six daily injections (days 4-9) of 0.30 mg/kg MK-801, followed by 5 days without injection (days 10-14) and re-challenged (day 15) with 0.30 mg/kg MK-801. The second group received a challenge dose of 2.5 mg/kg MPD (day 4) followed by 5 days of co-treatment with MK-801 (0.30 mg/kg) given 1 h prior to MPD (days 5-9). This group was then re-challenged with MPD (2.5 mg/kg) on day 15. The last group received six daily injections of 2.5 mg/kg MPD (days 4-9). They were then split into two subgroups of rats which received either no treatment (control) or five daily injections of 0.30 mg/kg MK-801 (days 10-14) before being re-challenged on day 15 with 2.5 mg/kg MPD. MK-801 sensitized to its own locomotor effects. MK-801 given after sensitization had developed (i.e., days 10-14) was able to mask the expression of a sensitized response on day 15, but the effect was only transient since the sensitized response was present 3 weeks later. Moreover, MK-801, when coadministered during the repeated treatment phase was able to block the development of a sensitized response, which suggest that NMDA receptors involved in the process of MPD sensitization.

The effects of intrathecally ( IT ) administered glibenclamide (Gli), an ATP-sensitive K + (K ATP ) channel blocker, on the antinociception produced by IT norepinephrine (NE), serotonin (5-HT), morphine (Mor), or adenosine agonist, 5′- N -ethylcarboxamide adenosine (NECA) were investigated using integrated EMG measurement of hindlimb flexor reflex (FR) in lightly pentobarbital-anesthetized rats. The results showed that: 1) NE (3, 6, or 12 nmol) or 5-HT (60, 120, or 240 nmol) each produced a dose-dependent suppression of FR EMG, respectively; 2) pretreatment with Gli (5, 10, or 20 nmol) antagonized the NE (6 nmol)-induced antinociception in a dose-dependent manner and failed to modulate the 5-HT (120 nmol)-induced suppression of FR EMG; 3) pretreatment with Gli (5, 10, or 20 nmol) also antagonize the Mor (2 nmol)-induced suppression of FR EMG in a dose-dependent manner; 4) pretreatment with naloxone (Nal, 60, 120, or 240 nmol) also antagonize the NE (6 nmol)-induced suppression of FR EMG in a dose-dependent manner; and 5) NECA (0.5, 1.0, or 2.0 nmol) produced a dose-dependent suppression of FR EMG, while pretreatment with Gli (5, 10, or 20 nmol) failed to modulate the NECA (1.0 nmol)-induced suppression of FR EMG. The results show that (a) ATP-sensitive K + channels are involved in the NE- and Mor-induced antinociception but not 5-HT- or NECA-induced antinociception at the spinal level; (b) endogenous opioids might act as a successor of NE and then activate K ATP channels to producing the antinociception.

Concomitant behavioral and dorsal raphe (DR) neuronal activity were recorded following acute and chronic dose response of methylphenidate (MPD) in freely moving rats previously implanted with permanent semi-microelectrodes using telemetric (wireless) technology. On experimental day (ED) 1, the neuronal and locomotor activity were recorded after saline (baseline) and MPD (0.6, 2.5 or 10.0 mg/kg) injection (i.p.). Animals were injected daily with a single dose of MPD for five consecutive days (ED 2–6) to elicit behavioral sensitization or tolerance. After three washout days, the neuronal and locomotor activity recording was resumed on ED 10 followed by saline and MPD rechallenge injection. The main findings were: (1) the same dose of chronic MPD administration elicited behavioral sensitization in some animals and behavioral tolerance in others. (2) 46%, 56% and 73% of DR units responded to acute 0.6, 2.5 and 10.0 mg/kg MPD respectively. (3) 89%, 70% and 86% of DR units changed their baseline activity on ED 10 compared to that on ED 1 in the 0.6, 2.5 and 10.0 mg/kg MPD groups respectively. (4) A significant difference in ED 10 baseline activity was observed in the DR neuronal population recording from animals expressing behavioral sensitization compared to that of animals expressing behavioral tolerance. (5) 89%, 78% and 88% of DR units responded to chronic 0.6, 2.5 and 10.0 mg/kg MPD respectively. (6) The DR neuronal population recording following acute MPD on ED 1 and rechallenge MPD on ED 10 from animals expressing behavioral sensitization was significantly different from the neuronal population recorded from animals exhibited behavioral tolerance. The correlation between the DR neuronal activity and animal's behavior following chronic MPD exposure suggested that the DR neuronal activity may play an important role in the expression of behavioral sensitization and tolerance induced by chronic MPD administration.

Methylphenidate (MPD) is the drug of choice prescribed to treat ADHD patients. More recently, MPD is also used as a cognitive enhancement and recreationally by young adults and its therapeutic effects are not fully understood. One of the neuroanatomical sites is reported to be the ventral tegmental area (VTA). The ventral tegmental area neuronal activity was recorded from freely behaving non-anesthetized rats implanted bilaterally with semi-permanent electrodes which were recorded from a wireless telemetric system. Thirty-three animals, divided randomly into four groups, were used: saline ( n = 10), 0.6 mg/kg ( n = 6), 2.5 mg/kg ( n = 7) and 10.0 mg/kg MPD ( n = 10). MPD caused an increase in locomotor activity with a dose response characteristic; 0.6 mg/kg MPD elicited some increase in locomotion, but not significantly, while 2.5 and 10.0 mg/kg MPD elicited significant increases in behavior of 191% and 870% respectively. A total of 209 ventral tegmental area units were recorded; 100% (36/36) units showed no response to saline; 89% (154/173) of the neurons responded to MPD, with the majority 66% (101/154) showing an increase in activity. In response to 0.6 mg/kg ( n = 52), the majority of units 54% (28/52) showed a decrease in activity. For both 2.5 ( n = 60) and 10.0 mg/kg ( n = 61), the majority of ventral tegmental area units responded with an increase in activity with 63% (38/60) and 70% (43/61) respectively. This study demonstrated that the majority of ventral tegmental area neurons respond to acute MPD in a dose response characteristic and are not related to the animal's locomotor activity.

The interactions between different doses of serotonin (5-HT) and norepinephrine (NE) in in vivo experiments on rat spinal cord dorsal horn cells was investigated using the integrated electromyography (EMG) measurement of the nociceptive hindlimb flexor reflex (FR). The results indicate that (1) intrathecal (IT) administration of low doses of 5-HT (60 nmol) or NE (1.5 nmol) suppresses the nociceptive FR by 40% for 20 min, respectively; (2) administration of higher doses of 5-HT (240 nmol, IT) multiplies the suppression of the nociceptive FR by 80% for 40 min, and NE (15 nmol, IT) produces similar suppression of the nociceptive FR for 80 min; (3) concomitant administration of low doses of 5-HT (60 nmol, IT) and NE (1.5 nmol, IT) produces a summation of the nociceptive FR suppression both in amplitude and duration; (4) concomitant administration of the higher doses of 5-HT (240 nmol IT) with NE (15 nmol, IT) produces similar effect obtained as 5-HT given separately, and no summation was obtained as observed following the lower dosages; (5) serotonin (240 nmol, IT) given 40 min before NE (15 nmol, IT) attenuates the duration of the suppression induced by NE; (6) pretreatment with a selective 5-HT2 receptor antagonist ketanserin (60 nmol, IT) failed to abolish the 5-HT effects; (7) pretreatment with ketanserin prior to concomitant administration of the higher doses of 5-HT and NE prolongs the time duration of the nociceptive FR suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Photic evoked responses were recorded from the striate cortex of Long-Evens hooded normal (control) rats and from monocular visual deprivation (MD) rats. The averaged visual evoked responses (AVER) were obtained from both hemispheres and provide comparison between the contralateral and the ipsilateral striate cortex with relation to the monocular deprived eye. The AVER recorded following binocular photic stimulation after 1 month of monocular deprivation demonstrated that the two visual cortexes responded differently. In the contralsteral hemisphere of the visual cortex (related to the MD eye), allthree components (P2, N2 and P3) of the AVER of the MD rats had significant increases M their peak amplitude as compared to the control recordings. In the ipsilateral cortex, the amplitude of component p2 and N2 was significantly reduced as a result of 1 month of MD. Comparing the AVER amplitudes of the two homotopic sites of the visual cortex obtained from the control group reveals no differences between the two hemispheres but markedly significant differences In P2, N2 and P3 components for the MD group. Based on the literature, the possibility that the monocular visual deprivation at the critical period in early developmental stage modulates the AVER as a result from the neurocytolopical alteration from ailering of GABA and ACh within the striate cortex was discussed. In conclusion, the AVER is a reliable and practical method for studying the effects of monocular deprivation and neuroplasticity in the rat visual cortex.

The effects of intrathecally (IT) administered naloxone (Nal) on the antinociception produced by IT norepinephrine (NE), serotonin (5-HT), or morphine (Mor) were observed and compared in rats using the tail-flick (TF) assay. The results show that: a) NE, 5-HT, and Mor in doses of 1 nmol, 240 nmol, and 0.5 nmol, respectively, produce similar increases in amplitude and time in TF latency (TFL); b) Nal treatment of 240 and 360 nmol has no effects on TFL; c) the antinociception produced by NE (1 nmol) can be blocked by Nal (240 nmol); d) antinociception produced by Mor (0.5 nmol) can also be blocked by Nal (240 nmol); e) 240 nmol of Nal does not affect the 5-HT (120 nmol)-produced antinociception, while 360 nmol of Nal show a delayed blockade to the 5-HT (120 nmol)-produced antinociception. The results suggest that endogenous opiate-like substances may be involved in both NE- or 5-HT-produced antinociception at the spinal level, and these effects may be mediated through different types of opiate receptors.

Methylphenidate (MPD) is currently one of the most prescribed drug therapies for attention deficit/hyperactivity disorder (ADHD) and moreover is abused for cognitive enhancement and used for recreation by the young and adults. Methylphenidate is used for prolonged periods of time and its mechanism of action on the brain is still unknown. The main action of MPD is known to act on the motive circuit of the brain, and one of these structures is the caudate nucleus (CN). The objective of this study was to investigate the neurophysiological properties of the CN neurons in response to acute and chronic administration of MPD in freely behaving animals, previously implanted with permanent semi microelectrodes. Twenty-six rats were permanently implanted with semi microelectrodes into the CN using general anesthesia. On experimental day one (ED1) the rat was placed into the testing chamber, and neuronal activity was recorded using a wireless (telemetric) headstage device following both a saline and a 2.5 mg/kg MPD injection. From ED2 to ED6 daily injections of 2.5 mg/kg MPD were administered without recordings to induce a chronic effect of the drug, preceded by three days of washout (ED7–ED9) where no injections were given. On ED10 rats were placed back into the testing chamber, the wireless headstage device was attached to skull cap and recordings were resumed for 1 h each following both a saline and re-challenge administration of 2.5 mg/kg MPD. Sixty-seven CN neuronal recorded units from twenty-six animals with identical shape and amplitude at ED1 and ED10 were evaluated. All the 67 CN units responded to MPD administration, 70% (47/67) CN units exhibited an increase in activity following initial 2.5 mg/kg MPD administration and 30% (20/67) exhibited a decrease in neuronal activity. On ED10 all the CN units showed a significant change in their firing rate baseline compared to ED1 baseline, 52% (35/67) exhibiting an increase in their ED10 baseline activity compared to ED1 baseline activity and 48% (32/67) of the CN units at ED10 exhibited decreasing activity. All the CN units responded significantly to MPD rechallenge at ED10, 57% (38/67) of the units exhibited increased neuronal activity while 43% (29/67) exhibited decreasing neuronal activity. The results indicate that the majority of the CN units exhibited neurophysiological sensitization.

The psychostimulant amphetamine (Amph) is widely used treatments for attention-deficit hyperactivity disorder (ADHD). Chronic intermittent exposure to psychostimulants induces behavioral sensitization. The objective of this study was to investigate the role of prefrontal cortex (PFC) in the acute and chronic effect of Amph using the open-field assay. Male Sprague-Dawley rats were assigned randomly to three groups, (1) an intact control group (2) a PFC sham-operated group, and (3) a PFC lesion group. All the three groups showed increases in locomotor activity after acute amphetamine injection (P0.05), and activity levels were especially augmented in PFC lesion group. Following chronic amphetamine, the control group and sham-operated group exhibited behavioral sensitization (P0.05). However, the PFC lesion group failed to exhibit behavioral sensitization and the pattern of locomotion was altered, which indicated that the nature of behavioral sensitization was changed. The results suggest that PFC lesion enhance the acute effects of amphetamine on locomotor activity and is required for development of behavior sensitization.

Restraint stress, electrical stimulation of the bed nucleus of the stria terminalis (BNST), and the combination of restraint stress and BNST stimulation were studied using a computerized animal activity monitoring system. Both restraint and the combination of restraint and BNST stimulation produced increases in locomotor, exploratory and stereotypic activity all of which returned to baseline within an hour while BNST stimulation alone also increased measurements of locomotor and exploratory behavior some of which remained elevated throughout the three-hour period of measurement. BNST stimulation also produced vigorous escape behavior and biting which were not seen with restraint alone. Thus electrical stimulation of BNST produces behavior which is qualitatively similar to the behavior produced by stress but differs in time course.

Methylphenidate (MPD), also known as Ritalin, is a widely used treatment for Attention Deficit Hyperactivity Disorder. Repeated administration of MPD causes dose-dependent sensitization. MPD binds to dopamine (DA) transporters, and DA, therefore, remain in the synaptic cleft for longer time, resulting in an indirect DA agonist effect. MPD affects neurotransmission in brain regions including the prefrontal cortex (PFC). The mechanisms of sensitization to MPD are not clear. The aim of this study was to investigate the role of prefrontal cortex in effects of acute and chronic MPD administration, using the open field assay and male Sprague–Dawley rats with bilateral electrolytic lesions of PFC. After 1 day of control recording, following saline injection, the animals were divided randomly into three groups, (1) an intact control group, (2) a sham group, and (3) a lesion group. Then, groups 2 and 3 underwent surgery, followed by 5 days of recovery. Recordings were resumed following 1 day of saline injection and following six consecutive daily injections of 2.5 mg/kg MPD, 3 days of washout period, and another day of re-challenge injection of 2.5 mg/kg MPD. Acute MPD elicited increases in locomotor activity, similar to those observed from intact animals, in both sham and lesion groups. The sham group was behaviorally sensitized while the PFC lesion group failed to exhibit behavioral sensitization. These results suggest that the PFC does not interfere with the acute effects of MPD on locomotor activity but is required for development of behavioral sensitization to MPD.

The nociceptive responses in parafascicular neurons (PF) were recorded and studied following electrical stimulation of locus coeruleus (LC) combined with intrathecal (IT) or intracerebroventricular (ICV) administration of phentolamine (Ph), an alpha-adrenoceptor antagonist. The results revealed the following. (1) Three different PF neuronal populations were observed according to their response pattern following noxious stimulation: nociceptive-on, nociceptive-off, and nonresponsive units. Only the nociceptive-on units were studied further. (2) The nociceptive discharges in majority of PF neurons (66/87) were inhibited by electrical stimulation of the LC. (3) The inhibitory effect of LC stimulation was prevented and even reversed by pretreatment of IT Ph (40 nmol) in 22 units, or by dorsolateral funiculi transection in 24 units tested. (4) The inhibitory effect of LC stimulation was strengthened by preadministration of ICV Ph (40 nmol) in 17 units tested. (5) ICV administration of norepinephrine (NE 30 nmol) resulted in PF neurons a biphasic response to nociceptive stimulation: an early brief inhibition and a late long-lasting facilitation. (6) Pretreatment of ICV Ph (40 nmol) prior to NE injection prevented the NE-induced biphasic response. The results suggest that stimulation of LC modulates the nociceptive response of PF neurons through both ascending and descending routes. These two diverse routes exert two different effects: a predominantly inhibitory role on the nociceptive transmission at the spinal cord level by descending NE-ergic fibers, and a facilitatory role on the responsiveness of PF to noxious inputs by ascending fibers.

The effects of intrathecally (i.t.) administered opioid antagonist naloxone (Nal), adenosine antagonist aminophylline (Aph), and gamma-aminobutyric acid (GABAA)-receptor antagonist picrotoxin (PTX) or Bicuculline (BIC) on the antinociception produced by i.t. norepinephrine (NE), dopamine (DA), morphine (Mor), 5'-N-ethylcarboxamidoadenosine (NECA, an adenosine agonist) or muscimol (MUS, a selective GABAA-receptor agonist) were studied and compared using the tail-flick test in rats. The results showed that: (1) both i.t. NE (0.3, 0.5 and 1.0 nmol) and DA (5.5, 8.3 and 16.5 nmol) produced significant and dose-dependent increases in tail-flick latencies (antinociception); (2) both Nal (240 nmol) and Aph (120 nmol) blocked the antinociception produced by NE (1.0 nmol); (3) both Nal (240 nmol) and Aph (120 nmol) blocked the antinociception produced by Mor (0.5 nmol), but only Aph (120 nmol) blocked the antinociception produced by NECA (0.5 nmol), while Nal (240 nmol) did not; (4) neither Nal (240 nmol) nor Aph (120 nmol) altered the antinociception produced by DA (16.5 nmol); (5) both i.t. PTX (1.5 nmol) and BIC (0.5 nmol) completely blocked the antinociception produced by DA (16.5 nmol), but showed no effects on that produced by NE (1.0 nmol); and (6) both PTX and BIC blocked the antinociception produced by MUS (1.0 nmol). These results suggest that: (a) endogenous opiate and adenosine may be involved in the mediation of NE-induced, but not DA-induced, antinociception; (b) NE, opioid and adenosine may act in a sequential order in NE-induced antinociception at the spinal level; (c) endogenous GABA may be involved in the mediation of DA-induced antinociception through the GABAA-receptors, but is not involved in NE-induced antinociception at the spinal level.

The objective of this study was to use noninvasive, subthreshold auricular electrical stimulation (AES) as a treatment to reduce the severity of precipitated and of abrupt opiate withdrawal. Sixty-four male Sprague-Dawley rats were divided into six groups. The first three groups were used to study the effects of AES on naloxone-precipitated withdrawal; the other three groups were used to examine the influence of AES on abrupt withdrawal. Morphine dependence was induced by multiple injections of the drug on an incremental staircase dosage regimen for 6 days. The results obtained from first three groups show that AES reduced the severity of the withdrawal signs precipitated by naloxone injection (0.5 mg/kg SC) by more than 75% (p < 0.01). The observations obtained from the other three groups show that AES reduced the severity of abrupt withdrawal for at least 4 h as assessed by measuring the locomotor behavior of the animals. This study demonstrates that noninvasive subthreshold AES is effective in reducing the severity of precipitated and of abrupt opiate withdrawal.

Parafascicular (PF) neurons responding to noxious stimuli and focal electrical stimulation of midbrain, diencephalon, and hypothalamic nuclei, which send projections to PF, modulates the PF spontaneous and noxious-evoked responses. Some cerebellar efferents ascend to PF. This investigation attempted to study the effect of cerebellar stimulation on spontaneous and noxious-evoked PF neuronal activity in rats. It was observed that 26% (73/280) of PF neurons responded to a noxious stimulus. The PF neuronal population exhibits two cell types according to their response pattern following the noxious stimulus. One type of PF neurons were excited (n = 53) and were classified as nociceptive-on cells. The second type of PF neurons responded to noxious stimulus by a decrease in the ongoing firing rate (n = 20) and were classified as nociceptive-off cells. The responses of these two types of nociceptively identified cells were tested following cerebellar lateral nucleus stimulation (Lat.N.S.) utilizing several current intensities. Lat.N.S. with lower intensities (0.1-0.2 mA) elicited suppression of both spontaneous and nociceptive-evoked discharges of the nociceptive-on neurons, although higher intensities (0.4-0.6 mA) elicited excitation on both discharges of this type of neuron. In contrast, Lat.N.S. induced a monophasic intensity-dependent suppression of both the spontaneous and the nociceptive-evoked discharges of the nociceptive-off neurons. The results indicate that Lat.N.S. modulates the nociceptive-evoked responses of PF neurons. The possible role and related pathways of cerebellum in modulating noxious input were discussed.

The properties of local application of glutamate, morphine and serotonin in the dorsal raphe (DR) area and the effects of DR electrical stimulation on the spontaneous activity and on the nociceptive responses of 135 parafascicularis (PF) neurons were studied. It was observed that local glutamate application within the DR exerts an effect upon the “nociceptive-on” PF neuronal activity similar to that induced by focal electrical stimulation of the DR in intact animals and in animals after dorsal spinal cord section. In addition, local application of morphine and serotonin in the DR area elicits different effects on the spontaneous activity versus the nociceptive responses of PF neurons. These observations suggest that opioids and serotonin at least in part participate in modulation of pathways from DR to PF. This observation is consistent with the hypothesis that the DR ascending path modulates nociceptive input to the PF (at least in part) via activations of both opioid and serotonergic receptors.

Single-cell experiments were undertaken to examine the hypothesis that serotonin (5-HT) and morphine participate in ascending pain suppression phenomena. The observations demonstrate that: 1. 1) dorsal raphe stimulation (DRS) modulates the spontaneous activity and the noxious-evoked responses of parafasciculus (PF) neurons, and the modulating effects of DRS are altered by either naloxone or methysergide: 2. 2) morphine ejection into the PF alters the spontaneous activity and the noxious-evoked responses of PF neurons, and naloxone prevents morphine effects: and 3. 3) serotonin ejection into the PF alters the spontaneous activity and the noxious-evoked responses of PF neurons and methysergide prevents the serotonin effects. These findings support the hypothesis that opioid and serotonin participate, at least in part, in the control of ascending pain mechanisms.

Spontaneous discharges and nociceptive responses of 47 parafascicularis thalami (PF) neurons were recorded extracellularly and comparisons were made between the effects of these discharges following focal dorsal raphe stimulation (DRS) and bilateral pinnal electrical stimulation (PES). Eighty-three percent of PF neurons (N=39) responded to noxious stimulus, about 69% of the PF responsive cells (fN=27) were excited during noxious stimuli and thus categorized as “nociceptive-on” cells. The remaining 31% (N=12) were suppressed by the noxious stimuliand were categorized as “nociceptive-off” cells. DRS and PES attenuated the spontaneous activity of the “nociceptive-on” neurons as well as the noxious input to these cells, while the spontaneous activity of the “nociceptive-off” cells was suppressed only following DRS and not following PES. Moreover, PES displayed disinhibiting properties, namely, it reduced the suppression effects elicited by noxious input. In conclusion, it was demonstrated that both focal DRS and noninvasive PES were effective in modulating pain input to single neurons in the PF.

The attempt of this study was to investigate the direct effects of increasing doses of morphine on the neuronal activity of the periaqueductal gray in morphine-naive and morphine-dependent rats. The microiontophoresis technique was used for this purpose. The four different responses induced by morphine exhibited dose-related patterns. Naloxone antagonized these responses in about 40% of the cases. Differences were found in the sensitivity of the neurons to morphine between naive and morphine-dependent rats. The phenomena of acute tolerance, chronic tolerance and dependence have been found. The results of this study indicate the presence of different neuronal populations in the periaqueductal gray in relation to their response to morphine, supporting the notion that subpopulations of opiate receptors exist within this brain area.

In single cell experiments, the characterization of the responses of medial thalamic neurons to noxious and nonnoxious stimulation was made to examine the effects of two substances involved in pain, morphine and 5-HT, and the action of one pain suppressor mechanism, dorsal raphe stimulation. Single cell activity was recorded in urethane anesthetized rats. Tail pinch and tail immersion in hot water were used as nociceptive stimuli. Skin strokes, air puffs and hair brushing were used as nonnociceptive stimuli. Morphine, 5-HT microiontophoresis and dorsal raphe stimulation were performed in all the recorded units. Fifty-eight percent from 61 medial thalamic recorded units responded both to noxious and nonnoxious stimulation; whereas only 18% and 24.6% of the units responded exclusively to noxious and nonnoxious stimulation, respectively. The noxious responding units were located in the most posterior portions of the medial thalamus. Dorsal raphe stimulation and 5-HT ejection prevented the excitation elicited by noxious input. Morphine ejection prevented both the noxious and nonnoxious input in medial thalamus, in a different population as compared to dorsal raphe stimulation or 5-HT ejection. These findings support the existence of a pain ascending mechanism mediated by an opioid-serotonergic interaction in the medial thalamus of the rat.

Experiments were undertaken to examine the involvement of CCK in the regulation of feeding behavior. The results indicate that 1) intact normal animals exhibited rhythmic circadian feeding behavior, with onset of feedings starting about two hr prior to dark period and continuing until 1 to 2 hr prior to the light period; 2) food deprivation and surgical isolation of the hypothalamus after this pattern of feeding behavior, to the point that animals spend more time eating with no identifiable pattern; 3) administration of CCK to either fed, fasted or hypothalamic island animals has a profound dose related effect on suppressing feeding behavior and in modifying the eating pattern over 24 hr. A possible involvement of CCK with the opiate system in controlling feeding behavior is discussed.

The effects, in rats, of peripherally administered capsaicin were evaluated on body temperature and on brain neurophysiological activity. Capsaicin (5 mg/kg, SC) produced a rapid, long-lasting fall in body temperature. A second dose given 4.5 hr after the first showed a moderate decrement in hypothermic effect. The same dose of capsaicin caused discernible changes in deep EEG activity in the anterior hypothalamus (AH), medial habenula (HB), substantia nigra (SN), and dorsal raphe (DR). The EEG changes were more pronounced at doses of 10 and 20 mg/kg. Capsaicin in all doses modified sensory evoked responses recorded from all four brain areas. Response amplitudes after acoustic stimulation were increased at all doses of capsaicin in a dose related pattern. Photic evoked responses, like body temperature effects, showed diminished effects with second and third doses. Peripherally administered capsaicin, therefore, can affect body temperature and brain electrical activity.